詳細

田中　薫 （タナカ　カオル）

  • 近畿大学病院　講師
Last Updated :2024/04/17

コミュニケーション情報 byコメンテータガイド

  • コメント

    肺がんの診断と抗がん剤治療、頭頸部がんの抗がん剤治療。

  • 報道関連出演・掲載一覧

    ＜報道関連出演・掲載一覧＞ ●2023/5/10 　毎日新聞 　がんの治験について ●2021/2/17 　朝日放送「キャスト」 　中咽頭がんを公表されていたワッキーさんの復帰について ●2020/2/4 　日本テレビ「news zero」 　世界がんデーの企画の中で治験中の患者さまの診察風景を撮影 ●2019/6/6 　NHK総合「おはよう日本」 　がんゲノム医療の特集 ●2019/3/29 　読売テレビ「ミヤネ屋」 　消化管間質腫瘍について ●2019/2/20 　読売テレビ「ミヤネ屋」 　さまざまながん腫の前兆について

研究者情報

学位

  • 医学博士（近畿大学）

ホームページURL

J-Global ID

研究キーワード

  • 気管支鏡   臨床腫瘍学   分子標的治療薬   頭頚部癌   分子生物学   肺癌   

現在の研究分野（キーワード）

    肺がんの診断と抗がん剤治療、頭頸部がんの抗がん剤治療。

研究分野

  • ライフサイエンス / 呼吸器内科学
  • ライフサイエンス / 腫瘍診断、治療学

経歴

  • 2014年04月 - 現在  近畿大学医学部附属病院腫瘍内科講師
  • 2011年04月 - 2014年03月  近畿大学医学部附属病院腫瘍内科助教
  • 2010年06月 - 2011年03月  南和歌山医療センター腫瘍内科医員
  • 2009年04月 - 2010年05月  近畿大学医学部附属病院腫瘍内科助教

学歴

  • 2005年04月 - 2009年03月   近畿大学大学院   医学研究科
  •         -   近畿大学   医学部   医学科

所属学協会

  • 日本呼吸器学会   日本肺癌学会   日本内科学会   日本臨床腫瘍学会   日本呼吸器内視鏡学会   

研究活動情報

論文

  • Saori Tatsuno; Hiroshi Doi; Masahiro Inada; Takuya Uehara; Yutaro Wada; Kazuki Ishikawa; Kaoru Tanaka; Mutsukazu Kitano; Yasumasa Nishimura
    Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] 2023年11月 
    PURPOSE: This study aimed to assess recurrence patterns and identify the optimal dose and target volumes of postoperative radiotherapy (PORT) in patients with oral cavity squamous cell carcinoma (OSCC). METHODS: Data of 111 patients who received PORT for OSCC between January 2010 and April 2020 were retrospectively reviewed. The median age was 68 years (range 19-88). PORT was administered as initial treatment to 63 patients and as salvage treatment for recurrent tumors to 48 patients. The median prescribed dose was 60 Gy (range 50-66) administered in 30 fractions (range 25-33). RESULTS: Median follow-up time was 73 months (range 24-147). Overall survival (OS), progression-free survival (PFS), local control (LC), and locoregional control (LRC) at 3 years were 55.6%, 45.6%, 74.6%, and 63.1%, respectively. There were no significant differences in OS, PFS, LC, and LRC between the initially diagnosed and postoperative recurrent cases. Of 22 patients (20%) who developed regional nodal recurrences, 17 (15%) and 11 (10%) had in-field and out-of-field recurrences, respectively. Of 105 patients who received irradiation to the primary tumor bed, 24 (23%) developed recurrence at the primary site. The PFS and LC rates were significantly worse in patients receiving ≤ 56 Gy to the primary site than those receiving > 56 Gy (p = 0.016 and p = 0.032, respectively). CONCLUSION: PORT was effective for postoperative recurrences as well as for initially diagnosed oral cavity cancer. Doses greater than 56 Gy to the primary site may be required in PORT for OSCC.
  • Yoshihiko Fujita; Hiromichi Matsuoka; Yasutaka Chiba; Junji Tsurutani; Takeshi Yoshida; Kiyohiro Sakai; Miki Nakura; Ryo Sakamoto; Chihiro Makimura; Yoichi Ohtake; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Tatsuya Okuno; Naoki Takegawa; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa
    Oncology letters 26 2 355 - 355 2023年08月 
    There have been few studies on predictive biomarkers that may be useful to select the most suitable opioids to optimize therapeutic efficacy in individual patients with cancer pain. We recently investigated the efficacy of morphine and oxycodone using single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) rs4680 gene as a biomarker (RELIEF study). To explore additional biomarkers that may enable the selection of an appropriate opioid for individual patients with cancer pain, three SNPs were examined: C-C motif chemokine ligand 11 (CCL11; rs17809012), histamine N-methyltransferase (HNMT; rs1050891) and transient receptor potential V1 (TRPV1; rs222749), which were screened from 74 pain-related SNPs. These SNPs, which were identified as being significantly associated with the analgesic effect of morphine, were then used to genotype the 135 patients in the RELIEF study who had been randomized into a morphine group (n=69) or an oxycodone group (n=66). The present study then assessed whether the SNPs could also be used as selective biomarkers to predict which opioid(s) might be the most suitable to provide pain relief for patients with cancer. Oxycodone tended to provide superior analgesic effects over morphine in patients carrying the genotype AA for the CCL11 rs17809012 SNP (P=0.012 for interaction), suggesting that it could serve as a potential biomarker for personalized analgesic therapy for patients suffering with cancer pain.
  • Takashi Kurosaki; Kenji Chamoto; Shinichiro Suzuki; Hiroaki Kanemura; Seiichiro Mitani; Kaoru Tanaka; Hisato Kawakami; Yo Kishimoto; Yasuharu Haku; Katsuhiro Ito; Toshiyuki Sato; Chihiro Suminaka; Mami Yamaki; Yasutaka Chiba; Tomonori Yaguchi; Koichi Omori; Takashi Kobayashi; Kazuhiko Nakagawa; Tasuku Honjo; Hidetoshi Hayashi
    Frontiers in immunology 14 1325462 - 1325462 2023年 
    INTRODUCTION: The clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) remains unclear. We here investigated the relation between the efficacy of PD-1 blockade and pretreatment plasma levels of sPD-1 and sPD-L1 across a broad range of cancer types. METHODS: We retrospectively analyzed clinical data from 171 patients with advanced solid tumors who received nivolumab or pembrolizumab monotherapy regardless of treatment line. The concentrations of sPD-1 and sPD-L1 were measured with a fully automated immunoassay (HISCL system). RESULTS: The study subjects comprised patients with head and neck cancer (n = 50), urothelial cancer (n = 42), renal cell cancer (n = 37), gastric cancer (n = 20), esophageal cancer (n = 10), malignant pleural mesothelioma (n = 6), or microsatellite instability-high tumors (n = 6). High or low levels of sPD-1 or sPD-L1 were not significantly associated with progression-free survival (PFS) or overall survival (OS) for PD-1 blockade in the entire study population. Comparison of treatment outcomes according to combinations of high or low sPD-1 and sPD-L1 levels, however, revealed that patients with low sPD-1 and high sPD-L1 concentrations had a significantly poorer PFS (HR of 1.79 [95% CI, 1.13-2.83], p = 0.01) and a tendency toward poorer OS (HR of 1.70 [95% CI, 0.99-2.91], p = 0.05) compared with all other patients. CONCLUSION: Our findings suggest that the combination of low sPD-1 and high sPD-L1 levels is a potential negative biomarker for PD-1 blockade therapy.
  • Shunji Takahashi; Nobuhiko Oridate; Kaoru Tanaka; Yasushi Shimizu; Yasushi Fujimoto; Koji Matsumoto; Tomoya Yokota; Tomoko Yamazaki; Masanobu Takahashi; Tsutomu Ueda; Nobuhiro Hanai; Hironori Yamaguchi; Hiroki Hara; Tomokazu Yoshizaki; Ryuji Yasumatsu; Masahiro Nakayama; Kiyoto Shiga; Takashi Fujii; Kenji Mitsugi; Kenichi Takahashi; Nijiro Nohata; Burak Gumuscu; Ramona F Swaby; Makato Tahara
    International journal of clinical oncology 27 12 1805 - 1817 2022年12月 
    BACKGROUND: Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab-chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). METHODS: Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67). RESULTS: At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09-0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25-1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31-1.41]). Pembrolizumab-chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23-2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55-2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55-2.22]). Median PFS was similar for pembrolizumab and pembrolizumab-chemotherapy versus EXTREME in all subgroups. Grades 3-5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab-chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab-chemotherapy died because of treatment-related pneumonitis. CONCLUSION: These results support the use of first-line pembrolizumab and pembrolizumab-chemotherapy for Japanese patients with R/M HNSCC. Clinical trial registry ClinicalTrials.gov, NCT02358031.
  • Hiromichi Matsuoka; Junji Tsurutani; Yasutaka Chiba; Yoshihiko Fujita; Kiyohiro Sakai; Takeshi Yoshida; Miki Nakura; Ryo Sakamoto; Chihiro Makimura; Yoichi Ohtake; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Tatsuya Okuno; Naoki Takegawa; Koji Haratani; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa
    The Oncologist 28 3 278-e166  2022年11月 [査読有り]
     
    Abstract Background We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain. Methods A randomized, multicenter, open-label trial was conducted at a Japanese hospital’s palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reduction ≥ 33% from baseline and up to ≤ 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype. Results Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; P = .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; P = 0.098). Conclusion Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief.
  • Kohsuke Isomoto; Koji Haratani; Takahiro Tsujikawa; Yusuke Makutani; Hisato Kawakami; Masayuki Takeda; Kimio Yonesaka; Kaoru Tanaka; Tsutomu Iwasa; Hidetoshi Hayashi; Akihiko Ito; Kazuto Nishio; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 174 71 - 82 2022年10月 
    OBJECTIVE: Immune checkpoint inhibitors (ICIs) have become a key therapeutic modality for advanced non-small cell lung cancer (NSCLC), but most patients experience primary or acquired resistance to these drugs. We here explored the mechanisms underlying both types of ICI resistance by analysis of the tumor immune microenvironment (TME). MATERIALS AND METHODS: Four patients who experienced a long-term response to ICI treatment (progression-free survival [PFS] of ≥12 months) followed by disease progression, after which a rebiopsy was immediately performed (cohort-A), as well as four patients who experienced early tumor progression during ICI treatment (PFS of <9 weeks, cohort-B) were enrolled in this retrospective study. The pretreatment TME was evaluated by 16- or 17-color multiplex immunohistochemistry (mIHC)-based spatial profiling at the single-cell level for both cohorts. In cohort-A, changes in the TME after disease progression during ICI treatment were also investigated by mIHC analysis and transcriptomic analysis. RESULTS: Pretreatment tumor tissue from cohort-B manifested poor infiltration of tumor-reactive CD8+ T cells characterized by CD39 and CD103 expression or by programmed cell death-1 expression, implicating insufficient recognition of tumor cells by CD8+ T cells as a mechanism of primary ICI resistance. Analysis of the paired tumor specimens from cohort-A revealed various changes in the TME associated with acquired ICI resistance, including substantial infiltration of myeloid-derived suppressor cells and M2-type tumor-associated macrophages without a marked decline in the number of tumor-reactive CD8+ T cells; a decrease in the number of tumor-reactive CD8+ T cells; and an apparent decrease in neoantigen presentation by tumor cells. CONCLUSION: The presence of intratumoral tumor-reactive CD8+ T cells may be a prerequisite for a long-term response to ICI treatment in advanced NSCLC, but it is not sufficient for cancer cell eradication. Various TME profiles are associated with acquired ICI resistance, suggesting that patient-specific strategies to overcome such resistance may be necessary.
  • Naomi Kiyota; Makoto Tahara; Junki Mizusawa; Takeshi Kodaira; Hirofumi Fujii; Tomoko Yamazaki; Hiroki Mitani; Shigemichi Iwae; Yasushi Fujimoto; Yusuke Onozawa; Nobuhiro Hanai; Takenori Ogawa; Hiroki Hara; Nobuya Monden; Eiji Shimura; Shujiro Minami; Takashi Fujii; Kaoru Tanaka; Akihiro Homma; Seiichi Yoshimoto; Nobuhiko Oridate; Koichi Omori; Tsutomu Ueda; Kenji Okami; Ichiro Ota; Kiyoto Shiga; Masashi Sugasawa; Takahiro Asakage; Yuki Saito; Shigeyuki Murono; Yasumasa Nishimura; Kenichi Nakamura; Ryuichi Hayashi
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 40 18 1980 - 1990 2022年06月 
    PURPOSE: The standard treatment for postoperative high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (100 mg/m2). However, whether chemoradiotherapy with weekly cisplatin (40 mg/m2) yields comparable efficacy with 3-weekly cisplatin in postoperative high-risk LA-SCCHN is unknown. PATIENTS AND METHODS: In this multi-institutional open-label phase II/III trial, patients with postoperative high-risk LA-SCCHN were randomly assigned to receive either chemoradiotherapy with 3-weekly cisplatin (100 mg/m2) or with weekly cisplatin (40 mg/m2) to confirm the noninferiority of weekly cisplatin. The primary end point of phase II was the proportion of treatment completion, and that of phase III was overall survival. A noninferiority margin of hazard ratio was set at 1.32. RESULTS: Between October 2012 and December 2018, a total of 261 patients were enrolled (3-weekly cisplatin, 132 patients; weekly cisplatin, 129 patients). At the planned third interim analysis in the phase III part, after a median follow-up of 2.2 (interquartile range 1.19-3.56) years, chemoradiotherapy with weekly cisplatin was noninferior to 3-weekly cisplatin in terms of overall survival, with a hazard ratio of 0.69 (99.1% CI, 0.374 to 1.273 [< 1.32], one-sided P for noninferiority = .0027 < .0043). Grade 3 or more neutropenia and infection were less frequent in the weekly arm (3-weekly v weekly, 49% v 35% and 12% v 7%, respectively), as were renal impairment and hearing impairment. No treatment-related death was reported in the 3-weekly arm, and two (1.6%) in the weekly arm. CONCLUSION: Chemoradiotherapy with weekly cisplatin is noninferior to 3-weekly cisplatin for patients with postoperative high-risk LA-SCCHN. These findings suggest that chemoradiotherapy with weekly cisplatin can be a possible treatment option for these patients.
  • Tomohiro Nakayama; Koji Haratani; Takashi Kurosaki; Kaoru Tanaka; Kazuhiko Nakagawa
    Translational Cancer Research 11 6 1824 - 1828 2022年06月 
    BACKGROUND: Proper management of chemotherapy-related gastrointestinal toxicities is essential to maximize therapeutic outcome for malignancies. Gastroparesis is an onerous syndrome characterized by delayed gastric emptying without gastrointestinal obstruction, but this has not been recognized as chemotherapy-related complication in solid malignancies. Here, we describe a case of gastroparesis possibly caused by neurotoxicity of taxane and platinum-based high-intensity chemotherapy against solid cancer. CASE DESCRIPTION: A 73-year-old male was diagnosed with stage IVA oropharyngeal cancer (cT4N2bM0) as a cause of swallowing difficulty. As a curative treatment of the oropharyngeal cancer, induction chemotherapy with the regimen of docetaxel, cisplatin and fluorouracil (TPF) was initiated with nutritional support by nasogastric tube feeding. Then, this case was complicated with late-onset gastric dysmotility as evidenced by abnormally dilated stomach even after cessation of feeding for more than a few days. After a careful exclusion of other diseases that could cause gastric dysmotility, we eventually diagnosed chemotherapy-induced gastroparesis as a cause of his symptom. Notably, this refractory gastroparesis was successfully controlled with 5-HT4 agonist, mosapride, resulting in recovery of gastric motility and safe completion of the subsequent curative treatment. CONCLUSIONS: Despite its rarity in patients with solid cancers, it is important to note chemotherapy-induced gastroparesis because delay in its management can be detrimental to their survival outcome. Thus, oncologists should consider gastroparesis in evaluating persistent upper abdominal symptoms after neurotoxic chemotherapies for solid cancer.
  • Yuki Saito; Akihiro Homma; Naomi Kiyota; Makoto Tahara; Nobuhiro Hanai; Takahiro Asakage; Kazuto Matsuura; Ichiro Ota; Tomoya Yokota; Daisuke Sano; Takeshi Kodaira; Atsushi Motegi; Koichi Yasuda; Shunji Takahashi; Kaoru Tanaka; Takuma Onoe; Susumu Okano; Yoshinori Imamura; Yosuke Ariizumi; Ryuichi Hayashi
    Japanese journal of clinical oncology 52 7 692 - 698 2022年04月 
    It was not until around 2000 that human papillomavirus-related oropharyngeal carcinoma was recognized as carcinoma with clinical presentations different from nonrelated head and neck carcinoma. Twenty years after and with the revision of the tumor-node-metastasis classification in 2017, various clinical trials focused on human papillomavirus-related oropharyngeal carcinoma to improve the prognosis and quality of life of patients with this disease. However, the incidence of human papillomavirus-related cancers is increasing, which is expected to be particularly prominent in Japan, where human papillomavirus vaccination is not widely available. In this review, we describe the current status of clinical trials (mainly focused on initial surgery and radiation dose reduction) for, primary and secondary prevention of, and the present status of human papillomavirus-related oropharyngeal carcinoma in Japan.
  • Yoshinori Imamura; Naomi Kiyota; Makoto Tahara; Nobuhiro Hanai; Takahiro Asakage; Kazuto Matsuura; Ichiro Ota; Yuki Saito; Daisuke Sano; Takeshi Kodaira; Atsushi Motegi; Koichi Yasuda; Shunji Takahashi; Tomoya Yokota; Susumu Okano; Kaoru Tanaka; Takuma Onoe; Yosuke Ariizumi; Akihiro Homma
    Japanese journal of clinical oncology 52 4 293 - 302 2022年02月 
    Salivary gland malignancies are rare neoplasms that have a broad histological spectrum and a variety of biologic behaviors. Salivary gland malignancies are known as chemo-resistant tumors, which render optimal treatment challenging. This review summarizes the role of systemic therapy for salivary gland malignancies. To date, the advantage of adding concurrent chemotherapy has remained undefined for both postoperative and inoperable locally advanced salivary gland malignancy patients undergoing radiotherapy. For recurrent/metastatic disease, local and/or systemic treatment options should be discussed in a multidisciplinary setting with consideration to both patient needs and tumor factors. For symptomatic patients or those who may compromise organ function, palliative systemic therapy can be a reasonable option based on the results of phase II studies. Platinum combination regimens as first-line therapy have been widely accepted. Personalized therapies have become established options, particularly for androgen receptor-positive, HER2-positive and NTRK fusion-positive salivary gland malignancies (i.e. androgen receptor and HER2 in salivary duct carcinoma and NTRK3 in secretory carcinoma). For patients with adenoid cystic carcinoma, multi-targeted tyrosine kinase inhibitors have also been developed. Anti-PD1 checkpoint inhibitors have shown limited activity to date. Investigation of active systemic treatments for salivary gland malignancy remains a significant unmet need. Future directions might include a more comprehensive genomic screening approach (usually next-generation sequencing-based) and combination strategies using immune checkpoint inhibitors. These are rare malignancies that require ongoing effort in the conduct of high-quality clinical trials.
  • Kimio Yonesaka; Junko Tanizaki; Osamu Maenishi; Koji Haratani; Hisato Kawakami; Kaoru Tanaka; Hidetoshi Hayashi; Kazuko Sakai; Yasutaka Chiba; Asuka Tsuya; Hiroki Goto; Eri Otsuka; Hiroaki Okida; Maki Kobayashi; Ryoto Yoshimoto; Masanori Funabashi; Yuuri Hashimoto; Kenji Hirotani; Takashi Kagari; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 28 2 390 - 403 2022年01月 
    PURPOSE: EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR-mutated non-small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR-mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR-mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR-mutated NSCLC. EXPERIMENTAL DESIGN: Paired tumor samples were obtained from 48 patients with EGFR-mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR-mutated NSCLC cells. RESULTS: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR-mutated cancers, and enhanced the anticancer activity of HER3-DXd. CONCLUSIONS: Our findings help clarify the mechanisms of HER3 regulation in EGFR-mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC.
  • Shinichiro Suzuki; Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Junko Tanizaki; Ryoji Kato; Seiichiro Mitani; Yusuke Kawanaka; Takashi Kurosaki; Yoshikazu Hasegawa; Takafumi Okabe; Kaoru Tanaka; Yusaku Akashi; Tomohiro Ozaki; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    European journal of cancer (Oxford, England : 1990) 161 44 - 54 2022年01月 
    BACKGROUND: Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown. METHODS: A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included. TB was estimated on the basis of the sum of the diameters of measurable target lesions as per Response Evaluation Criteria in Solid Tumours. Progression-free survival (PFS) in the ICI cohort was evaluated as per TB as a preplanned primary objective, with the analysis based on propensity score-weighted survival curves and estimation of restricted mean survival time (RMST). The Chemo cohort served as a control to determine whether TB is predictive of ICI treatment outcomes. The ICI+Chemo cohort was exploratory. The relation of TB to tumour immune status was assessed by immune-related gene expression profiling (irGEP) of pretreatment tumour tissue. RESULTS: In the ICI cohort, patients with a low TB showed a significantly longer PFS than did those with a high TB (median, 17.9 vs 4.3 months; weighted hazard ratio, 0.32 [95% confidence interval, 0.19-0.53]). No such difference was apparent in the other cohorts. A significant difference in overall survival was also observed only in the ICI cohort. RMST-based analysis confirmed these results. The irGEP analysis implicated M2-type macrophages, angiogenesis and transforming growth factor-β as well as protumourigenic signalling pathways in ICI resistance conferred by a high TB. CONCLUSION: A high TB was associated with a poor outcome of ICI therapy for advanced NSCLC as a result of immunosuppressive phenotypes. Development of combination or novel treatment strategies for such disease is thus warranted.
  • 谷崎 潤子; 鈴木 慎一郎; 金村 宙昌; 岩朝 勤; 川上 尚人; 田中 薫; 吉田 健史; 米阪 仁雄; 伊藤 彰彦; 坂井 和子; 木寺 康裕; 福岡 和也; 千葉 康敬; 西尾 和人; 中川 和彦; 林 秀敏
    近畿大学医学雑誌 46 3-4 20A - 20A 近畿大学医学会 2021年12月
  • Yoshinori Imamura; Kaoru Tanaka; Naomi Kiyota; Hidetoshi Hayashi; Ichiro Ota; Akihito Arai; Shigemichi Iwae; Shujiro Minami; Katsunari Yane; Tomoko Yamazaki; Yoshiaki Nagatani; Masanori Toyoda; Takayuki Takahama; Kazuko Sakai; Kazuto Nishio; Naoki Otsuki; Ken-ichi Nibu; Hironobu Minami
    Medical Oncology 38 11 128 - 128 2021年11月 
    The clinical utility of systemic therapy and genomic profiling in non-squamous-cell head and neck cancer (NSCHNC) has not been fully elucidated. This phase II trial evaluated the efficacy and safety of docetaxel and cisplatin combination in the first-line setting. Eligibility criteria were recurrent and/or metastatic NSCHNC; progressive disease within the last 6 months; no prior systemic therapy; and ECOG performance status of 0-1. Patients received docetaxel (75 mg/m2 on day 1) and cisplatin (75 mg/m2 on day 1), repeated every 21 days for 6 cycles. The primary endpoint was confirmed objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Next-generation sequencing (NGS) was performed using the Ion AmpliSeq Cancer Hotspot Panel v2. Twenty-three patients were enrolled from November 2012 to October 2016, of whom 8 were male. Median age was 57 years. Ninety-six percent of cases were metastatic. Among 22 evaluable patients, confirmed ORR was 45% (95% confidential interval 24-68%). With a median follow-up period of 18.8 months, median PFS and OS were 6.7 and 20.1 months, respectively. Grade 3/4 adverse events included febrile neutropenia (39%) and anemia (22%). No treatment-related deaths were observed. NGS analysis revealed potential treatment targets, including ERBB2, KIT, and ALK. The docetaxel and cisplatin combination regimen can be considered a new treatment option in recurrent and/or metastatic NSCHNC, although primary prophylaxis for febrile neutropenia should be considered. Diverse genomic alterations may lead novel treatment options.This trial was registered with the UMIN Clinical Trials Registry as UMIN000008333 on [September 1st, 2012].
  • 白石 直樹; 田中 薫; 高濱 隆幸; 鈴木 慎一郎; 金村 宙昌; 磯本 晃佑; 林 秀敏; 米阪 仁雄; 中川 和彦
    肺癌 61 6 649 - 649 (NPO)日本肺癌学会 2021年10月
  • 米阪 仁雄; 谷崎 潤子; 前西 修; 川上 尚人; 田中 薫; 林 秀敏; 坂井 和子; 後藤 大輝; 小林 真季; 吉本 龍人; 大塚 絵里; 沖田 弘明; 舟橋 賢記; 橋本 悠里; 廣谷 賢志; 明松 隆志; 西尾 和人; 中川 和彦
    肺癌 61 6 623 - 623 2021年10月
  • オンコマイン検査成功率改善に向けた検査内製化と検査工程の見直し
    白石 直樹; 田中 薫; 高濱 隆幸; 鈴木 慎一郎; 金村 宙昌; 磯本 晃佑; 林 秀敏; 米阪 仁雄; 中川 和彦
    肺癌 61 6 649 - 649 (NPO)日本肺癌学会 2021年10月
  • Mitsuo P Sato; Naoki Otsuki; Mutsukazu Kitano; Kazuki Ishikawa; Kaoru Tanaka; Takayuki Kimura; Katsumi Doi
    Head & neck 43 12 3810 - 3819 2021年09月 
    BACKGROUND: The advantage of up-front neck dissection (UFND) followed by chemoradiotherapy (CRT) for hypopharyngeal cancer (HPC) with advanced neck involvement remains controversial. We aimed to determine the indications. METHODS: The data of 41 and 14 patients with stage IVA/B (T1-T3 and ≥N2a) HPC who underwent UFND followed by CRT and received CRT, respectively, were retrospectively analyzed and compared. RESULTS: The 5-year overall survival (OS) and disease-specific survival rates for the UFND and CRT groups were 61% and 52% (p = 0.1019), and 89% and 74% (p = 0.2333), respectively. Moreover, patients aged ≥70 years or those with a pulmonary disease history had a significantly poorer prognosis due to aspiration pneumonia in the UFND group. The 5-year regional control (RC) for the UFND and CRT groups were 92% and 57%, respectively (p = 0.0001). CONCLUSIONS: UFND followed by CRT was feasible with satisfactory RC. To further improve OS, aspiration pneumonia prevention is essential.
  • Ryoji Kato; Hidetoshi Hayashi; Kazuko Sakai; Shinichiro Suzuki; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Yoshikane Nonagase; Kaoru Tanaka; Takeshi Yoshida; Masayuki Takeda; Kimio Yonesaka; Hiroyasu Kaneda; Kazuto Nishio; Kazuhiko Nakagawa
    International journal of clinical oncology 26 9 1628 - 1639 2021年09月 
    BACKGROUND: We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance mechanisms in osimertinib-treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC). METHODS: The study included patients with EGFR activating mutation-positive advanced NSCLC who were positive for T790M in tumor tissue or plasma after previous treatment with an EGFR tyrosine kinase inhibitor, who received osimertinib at Kindai University Hospital between August 2014 and September 2017, and for whom plasma collected after progression on osimertinib was available. Clinical data were extracted from medical records. Patients with innate resistance to osimertinib were defined as those whose best response was progressive disease or stable disease for < 6 months, whereas patients with a complete or partial response or stable disease for > 6 months were considered as having acquired resistance. RESULTS: We performed CAPP-seq for 20 patients at progression on osimertinib. Distinct patterns of genomic alterations were apparent in patients with innate versus acquired resistance. Mutations in PIK3CA, KRAS, or BRAF and copy number gain for EGFR, ERBB2, or MET were more common in patients with innate resistance than in those with acquired resistance. In addition, one patient who underwent a repeat biopsy was found to harbor the C797S mutation of EGFR after disease progression during osimertinib rechallenge, with this mutation not having been detected at the time of initial progression on osimertinib. CONCLUSIONS: CAPP-seq analysis of ctDNA was able to identify potentially targetable genetic alterations in patients with osimertinib resistance.
  • Kimio Yonesaka; Junko Tanizaki; Osamu Maenishi; Hisato Kawakami; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Kazuko Sakai; Maki Kobayashi; Ryoto Yoshimoto; Hiroki Goto; Masanori Funabashi; Yuuri Hashimoto; Kenji Hirotani; Takashi Kagari; Kazuto Nishio; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 32 S296 - S296 2021年07月
  • 下咽頭癌頸部転移に対する先行頸部郭清術の検討
    佐藤 満雄; 北野 睦三; 木村 隆幸; 石川 一樹; 田中 薫; 大月 直樹; 土井 勝美
    頭頸部癌 47 2 199 - 199 (一社)日本頭頸部癌学会 2021年05月
  • Hidetoshi Hayashi; Masakazu Ogura; Takashi Niwa; Toshihide Yokoyama; Junko Tanizaki; Tomohiro Ozaki; Hiroshige Yoshioka; Takayasu Kurata; Yosuke Tamura; Yasuhito Fujisaka; Kaoru Tanaka; Yoshikazu Hasegawa; Keita Kudo; Yasutaka Chiba; Kazuhiko Nakagawa
    The oncologist 26 1 19-e52  2021年01月 
    LESSONS LEARNED: The combination of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer is a promising therapeutic strategy. Further investigation is warranted. BACKGROUND: We conducted a phase I/II trial of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab-paclitaxel and to evaluate the safety and efficacy of this regimen. METHODS: In the phase I study, escalating doses of weekly nab-paclitaxel were administered together with cisplatin at 75 mg/m2 every 3 weeks and concurrent radiotherapy. In the phase II study, nab-paclitaxel was administered at the RD. RESULTS: In the phase I study, whereas no dose-limiting toxicity (DLT) was observed with nab-paclitaxel at 50 or 60 mg/m2 , one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m2 , determined as the RD. Twenty-four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment-related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2-year overall survival and progression-free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%-74.7%), respectively. CONCLUSION: Concurrent chemoradiation with nab-paclitaxel at 70 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.
  • Takashi Kurosaki; Seiichiro Mitani; Kaoru Tanaka; Shinichiro Suzuki; Hiroaki Kanemura; Koji Haratani; Soichi Fumita; Tsutomu Iwasa; Hidetoshi Hayashi; Takeshi Yoshida; Kazuki Ishikawa; Mutsukazu Kitano; Naoki Otsuki; Yasumasa Nishimura; Katsumi Doi; Kazuhiko Nakagawa
    Anti-cancer drugs 32 1 95 - 101 2021年01月 
    Immunotherapy has been shown to prolong survival in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in front-line use; however, subsequent systemic therapy has not been optimized. This study aimed to evaluate the safety and efficacy of cetuximab-containing chemotherapy after immunotherapy. We retrospectively analyzed patients with recurrent or metastatic SCCHN who underwent cetuximab-containing regimens after progression on immunotherapy. Of the 22 patients who met the inclusion criteria, 21 received paclitaxel and cetuximab, and 1 carboplatin and fluorouracil and cetuximab after immunotherapy. Nine patients achieved a partial response, 10 patients had stable disease as their best response on cetuximab-containing chemotherapy, yielding an overall response rate and disease control rate of 40.9 and 86.4%, respectively. The median progression-free survival was 5.2 months, and the median overall survival was 14.5 months. Ten patients developed grade 3-4 adverse events, including neutropenia (31.8%), acneiform rash (9.1%), anemia (4.5%), hypertransaminasemia (4.5%) and stomatitis (4.5%). The most frequent cetuximab-related toxicities across all grades were skin reactions (77.3%), hypomagnesemia (40.9%), stomatitis (27.3%), paronychia (13.6%) and keratitis (4.5%). There was no treatment-related death. Taken together, cetuximab-containing chemotherapy was effective and feasible even after immunotherapy.
  • Masayuki Takeda; Takayuki Takahama; Kazuko Sakai; Shigeki Shimizu; Satomi Watanabe; Hisato Kawakami; Kaoru Tanaka; Chihiro Sato; Hidetoshi Hayashi; Yoshikane Nonagase; Kimio Yonesaka; Naoki Takegawa; Tatsuya Okuno; Takeshi Yoshida; Soichi Fumita; Shinichiro Suzuki; Koji Haratani; Kazumasa Saigoh; Akihiko Ito; Tetsuya Mitsudomi; Hisashi Handa; Kazuya Fukuoka; Kazuhiko Nakagawa; Kazuto Nishio
    The oncologist 26 4 e588-e596  2020年12月 
    BACKGROUND: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. MATERIALS AND METHODS: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan. RESULTS: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. CONCLUSION: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. IMPLICATIONS FOR PRACTICE: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.
  • Ryoji Kato; Koji Haratani; Hidetoshi Hayashi; Kazuko Sakai; Hitomi Sakai; Hisato Kawakami; Kaoru Tanaka; Masayuki Takeda; Kimio Yonesaka; Kazuto Nishio; Kazuhiko Nakagawa
    British journal of cancer 124 5 914 - 924 2020年12月 
    BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects. METHODS: We performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB). RESULTS: Whereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity. Gene expression profiling indeed showed that nintedanib influenced antitumour immunity and fibrosis. Tumoural infiltration of CD8+ T cells and granzyme B production were increased by nintedanib, and its antitumour activity was attenuated by antibody-mediated depletion of these cells, indicating that nintedanib suppressed tumour growth in a CD8+ T cell-dependent manner. Moreover, nintedanib inhibited the proliferation and activation of fibroblasts. Finally, the combination of nintedanib with ICB showed enhanced antitumour efficacy in B16-F10 tumour-bearing mice. CONCLUSIONS: Our results suggest that nintedanib targeted CAFs and thereby attenuated the immunosuppressive nature of the TME and promoted the intratumoural accumulation and activation of CD8+ T cells, with these effects contributing to enhanced antitumour activity in combination with ICB.
  • Susumu Okano; Akihiro Homma; Naomi Kiyota; Makoto Tahara; Nobuhiro Hanai; Takahiro Asakage; Kazuto Matsuura; Takenori Ogawa; Yuki Saito; Daisuke Sano; Takeshi Kodaira; Atsushi Motegi; Koichi Yasuda; Shunji Takahashi; Kaoru Tanaka; Takuma Onoe; Tomoya Yokota; Yoshinori Imamura; Yosuke Ariizumi; Tetsuo Akimoto; Ryuichi Hayashi
    Japanese journal of clinical oncology 51 2 173 - 179 2020年12月 
    In order to maximize the benefit of induction chemotherapy, practice based on a comprehensive interpretation of a large number of clinical trials, as in this review, is essential. The standard treatment for locally advanced squamous cell carcinoma of the head and neck is surgery or chemoradiation. However, induction chemotherapy followed by (chemo) radiotherapy may be used in some circumstances. Although many clinical trials of induction chemotherapy have been conducted, a rationale other than to preserve the larynx is still controversial. Selection of this modality should therefore be made with care. The current standard regimen for induction chemotherapy is docetaxel, cisplatin and 5-FU, but concerns remain about toxicity, cost and the duration of treatment. Regarding treatment after induction chemotherapy, it is also unclear whether radiation alone or chemoradiation is the better option. Furthermore, there is no answer as to what drugs should be used in combination with radiation therapy after induction chemotherapy. Several new induction chemotherapy treatment developments are currently underway, and future developments are expected. This review article summarizes the current position of induction chemotherapy for head and neck squamous cell carcinoma, based on the evidence produced to date, and discusses the future prospects for this treatment.
  • 金村 宙昌; 林 秀敏; 磯本 晃佑; 鈴木 慎一郎; 田中 薫; 吉田 健史; 武田 真幸; 中川 和彦
    肺癌 60 6 476 - 476 (NPO)日本肺癌学会 2020年10月
  • Tomoya Yokota; Akihiro Homma; Naomi Kiyota; Makoto Tahara; Nobuhiro Hanai; Takahiro Asakage; Kazuto Matsuura; Takenori Ogawa; Yuki Saito; Daisuke Sano; Takeshi Kodaira; Atsushi Motegi; Koichi Yasuda; Shunji Takahashi; Kaoru Tanaka; Takuma Onoe; Susumu Okano; Yoshinori Imamura; Yosuke Ariizumi; Ryuichi Hayashi
    Japanese journal of clinical oncology 50 10 1089 - 1096 2020年09月 [査読有り]
     
    Squamous cell carcinoma of the head and neck is characterized by an immunosuppressive environment and evades immune responses through multiple resistance mechanisms. A breakthrough in cancer immunotherapy employing immune checkpoint inhibitors has evolved into a number of clinical trials with antibodies against programmed cell death 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for patients with squamous cell carcinoma of the head and neck. CheckMate141 and KEYNOTE-048 were practice-changing randomized phase 3 trials for patients with platinum-refractory and platinum-sensitive recurrent or metastatic squamous cell carcinoma of the head and neck, respectively. Furthermore, many combination therapies using anti-CTLA-4 inhibitors, tyrosine kinase inhibitors and immune accelerators are currently under investigation. Thus, the treatment strategy of recurrent or metastatic squamous cell carcinoma of the head and neck is becoming more heterogeneous and complicated in the new era of individualized medicine. Ongoing trials are investigating immunotherapeutic approaches in the curative setting for locoregionally advanced disease. This review article summarizes knowledge of the role of the immune system in the development and progression of squamous cell carcinoma of the head and neck, and provides a comprehensive overview on the development of immunotherapeutic approaches in both recurrent/metastatic and locoregionally advanced diseases.
  • Kaoru Tanaka; Satoshi Morita; Masahiko Ando; Takuma Yokoyama; Atsushi Nakamura; Hiroshige Yoshioka; Takashi Ishiguro; Satoru Miura; Ryo Toyozawa; Tetsuya Oguri; Haruko Daga; Ryo Ko; Akihiro Bessho; Motoko Tachihara; Yasuo Iwamoto; Katsuya Hirano; Yoichi Nakanishi; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Isamu Okamoto
    Cancer 126 16 3648 - 3656 2020年08月 [査読有り]
     
    BACKGROUND: A randomized phase 3 study was performed to investigate the efficacy and safety of maintenance therapy with S-1 after induction therapy with carboplatin plus S-1 in patients with advanced squamous non-small cell lung cancer (NSCLC). METHODS: Chemotherapy-naive patients with advanced or relapsed squamous NSCLC were treated with carboplatin (area under the curve of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1-14 every 3 weeks) as induction therapy. Patients who did not progress after 4 cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective of the study was to confirm the superiority of S-1 plus BSC in comparison with BSC alone with respect to progression-free survival. RESULTS: Of the 365 patients enrolled in the study, 347 participated in the induction phase, and 131 of these individuals were randomized to receive S-1 plus BSC (n = 67) or BSC alone (n = 64). The risk of disease progression was significantly lower for patients in the S-1 plus BSC arm than those in the BSC-alone arm (hazard ratio, 0.548; 95% confidence interval, 0.374-0.802; P = .0019). The most common toxicities during maintenance therapy with S-1 included anorexia, anemia, and fatigue, but most cases were not severe. CONCLUSIONS: Continued maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC previously treated with carboplatin plus S-1.
  • 当院での進行頭頸部癌に対するニボルマブの有効性と安全性
    鈴木 慎一郎; 田中 薫; 佐藤 千尋; 金村 宙昌; 磯本 晃佑; 加藤 了資; 原谷 浩司; 三谷 誠一郎; 林 秀敏; 北野 睦三; 石川 一樹; 土井 勝美; 西村 恭昌; 中川 和彦
    頭頸部癌 46 2 151 - 151 (一社)日本頭頸部癌学会 2020年07月
  • 頭頸部癌における免疫チェックポイント阻害薬後のセツキシマブ使用の有効性および安全性
    三谷 誠一郎; 田中 薫; 鈴木 慎一郎; 原谷 浩司; 文田 壮一; 川上 尚人; 吉田 健史; 林 秀敏; 北野 睦三; 土井 勝美; 石川 一樹; 西村 恭昌; 中川 和彦
    頭頸部癌 46 2 218 - 218 (一社)日本頭頸部癌学会 2020年07月
  • Kaoru Tanaka
    Gan to kagaku ryoho. Cancer & chemotherapy 47 7 1050 - 1054 2020年07月
  • Kohsuke Isomoto; Koji Haratani; Hidetoshi Hayashi; Shigeki Shimizu; Shuta Tomida; Takashi Niwa; Toshihide Yokoyama; Yasushi Fukuda; Yasutaka Chiba; Ryoji Kato; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Takashi Ogura; Tadashi Ishida; Akihiko Ito; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 26 8 2037 - 2046 2020年04月 [査読有り]
     
    PURPOSE: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear. EXPERIMENTAL DESIGN: We retrospectively identified 138 patients with EGFR-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing. RESULTS: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (P = 0.0010). Whereas CD8+ and FOXP3+ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8+ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months. CONCLUSIONS: EGFR-TKI treatment was associated with changes in the TME of EGFR-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.
  • Hitomi Sakai; Atsuko Koyama; Kaoru Tanaka; Satomi Watanabe; Miki Nakura; Toshiko Yasuda; Makiko Hayashi; Miyuki Endo; Kazuhiko Nakagawa
    Asia-Pacific journal of clinical oncology 16 5 e185-e191  2020年04月 [査読有り]
     
    PURPOSE: Cancer treatment can alter patient appearance, leading to psychological, social, and behavioral issues. This study aimed to investigate distress and difficulties related to appearance concerns in Japanese cancer patients and to identify information and support needs among them. METHODS: We conducted a questionnaire survey using the Derriford Appearance Scale 59 (DAS59) among cancer patients with a prior history of chemotherapy, molecular targeted therapy, or immunotherapy, who were recruited from the Departments of Medical Oncology and Psychosomatic Medicine, Kindai University Hospital. RESULTS: Participants were 114 patients with a mean age of 62.9 years; 70.2% were female, 86.0% had metastatic or locally advanced unresectable cancer, and 78.1% had concerns about some aspect of their appearance. Mean DAS59 full-scale score was 77.7 ± 36.4. Younger and female participants were found to have higher full-scale scores in univariate analysis (P < .05 for both), and younger participants were found to have higher full-scale scores in multivariate analysis (P < .05). CONCLUSIONS: DAS59 scores had a wide distribution, suggesting that psychological distress due to appearance changes showed large individual differences. Young and female patients tended to have high DAS59 full-scale scores, but some older and male patients also had high scores. Basic information regarding appearance changes should be provided to all patients before initiating cancer treatment. Both information provision prior to treatment and care at the time of actual appearance changes are important, and should be handled through a multidisciplinary approach.
  • Koji Haratani; Kimio Yonesaka; Shiki Takamura; Osamu Maenishi; Ryoji Kato; Naoki Takegawa; Hisato Kawakami; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Naoyuki Maeda; Takashi Kagari; Kenji Hirotani; Junji Tsurutani; Kazuto Nishio; Katsumi Doi; Masaaki Miyazawa; Kazuhiko Nakagawa
    The Journal of clinical investigation 130 1 374 - 388 2020年01月 [査読有り]
     
    Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3-targeting (HER3-targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti-PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor-resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.
  • Masayuki Takeda; Kazuko Sakai; Hidetoshi Hayashi; Kaoru Tanaka; Koji Haratani; Takayuki Takahama; Ryoji Kato; Kimio Yonesaka; Kazuto Nishio; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 139 28 - 34 2020年01月 [査読有り]
     
    OBJECTIVES: The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation-positive non-small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment. MATERIALS AND METHODS: A total of 57 EGFR mutation-positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software. RESULTS: Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P =  0.049). CONCLUSIONS: Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.
  • Kimio Yonesaka; Eiji Iwama; Hidetoshi Hayashi; Shinichiro Suzuki; Ryoji Kato; Satomi Watanabe; Takayuki Takahama; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Kazuko Sakai; Koichi Azuma; Yasutaka Chiba; Shinji Atagi; Kazuto Nishio; Isamu Okamoto; Kazuhiko Nakagawa
    Scientific reports 9 1 19501 - 19501 2019年12月 [査読有り]
     
    Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC). Preclinically, HER3 ligand heregulin induces resistance to EGFR-TKIs, whereas the pan-human EGFR family inhibitor afatinib remains effective. Here, we examined whether soluble heregulin levels have clinical implications for EGFR-mutant NSCLC treated with EGFR-TKIs. Soluble heregulin was immunologically measured in plasma from EGFR-mutant NSCLC patients. Cutoff values were determined by 1-year PFS ROC curve. The relationship between soluble heregulin and PFS following EGFR-TKI therapy was analyzed by Cox proportional hazards model. Seventy-three patients were enrolled: 44 were treated with 1st-generation and 29 with 2nd-generation EGFR-TKIs. Soluble heregulin levels varied (range: 274-7,138 pg/mL, median: 739 pg/mL). Among patients treated with 1st-generation EGFR-TKIs, those with high heregulin (n = 20, >800 pg/mL) had a tendency for shorter PFS than those with low heregulin (n = 24, <800 pg/mL), with median PFS of 322 and 671 days, respectively. Cox proportional hazards model also indicated a trend toward resistance against 1st-generation EGFR-TKIs (HR: 1.825, 95% CI: 0.865-4.318) but not against 2nd-generation EGFR-TKIs. Soluble heregulin potentially correlates with resistance to EGFR-TKIs but not 2nd-generation EGFR-TKIs in patients with EGFR-mutant NSCLC.
  • Kazuko Sakai; Masayuki Takeda; Shigeki Shimizu; Takayuki Takahama; Takeshi Yoshida; Satomi Watanabe; Tsutomu Iwasa; Kimio Yonesaka; Shinichiro Suzuki; Hidetoshi Hayashi; Hisato Kawakami; Yoshikane Nonagase; Kaoru Tanaka; Junji Tsurutani; Kazumasa Saigoh; Akihiko Ito; Tetsuya Mitsudomi; Kazuhiko Nakagawa; Kazuto Nishio
    Scientific Reports 9 1 11340 - 11340 2019年12月 [査読有り]
     
    © 2019, The Author(s). Medical oncologists are challenged to personalize medicine with scientific evidence, drug approvals, and treatment guidelines based on sequencing of clinical samples using next generation sequencer (NGS). Knowledge-based curation systems have the potential to help address this challenge. We report here the results of examining the level of evidence regarding treatment approval and clinical trials between recommendations made by Watson for Genomics (WfG), QIAGEN Clinical Insight Interpret (QCII), and Oncomine knowledge-based reporter (OKR). The tumor samples obtained from the solid cancer patients between May to June 2018 at Kindai University Hospital. The formalin-fixed paraffin-embedded tumor samples (n = 31) were sequenced using Oncomine Comprehensive Assay v3. Variants including copy number alteration and gene fusions identified by the Ion reporter software were used commonly on three curation systems. Curation process of data were provided for 25 solid cancers using three curation systems independently. Concordance and distribution of curated evidence levels of variants were analyzed. As a result of sequencing analysis, nonsynonymous mutation (n = 58), gene fusion (n = 2) or copy number variants (n = 12) were detected in 25 cases, and subsequently subjected to knowledge-based curation systems (WfG, OKR, and QCII). The number of curated information in any systems was 51/72 variants. Concordance of evidence levels was 65.3% between WfG and OKR, 56.9% between WfG and QCII, and 66.7% between OKR and QCII. WfG provided great number of clinical trials for the variants. The annotation of resistance information was also observed. Larger differences were observed in clinical trial matching which could be due to differences in the filtering process among three curation systems. This study demonstrates knowledge-based curation systems (WfG, OKR, and QCII) could be helpful tool for solid cancer treatment decision making. Difference in non-concordant evidence levels was observed between three curation systems, especially in the information of clinical trials. This point will be improved by standardized filtering procedure and enriched database of clinical trials in Japan.
  • Yoshikane Nonagase; Masayuki Takeda; Koichi Azuma; Hidetoshi Hayashi; Koji Haratani; Kaoru Tanaka; Kimio Yonesaka; Hidenobu Ishii; Tomoaki Hoshino; Kazuhiko Nakagawa
    Thoracic Cancer 10 10 1928 - 1935 2019年10月 [査読有り]
     
    © 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd Background: Non-small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene is initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) but eventually develops resistance to these drugs. Upregulation of the receptor tyrosine kinase AXL in tumor tissue has been detected in about one-fifth of NSCLC patients with acquired resistance to EGFR-TKIs. However, the clinical relevance of the levels of AXL and its ligand GAS6 in plasma remains unknown. Methods: Tumor tissue and plasma specimens were collected from 25 EGFR-mutated NSCLC patients before EGFR-TKI treatment or after treatment failure. The levels of AXL and of GAS6 mRNA in tumor tissue were evaluated by immunohistochemistry and chromogenic in situ hybridization, respectively. The plasma concentrations of AXL and GAS6 were measured with enzyme-linked immunosorbent assays. Results: AXL expression was detected in three of 12 (25%) and nine of 19 (47%) tumor specimens obtained before and after EGFR-TKI treatment, respectively. All tumor specimens assayed were positive for GAS6 mRNA. The median values for the plasma AXL concentration before and after EGFR TKI treatment were 1 635 and 1 460 pg/mL, respectively, and those for the plasma GAS6 concentration were 4 615 and 6 390 pg./mL, respectively. There was no significant correlation between the plasma levels of AXL or GAS6 and the corresponding expression levels in tumor tissue. Conclusion: Plasma concentrations of AXL and GAS6 do not reflect tumor expression levels, and their measurement is thus not a viable alternative to direct analysis of tumor tissue in EGFR-mutated NSCLC.
  • Kimio Yonesaka; Kaoru Tanaka; Mutsukazu Kitano; Hisato Kawakami; Hidetoshi Hayashi; Masayuki Takeda; Kazuko Sakai; Kazuto Nishio; Katsumi Doi; Kazuhiko Nakagawa
    Oncogenesis 8 10 54 - 54 2019年09月 [査読有り]
     
    The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is standard therapy for head and neck squamous cell carcinoma (HNSCC). However, most HNSCC tumors are resistant to it and require alternative treatments. Here, we explored the mechanism of cetuximab resistance and evaluated its clinical relevance in HNSCC. An unbiased comprehensive transcriptome analysis was performed on cetuximab-resistant HNSCC FaDuCR cells. The causative resistance genome was knocked down with siRNA, cell signaling was immunologically analyzed, and drug efficacy was evaluated in vitro and in vivo. The mRNA in situ hybridization (ISH) of the causative genome was performed using 28 excised HNSCC tumors and its relationship with cetuximab efficacy was analyzed. FaDuCR cells were resistant to cetuximab, whereas parental FaDu cells were susceptible to it. FaDuCR cells expressed consistently higher levels of phosphorylated Akt than FaDu cells despite cetuximab exposure. A comprehensive transcriptome analysis revealed that the HER3-ligand heregulin was upregulated in FaDuCR cells compared to FaDu cells. Heregulin knockdown in FaDuCR cells repressed HER3 and Akt phosphorylation and recovered cetuximab anticancer efficacy. In contrast, pan-HER family tyrosine kinase inhibitors such as afatinib decreased HER3 and Akt phosphorylation in FaDuCR cells and inhibited FaDuCR tumor growth. Two of the 28 HNSCC tumor samples presented aberrant heregulin expression comparable to that of FaDuCR cells and were resistant to cetuximab therapy. In HNSCC, heregulin-mediated HER3-Akt activation causes resistance to cetuximab but not to second-generation EGFR-tyrosine kinase inhibitors. Subpopulations with aberrant heregulin-expressing HNSCC might be resistant to cetuximab.
  • Udagawa H; Akamatsu H; Tanaka K; Takeda M; Kanda S; Kirita K; Teraoka S; Nakagawa K; Fujiwara Y; Yasuda I; Okubo S; Shintani M; Kosloski MP; Scripture C; Tamura T; Okamoto I
    Lung cancer (Amsterdam, Netherlands) 135 145 - 150 2019年09月 [査読有り]
     
    OBJECTIVES: Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) on small cell lung cancer (SCLC) tumors, is internalized and releases the toxin pyrrolobenzodiazepine to induce cell death. This open label phase I study was the first study of Rova-T in Japanese patients. The aim of this study was to evaluate, safety, pharmacokinetics, and preliminary efficacy of Rova-T in Japanese patients with advanced recurrent SCLC. MATERIALS AND METHODS: Patients received Rova-T (0.2 or 0.3 mg/kg) by intravenous infusion on Day (D) 1 of each 6-week cycle for 2 doses and dexamethasone (8 mg BID oral) on D-1, D1, and D2 of each 6-week cycle. Retreatment with Rova-T was permitted for patients who tolerated their initial doses and then progressed after disease control (defined as stable disease or better) was observed for at least 12 weeks after their last dose of Rova-T. RESULTS: Rova-T exhibited toxicity that was generally manageable in Japanese patients (N = 29). No dose-limiting toxicities were experienced. The most common treatment-related adverse events (≥25% of patients, all grades) were platelet count decreased, pleural effusion, peripheral edema, aspartate aminotransferase increased, white blood cell count decreased, neutrophil count decreased, alanine aminotransferase increased, hypoalbuminaemia, anemia and decreased appetite. Safety and pharmacokinetics exposures were similar to previous observations in non-Japanese populations. Per investigator assessment of DLL3 high patients, 17% (3/18) had confirmed partial responses, and the disease control rate was 56%, mPFS was 2.9 months, and mOS was 7.4 months. CONCLUSIONS: These preliminary data support further exploration of Rova-T treatment in Japanese patients with SCLC in global studies. This trial was registered with ClinicalTrials.gov as NCT03086239.
  • Hitomi Sakai; Masayuki Takeda; Kazuko Sakai; Yasushi Nakamura; Akihiko Ito; Hidetoshi Hayashi; Kaoru Tanaka; Kazuto Nishio; Kazuhiko Nakagawa
    Lung Cancer 127 59 - 65 2019年01月 [査読有り]
     
    © 2018 Elsevier B.V. Objectives: Immune-checkpoint inhibitors (ICIs) are now an established therapeutic option for advanced non–small cell lung cancer (NSCLC). It has remained unclear, however, whether cytotoxic chemotherapy affects the immune microenvironment in NSCLC wild type for EGFR and ALK. Materials and methods: We retrospectively evaluated changes in programmed cell death 1–ligand 1 (PD-L1) expression, tumor mutation burden (TMB), and CD8+ tumor-infiltrating lymphocyte (TIL) density in NSCLC patients who underwent rebiopsy at the site of recurrence after postoperative platinum-based adjuvant chemotherapy, or in those who underwent rebiopsy after one or more chemotherapeutic regimens at the advanced stage. The PD-L1 tumor proportion score (TPS) and CD8+ TIL density were determined by immunohistochemistry. TMB was estimated by next-generation sequencing with a cancer gene panel (409 genes). Results: Seventeen patients with NSCLC wild type for EGFR and ALK were enrolled. Although PD-L1 TPS tended to be increased in rebiopsy samples compared with initial biopsy tissue, this difference was not significant (P = 0.113). Seven patients showed an increase in PD-L1 TPS, with this change being pronounced in four. Two cases in which PD-L1 TPS increased from 0 to 90% or from 0 to 95% after cytotoxic chemotherapy also showed a durable response to subsequent treatment with an ICI. No substantial correlation between PD-L1 TPS and TMB was apparent either before (R = 0.112) or after (R = 0.101) chemotherapy. A moderate correlation was detected between PD-L1 TPS and CD8+ TIL density before chemotherapy (R = 0.517) and a negligible correlation after (R = 0.0219). Conclusion: Cytotoxic chemotherapy may change the biological characteristics of tumors including PD-L1 expression level and TMB.
  • Yoshikane Nonagase; Masayuki Takeda; Kaoru Tanaka; Hidetoshi Hayashi; Tsutomu Iwasa; Kazuhiko Nakagawa
    Oncotarget 9 50 29532 - 29535 2018年06月 [査読有り]
     
    © Nonagase et al. Malignant tumors can induce a hypercoagulable state known as Trousseau syndrome that increases the risk for venous thromboembolism including disabling cerebral infarction. Anticoagulant therapy without anticancer treatment is not effective for amelioration of this coagulation abnormality. Most patients with lung cancer positive for activating mutations of the epidermal growth factor receptor (EGFR) are sensitive to EGFR tyrosine kinase inhibitors (TKIs), but the efficacy and safety of EGFR-TKIs in such patients with a poor performance status (PS) due to Trousseau syndrome has been unclear. We here describe a patient with EGFR mutation-positive lung cancer who developed disabling cerebral infarction due to Trousseau syndrome. Administration of the EGFR-TKI gefitinib and anticoagulant therapy resulted in a partial tumor response and recovery from both the coagulation abnormality and the severe neurological symptoms. After the development of resistance to gefitinib, the EGFR-TKI osimertinib was safely administered until disease progression without recurrence of the coagulation abnormality. This case suggests that gefitinib followed by osimertinib may be a safe and effective treatment option for patients with EGFR mutation-positive lung cancer who experience disabling cerebral infarction due to Trousseau syndrome.
  • Kimio Yonesaka; Koji Haratani; Shiki Takamura; Hitomi Sakai; Ryoji Kato; Naoki Takegawa; Takayuki Takahama; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Sigeki Kato; Osamu Maenishi; Kazuko Sakai; Yasutaka Chiba; Takafumi Okabe; Keita Kudo; Yoshikazu Hasegawa; Hiroyasu Kaneda; Michiko Yamato; Kenji Hirotani; Masaaki Miyazawa; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical Cancer Research 24 11 2653 - 2664 2018年06月 [査読有り]
     
    © 2018 American Association for Cancer Research. Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non–small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting. Experimental Design: B7-H3 expression was evaluated immu-nohistochemically in patients with NSCLC (n ¼ 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8þ tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry. Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8þ TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8þ TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8þ TILs and recovery of effector function. CD8þ T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8þ T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction. Conclusions: B7-H3 expressed on tumor cells potentially circumvents CD8þ-T-cell–mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3–expressing NSCLCs.
  • Yosuke Makuuchi; Hidetoshi Hayashi; Koji Haratani; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Kazuko Sakai; Shigeki Shimizu; Akihiko Ito; Kazuto Nishio; Kazuhiko Nakagawa
    Oncotarget 9 33 23315 - 23319 2018年05月 [査読有り]
     
    © Makuuchi et al. The second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) alectinib and ceritinib are standard treatment options for patients with non-small cell lung cancer (NSCLC) positive for ALK fusion genes. However, almost all patients eventually develop resistance to these drugs. We here report a case of ALK-rearranged NSCLC that developed resistance to alectinib but remained sensitive to ceritinib. The L1196M mutation within the ALK fusion gene was detected after failure of consecutive treatment with crizotinib and alectinib, but no other mechanism underlying acquired resistance to ALK-TKIs was found to be operative. Given the increasing application of ALK-TKIs to the treatment of patients with ALK-rearranged NSCLC, further clinical evaluation is warranted to provide a better understanding of the mechanisms of acquired resistance to these agents and to inform treatment strategies for such tumors harboring secondary mutations.
  • Masayuki Takeda; Kazuko Sakai; Hidetoshi Hayashi; Kaoru Tanaka; Junko Tanizaki; Takayuki Takahama; Koji Haratani; Kazuto Nishio; Kazuhiko Nakagawa
    Oncotarget 9 30 21132 - 21140 2018年04月 [査読有り]
     
    Unlike common epidermal growth factor receptor gene (EGFR) mutations that confer sensitivity to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), mutations in exon 20 of either EGFR or the human EGFR2 gene (HER2) are associated with insensitivity to EGFR-TKIs, with treatment options for patients with such mutations being limited. Clinical characteristics, outcome of EGFR-TKI or nivolumab treatment, and the presence of coexisting mutations were reviewed for NSCLC patients with exon- 20 mutations of EGFR or HER2 as detected by routine application of an amplicon-based next-generation sequencing panel. Between July 2013 and June 2017, 206 patients with pathologically confirmed lung cancer were screened for genetic alterations including HER2 and EGFR mutations. Ten patients harbored HER2 exon-20 insertions (one of whom also carried an exon-19 deletion of EGFR), and 12 patients harbored EGFR exon- 20 mutations. Five of the 13 patients with EGFR mutations were treated with EGFR-TKIs, two of whom manifested a partial response, two stable disease, and one progressive disease. Among the seven patients treated with nivolumab, one patient manifested a partial response, three stable disease, and three progressive disease, with most (86%) of these patients discontinuing treatment as a result of disease progression within 4 months. The H1047R mutation of PIK3CA detected in one patient was the only actionable mutation coexisting with the exon-20 mutations of EGFR or HER2. Potentially actionable mutations thus rarely coexist with exon-20 mutations of EGFR or HER2, and EGFR-TKIs and nivolumab show limited efficacy in patients with such exon-20 mutations.
  • 悪性リンパ腫放射線治療後、2次発癌として進行食道癌を併発した1例
    奥野 達哉; 植田 勲人; 武川 直樹; 野長瀬 祥兼; 川上 尚人; 谷崎 潤子; 林 秀敏; 田中 薫; 武田 真幸; 鶴谷 純司; 中川 和彦
    日本消化器病学会雑誌 115 臨増総会 A328 - A328 (一財)日本消化器病学会 2018年03月
  • Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Keita Kudo; Kimio Yonesaka; Ryoji Kato; Hiroyasu Kaneda; Yoshikazu Hasegawa; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa
    JAMA Oncology 4 3 374 - 378 2018年03月 [査読有り]
     
    IMPORTANCE Immune-related adverse events (irAEs) have been associated with the efficacy of PD-1 (programmed cell death protein 1) inhibitors in patients with melanoma, but whether such an association exists for non-small cell lung cancer (NSCLC) has remained unknown. OBJECTIVE To evaluate the relation of irAEs to nivolumab efficacy in NSCLC. DESIGN, SETTING, AND PARTICIPANTS In this study based on landmark and multivariable analyses, a total of 134 patients with advanced or recurrent NSCLC who were treated with nivolumab in the second-line setting or later between December 2015 and August 2016 were identified from a review of medical records from multiple institutions, including a university hospital and community hospitals. Data were updated as of December 31, 2016. EXPOSURES The absence or presence of any irAE before the landmark date. MAIN OUTCOMES AND MEASURES Kaplan-Meier curves of progression-free survival (PFS) according to the development of irAEs in 6-week landmark analysis were evaluated with the log-rank test as a preplanned primary objective. Overall survival (OS) was similarly evaluated. Multivariable analysis of both PFS and OS was performed with Cox proportional hazard regression models. RESULTS In a cohort of 134 patients (median [range] age, 68 [33-85] years 90 men [67%], 44 women [33%]), irAEs were observed in 69 of the 134 study patients (51%), including 12 patients (9%) with such events of grade 3 or 4, and 24 patients (18%) requiring systemic corticosteroid therapy. In 6-week landmark analysis, median PFS was 9.2 months (95% CI, 4.4 to not reached [NR]) and 4.8 months (95% CI, 3.0 to 7.5) (P = .04) whereas median OS was NR (95% CI, 12.3 to NR) and 11.1 months (95% CI, 9.6 to NR) (P = .01) for patients with or without irAEs, respectively. Multivariable analysis also revealed that irAEs were positively associated with survival outcome, with hazard ratios of 0.525 (95% CI, 0.287 to 0.937 P = .03) for PFS and 0.282 (95% CI, 0.101 to 0.667 P = .003) for OS. CONCLUSIONS AND RELEVANCE Development of irAEs was associated with survival outcome of nivolumab treatment in patients with advanced or recurrent NSCLC. Further studies are needed to confirm our findings.
  • Tanizaki J; Haratani K; Hayashi H; Chiba Y; Nakamura Y; Yonesaka K; Kudo K; Kaneda H; Hasegawa Y; Tanaka K; Takeda M; Ito A; Nakagawa K
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13 1 97 - 105 2018年01月 [査読有り]
     
    Objective The aim of this study was to identify baseline peripheral blood biomarkers associated with clinical outcome in patients with NSCLC treated with nivolumab. Methods Univariable and multivariable analyses were performed retrospectively for 134 patients with advanced or recurrent NSCLC treated with nivolumab to evaluate the relationship between survival and peripheral blood parameters measured before treatment initiation, including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and absolute eosinophil count (AEC), as well as serum C-reactive protein and lactate dehydrogenase levels. Progression-free survival, overall survival, and response rate were determined. Results Among the variables selected by univariable analysis, a low ANC, high ALC, and high AEC were significantly and independently associated with both better progression-free survival (p = 0.001, p = 0.04, and p = 0.02, respectively) and better overall survival (p = 0.03, p = 0.03, and p = 0.003, respectively) in multivariable analysis. Categorization of patients according to the number of favorable factors revealed that those with only one factor had a significantly worse outcome than those with two or three factors. A similar trend was apparent for patients with a programmed death 1 ligand tumor proportion score less than 50%, whereas all patients with a score of 50% or higher had at least two favorable factors. Conclusions A baseline signature of a low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate.
  • Kato R; Hayashi H; Chiba Y; Tanaka K; Takeda M; Nakagawa K
    Clinical lung cancer 18 6 E449 - E455 2017年11月 [査読有り]
     
    Minimal (< 10 mm in thickness) pericardial effusion can be incidentally detected by computed tomography at diagnosis in patients with lung cancer. We retrospectively analyzed 428 patients diagnosed with advanced nonesmall-cell lung cancer. Our study found that 14.3% of patients presented with minimal pericardial effusion at first diagnosis, and its presence was an independent prognostic factor for reduced survival in patients with advanced nonesmall-cell lung cancer. Introduction: Minimal (< 10 mm in thickness) pericardial effusion (PCE) can be incidentally detected by computed tomography at the time of diagnosis in patients with lung cancer. Although malignant PCE is known to be associated with poor prognosis, the impact of minimal PCE on outcome has remained unclear. We therefore examined the prognostic relevance of minimal PCE in patients with advanced nonesmall-cell lung cancer (NSCLC). Patients and Methods: We retrospectively analyzed consecutive patients diagnosed with stage IV NSCLC at Kindai University Hospital between April 2009 and March 2015. The patients were classified into 3 groups on the basis of the presence and thickness of PCE: no PCE, minimal (< 10 mm) PCE, and malignant (< 10 mm) PCE. The relation between overall survival and PCE status was examined with a Cox proportional hazards model. Results: The total of 428 enrolled patients included 327 (76.4%) in the no PCE group, 61 (14.3%) in the minimal PCE group, and 40 (9.3%) in the malignant PCE group. Median overall survival was 15.0, 10.1, and 7.6 months in the no PCE, minimal PCE, and malignant PCE groups, respectively, with the survival of patients with minimal PCE thus being intermediate between that of the other 2 groups (P = .003). Multivariable analysis revealed that minimal PCE was independently associated with reduced survival (hazard ratio, 1.46; 95% confidence interval, 1.07-1.96; P = .019). Conclusions: The presence of minimal PCE was an independent prognostic factor for reduced survival in patients with advanced NSCLC. (C) 2017 Elsevier Inc. All rights reserved.
  • Hisato Kawakami; Junko Tanizaki; Kaoru Tanaka; Koji Haratani; Hidetoshi Hayashi; Masayuki Takeda; Ken Kamata; Mamoru Takenaka; Masatomo Kimura; Takaaki Chikugo; Takao Sato; Masatoshi Kudo; Akihiko Ito; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 35 4 529 - 536 2017年08月 [査読有り]
     
    Background Nivolumab demonstrates promising efficacy for the treatment of non-small cell lung cancer and other malignancies. The clinical benefit of nivolumab, however, may be hampered by specific immune-related adverse events (irAEs), and little is known regarding nivolumab-related cholangitis. Methods A computerized search of our clinical database identified 3 metastatic non-small cell lung cancer patients with nivolumab-related cholangitis. All patients were treated with in-travenous nivolumab monotherapy (3.0 mg/kg) every 2 weeks until disease progression or irAEs occurred. Clinical data regarding the duration of nivolumab treatment, symptoms, laboratory abnormalities, pathological findings of liver parenchyma biopsy specimens, and management of nivolumab-related cholangitis were analyzed. Results Our analysis revealed that nivolumab-related cholangitis was characterized by (1) localized extrahepatic bile duct dilation without obstruction; (2) diffuse hypertrophy of the extrahepatic bile duct wall; (3) a dominant increase in the biliary tract enzymes alkaline phosphatase and gamma-glutamyl transpeptidase relative to the hepatic enzymes aspartate and alanine aminotransferase; (4) normal or reduced levels of the serum immunological markers antinuclear antibody, antimitochondrial antibody, smooth muscle antibody, and immunoglobulin G4; (5) the pathological finding of biliary tract cluster of differentiation 8-positive T cell infiltration from liver biopsy; and (6) amoderate to poor response to steroid therapy. Conclusions Nivolumab-related cholangitis is associated with distinct imaging and clinicopathological features that distinguish it from acute cholangitis of common etiologies and other immune-related cholangitis. Further studies are warranted to establish the optimal management of patients with this irAE.
  • Kato R; Hayashi H; Tanizaki J; Tanaka K; Takeda M; Nakagawa K
    ESMO open 2 1 e000145  2017年 [査読有り]
  • ALK融合遺伝子陽性NSCLCに対するクリゾチニブ、アレクチニブ逐次療法の生存解析
    渡邉 諭美; 林 秀敏; 岡本 邦男; 田中 薫; 武田 真幸; 中川 和彦; 金田 裕靖; 藤原 季美子; 長谷川 喜一
    肺癌 56 7 1064 - 1064 (NPO)日本肺癌学会 2016年12月
  • Junko Tanizaki; Hidetoshi Hayashi; Masatomo Kimura; Kaoru Tanaka; Masayuki Takeda; Shigeki Shimizu; Akihiko Ito; Kazuhiko Nakagawa
    LUNG CANCER 102 44 - 48 2016年12月 [査読有り]
     
    The recent approval of nivolumab and other immune-checkpoint inhibitors for the treatment of certain solid tumors including non small cell lung cancer (NSCLC) has transformed cancer therapy. However, it will be important to characterize effects of such agents not seen with classical cytotoxic drugs or other targeted therapeutics. We here report two cases of NSCLC showing so-called pseudoprogression during nivolumab treatment. In both cases, imaging assessment revealed that liver metastatic lesions initially progressed but subsequently shrank during continuous nivolumab administration, with treatment also resulting in a decline in serum levels of carcinoembryonic antigen. Histological evaluation of the liver metastatic lesion of one case after regression revealed fibrotic tissue containing infiltrated lymphocytes positive for CD3, CD4, or CD8 but no viable tumor cells, suggestive of a durable immune reaction even after a pathological complete response. Given the increasing use of immune-checkpoint inhibitors in patients with NSCLC or other solid tumors, further clinical evaluation and pathological assessment are warranted to provide a better understanding of such pseudoprogression. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Kaname Nosaki; Miyako Satouchi; Takayasu Kurata; Tatsuya Yoshida; Isamu Okamoto; Nobuyuki Katakami; Fumio Imamura; Kaoru Tanaka; Yuki Yamane; Nobuyuki Yamamoto; Terufumi Kato; Katsuyuki Kiura; Hideo Saka; Hiroshige Yoshioka; Kana Watanabe; Keiko Mizuno; Takashi Seto
    LUNG CANCER 101 1 - 8 2016年11月 [査読有り]
     
    Objective: Disease progression because of acquired resistance is common in advanced or metastatic epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC), despite initial response to EGFR-tyrosine kinase inhibitors (TKI5). In Japan, transbronchial tissue biopsy is the most common sampling method used for re-biopsy to identify patients eligible for treatment. We aimed to investigate the success rate of re-biopsy and re-biopsy status of patients with advanced or metastatic NSCLC completing first-line EGFR-TKI therapy. Patients and methods: This was a retrospective, multi-center, Japanese study. The target patients in the study were EGFR mutation-positive NSCLC patients. The primary endpoint was the success rate (number of cases in which tumor cells were detected/total number of re-biopsies performed x 100). Secondary endpoints included differences between the status of the first biopsy and that of the re-biopsy in the same patient population, and the details of cases in which re-biopsy could not be carried out. Re-biopsy associated complications were also assessed. Results: Overall, 395 patients were evaluated (median age 63 years), with adenocarcinoma being the most common tumor type. Re-biopsy was successful in 314 patients (79.5%). Compared with the sampling method at first biopsy, at re-biopsy, the surgical resection rate increased from 1.8% to 7.8%, and percutaneous tissue biopsy increased from 7.6% to 29.1%, suggesting the difficulty of performing re biopsy. Approximately half of the patients had T790M mutations, which involved a Dell 9 mutation in 55.6% of patients and an L858R mutation in 43.0%. Twenty-three patients (5.8%) had re-biopsy-associated complications, most commonly pneumothorax. Conclusions: Success rate for re-biopsy in this study was approximately 80%. Our study sheds light on the re-biopsy status after disease progression in patients with advanced or metastatic NSCLC. This information is important to improve the selection of patients who may benefit from third-generation TKIs. (C) 2016 AstraZeneca K.K. Published by Elsevier Ireland Ltd.
  • Kiyohiro Sakai; Masayuki Takeda; Hidetoshi Hayashi; Kaoru Tanaka; Takeshi Okuda; Amami Kato; Yasumasa Nishimura; Tetsuya Mitsudomi; Atsuko Koyama; Kazuhiko Nakagawa
    THORACIC CANCER 7 6 670 - 675 2016年11月 [査読有り]
     
    IntroductionThe concept of oligometastasis has emerged as a basis on which to identify patients with stage IV non-small cell lung cancer (NSCLC) who might be most amenable to curative treatment. Limited data have been available regarding the survival of patients with node-negative oligometastatic NSCLC. Patients and methodsConsecutive patients with advanced NSCLC who attended Kindai University Hospital between January 2007 and January 2016 were recruited to this retrospective study. Patients with regional lymph node-negative disease and a limited number of metastatic lesions (5) per organ site and a limited number of affected organ sites (1 or 2) were eligible. ResultsEighteen patients were identified for analysis during the study period. The most frequent metastatic site was the central nervous system (CNS, 72%). Most patients (83%) received systemic chemotherapy, with only three (17%) undergoing surgery, for the primary lung tumor. The CNS failure sites for patients with CNS metastases were located outside of the surgery or radiosurgery field. The median overall survival for all patients was 15.9months, with that for EGFR mutation-positive patients tending to be longer than that for EGFR mutation-negative patients. ConclusionCure is difficult to achieve with current treatment strategies for NSCLC patients with synchronous oligometastases, although a few long-term survivors and a smaller number of patients alive at last follow-up were present among the study cohort. There is an urgent clinical need for prospective evaluation of surgical resection as a treatment for oligometastatic NSCLC, especially negative for driver mutations.
  • Satomi Watanabe; Hidetoshi Hayashi; Kunio Okamoto; Kimiko Fujiwara; Yoshikazu Hasegawa; Hiroyasu Kaneda; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 17 6 528 - 534 2016年11月 [査読有り]
     
    We identified 11 patients with ALK-rearranged non-small cell lung cancer treated with sequential crizotinib and alectinib. The median combined progression-free survival and overall survival in the present study was 18.2 and 48.6 months, respectively. These findings suggest that this regimen produces durable survival and therefore warrants further investigation. Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4-ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first-and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK-rearranged NSCLC. Materials and Methods: Eleven patients with ALK-rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records. Results: The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 020.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively. Conclusion: Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK-rearranged NSCLC.
  • Hidetoshi Hayashi; Masakazu Ogura; Takashi Niwa; Satoshi Ikeo; Takashi Yokoi; Yoshitaro Torii; Kunio Okamoto; Yosuke Tamura; Kaoru Tanaka; Yasuhito Fujisaka; Isao Goto; Hiroyasu Kaneda; Takayasu Kurata; Hiroshige Yoshioka; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 34 15 2016年05月 [査読有り]
  • Toshio Shimizu; Kazuto Nishio; Kazuko Sakai; Hidetoshi Hayashi; Kunio Okamoto; Masayuki Takeda; Tsutomu Iwasa; Kaoru Tanaka; Koji Aoyama; Maiko Morishita; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 34 15 2016年05月 [査読有り]
  • Yoshikane Nonagase; Kunio Okamoto; Tsutomu Iwasa; Takeshi Yoshida; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Toshio Shimizu; Junji Tsurutani; Kazuhiko Nakagawa
    ANTI-CANCER DRUGS 27 3 251 - 253 2016年03月 [査読有り]
     
    Both afatinib and erlotinib are tyrosine kinase inhibitors that inhibit aberrant epidermal growth factor receptor (EGFR) signals in non-small-cell lung cancer (NSCLC). Afatinib is an irreversible inhibitor directed against EGFR, ErbB-2, and ErbB-4, whereas erlotinib is a reversible inhibitor directed against EGFR only. Although afatinib has been shown to be effective in the treatment for erlotinib-refractory and/or gefitinib-refractory central nervous system metastases from NSCLC, little is known about the efficacy of erlotinib for afatinib-refractory central nervous system metastases. In the present report we describe a case of EGFR mutation-positive NSCLC in which brain metastases developed during first-line afatinib treatment. Whole-brain radiation therapy and substitution of erlotinib for afatinib led to successful shrinkage of the brain metastases. Our report highlights the potential benefit of erlotinib for the management of brain metastases refractory over afatinib in patients with NSCLC.
  • Shinichiro Ryuge; Noriyuki Masuda; Nobuyuki Yamamoto; Toshiaki Takahashi; Haruyasu Murakami; Koji Takeda; Haruko Daga; Kimio Yonesaka; Hiroshi Tsukuda; Kazuhiko Nakagawa; Kaoru Tanaka; Katsuyuki Kiura; Nagio Takigawa; Toyoaki Hida; Takashi Seto; Masanori Yokoba; Shinzoh Kudoh; Takeshi Takagaki; Kazushige Shono; Hideo Kitagawa; Takeshi Kurihara; Masahiro Fukuoka
    Cancer Treatment and Research Communications 9 81 - 87 2016年 [査読有り]
     
    Objective The pharmacokinetics of amrubicin in patients with impaired hepatic function have not been reported. The aim of this study was to compare the pharmacokinetics of amrubicin and its major metabolite, amrubicinol, and to assess the safety of amrubicin in lung cancer patients with impaired hepatic function and those with normal hepatic function. Materials and methods Five patients with impaired hepatic function (arm I) and 10 patients with normal hepatic function (arm N) with small or non-small cell lung carcinoma were enrolled. Liquid chromatography with tandem mass spectrometry was used to determine the amrubicin and amrubicinol concentrations. Pharmacokinetic parameters were estimated by non-compartmental analysis. Results The terminal half-lives of amrubicin and amrubicinol in whole blood and plasma were slightly longer in arm I than in arm N. The area under the concentration–time curve (AUC0–24h) values of amrubicin in plasma and AUC0–120h of amrubicinol in whole blood in arm I were not larger than those in arm N because of dose adjustments based on prior treatment history and baseline values of total bilirubin, aspartate aminotransferase and alanine aminotransferase. The dose-normalized AUCs (dose 40 mg/m2) of amrubicin and amrubicinol in arm I were slightly larger than those in arm N. There were two deaths in arm I, one related to disease progression and one from an unknown cause. Conclusion If an adjusted dose of amrubicin is used in patients with impaired hepatic function, the exposure of amrubicin and amrubicinol would be within the range of variation observed in patients with normal hepatic function.
  • Kimio Yonesaka; Keita Kudo; Satomi Nishida; Takayuki Takahama; Tsutomu Iwasa; Takeshi Yoshida; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Isamu Okamoto; Kazuto Nishio; Kazuhiko Nakagawa
    ONCOTARGET 6 32 33602 - 33611 2015年10月 [査読有り]
     
    Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non-small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF-TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulin-overexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulin-mediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance.
  • Masayuki Takeda; Kazuko Sakai; Masato Terashima; Hiroyasu Kaneda; Hidetoshi Hayashi; Kaoru Tanaka; Tsutomu Iwasa; Takeshi Yoshida; Takayuki Takahama; Kazuto Nishio; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 10 9 S700 - S701 2015年09月 [査読有り]
  • Patrick Schnell; Cynthia H. Bartlett; Benjamin J. Solomon; Vanessa Tassell; Alice T. Shaw; Tommaso de Pas; Soo-Hyun Lee; Geon Kook Lee; Kaoru Tanaka; Weiwei Tan; Yiyun Tang; Keith D. Wilner; Allan Safferman; Ji-Youn Han
    CANCER MEDICINE 4 6 887 - 896 2015年06月 [査読有り]
     
    An apparent causal association between crizotinib treatment and renal cyst development emerged during clinical trials in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Serious adverse event (SAE) reports of renal cysts from a safety database of 1375 patients from four clinical trials were reviewed. A blinded, retrospective, independent radiologic review (IRR) was performed using scans from patients on study for 6months in three clinical trials; risk factors for renal cyst development were assessed. Among 17 patients with renal cysts reported as SAEs, evidence of invasion into adjacent structures was noted in seven patients, with no evidence of malignancy found. These patients generally did not require dose reductions, none required permanent crizotinib discontinuation due to this AE, and most continued treatment with clinical benefit. In the blinded IRR, among 255 crizotinib-treated patients, 22%, 3%, and 2% had preexisting simple cysts, complex cysts, or both, respectively. At the 6-month tumor assessment, 9% of all patients had acquired new cysts, and 2% of patients with preexisting cysts had developed new cysts and enlargements (>50%) of preexisting simple cysts. Asians appeared to have an increased risk of developing new cysts on treatment; Koreans in particular had 5.18 times higher odds of developing cysts than non-Asians (95% confidence interval, 1.51-17.78; P=0.05). Crizotinib treatment appears to be associated with an increased risk of development and progression of renal cysts in patients with ALK-positive NSCLC. While close monitoring is recommended, dosing modification was not generally necessary, allowing patients to remain on crizotinib treatment.
  • Yukio Hosomi; Kiyotaka Yoh; Kazuo Kasahara; Kazuhiko Yamada; Toshiaki Takahashi; Kaoru Tanaka; Toyoaki Hida; Hiroshige Yoshioka; Terufumi Kato; Koji Takeda; Makoto Nishio; Hiroshi Sakai; Makoto Maemondo; Mitsuhiro Takenoyama; Hiroshi Nokihara; Masumi Tatsumi; Takashi Nakamura; Sotaro Enatsu; Tomohide Tamura; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 33 15 2015年05月 [査読有り]
  • Yasuhito Fujisaka; Takayasu Kurata; Kaoru Tanaka; Toshihiro Kudo; Kunio Okamoto; Junji Tsurutani; Hiroyasu Kaneda; Isamu Okamoto; Masayuki Namiki; Chifumi Kitamura; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 33 2 380 - 388 2015年04月 [査読有り]
     
    Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5 %) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4 %) and pyrexia (23.5 %). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).
  • Hidetoshi Hayashi; Isamu Okamoto; Junko Tanizaki; Kaoru Tanaka; Takeshi Okuda; Amami Kato; Yasumasa Nishimura; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 32 36 E122 - E124 2014年12月 [査読有り]
  • Tsutomu Iwasa; Tsutomu Sakiyama; Junji Tsurutani; Kaoru Tanaka; Takeshi Yoshida; Yoshikane Nonagase; Yasuhito Fujisaka; Takayasu Kurata; Yoshifumi Komoike; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 25 2014年10月 [査読有り]
  • Hiroyasu Kaneda; Masayuki Takeda; Kaoru Tanaka; Takeshi Yoshida; Tsutomu Iwasa; Kunio Okamoto; Hisato Kawakami; Takayuki Takahama; Toshio Shimizu; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 25 2014年10月 [査読有り]
  • Yasuhiro Kidera; Hisato Kawakami; Tsutomu Sakiyama; Kunio Okamoto; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Shin-ichi Nishina; Junji Tsurutani; Kimiko Fujiwara; Morihiro Nomura; Yuzuru Yamazoe; Yasutaka Chiba; Shozo Nishida; Takao Tamura; Kazuhiko Nakagawa
    PLOS ONE 9 7 e101902  2014年07月 [査読有り]
     
    Background: Nephrotoxicity remains a problem for patients who receive cisplatin chemotherapy. We retrospectively evaluated potential risk factors for cisplatin-induced nephrotoxicity as well as the potential impact of intravenous magnesium supplementation on such toxicity. Patients and Methods: We reviewed clinical data for 401 patients who underwent chemotherapy including a high dose (>= 60 mg/m(2)) of cisplatin in the first-line setting. Nephrotoxicity was defined as an increase in the serum creatinine concentration of at least grade 2 during the first course of cisplatin chemotherapy, as assessed on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The severity of nephrotoxicity was evaluated on the basis of the mean change in the serum creatinine level. Magnesium was administered intravenously to 67 patients (17%). Results: Cisplatin-induced nephrotoxicity was observed in 127 patients (32%). Multivariable analysis revealed that an Eastern Cooperative Oncology Group performance status of 2 (risk ratio, 1.876; P = 0.004) and the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) (risk ratio, 1.357; P = 0.047) were significantly associated with an increased risk for cisplatin nephrotoxicity, whereas intravenous magnesium supplementation was associated with a significantly reduced risk for such toxicity (risk ratio, 0.175; P = 0.0004). The development of hypomagnesemia during cisplatin treatment was significantly associated with a greater increase in serum creatinine level (P = 0.0025). Magnesium supplementation therapy was also associated with a significantly reduced severity of renal toxicity (P = 0.012). Conclusions: A relatively poor performance status and the regular use of NSAIDs were significantly associated with cisplatin-induced nephrotoxicity, although the latter association was marginal. Our findings also suggest that the ability of magnesium supplementation to protect against the renal toxicity of cisplatin warrants further investigation in a prospective trial.
  • Hidetoshi Hayashi; Isamu Okamoto; Shinya Ueda; Kaoru Tanaka; Kunio Okamoto; Hisato Kawakami; Shinichi Nishina; Masayuki Takeda; Yasuhito Fujisaka; Taroh Satoh; Kyoichi Terao; Yasumasa Nishimura; Katsumi Doi; Kazuhiko Nakagawa
    Anticancer research 33 12 5699 - 705 2013年12月 [査読有り]
     
    AIM: We performed a pharmacokinetic phase I trial of the combination of S-1 granules and nedaplatin for head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients were treated with both nedaplatin on day 1 at a dose starting at 80 mg/m(2) (level 1) escalating up to 90 mg/m(2) (level 2), and S-1 granules at a daily dose of 80 mg/m(2) on days 1 to 14 every three weeks. The primary end-point was determination of the recommended dose. RESULTS: Twenty patients were enrolled. Dose-limiting toxicities occurred in one out of six patients at dose level 1 (neutropenia) and in all three patients at level 2 (neutropenia and thrombocytopenia). The recommended dose was determined as level 1. Pharmacokinetic parameters of S-1 granule did not differ from the capsula formulation. The response rate was 42.1%. CONCLUSION: This combination was well-tolerated and manifested a promising activity against HNSCC.
  • Hisato Kawakami; Isamu Okamoto; Kyoichi Terao; Kazuko Sakai; Minoru Suzuki; Shinya Ueda; Kaoru Tanaka; Kiyoko Kuwata; Yume Morita; Koji Ono; Kazuto Nishio; Yasumasa Nishimura; Katsumi Doi; Kazuhiko Nakagawa
    CANCER MEDICINE 2 6 933 - 941 2013年12月 [査読有り]
     
    Human papillomavirus (HPV) is a major etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC). However, little is known about HPV-related OPSCC in Japan. During the study, formalin-fixed, paraffin-embedded OPSCC specimens from Japanese patients were analyzed for HPV DNA by the polymerase chain reaction (PCR) and for the surrogate marker p16 by immunohistochemistry. For HPV DNA-positive, p16-negative specimens, the methylation status of the p16 gene promoter was examined by methylation-specific PCR. Overall survival was calculated in relation to HPV DNA and p16 status and was subjected to multivariate analysis. OPSCC cell lines were examined for sensitivity to radiation or cisplatin in vitro. The study results showed that tumor specimens from 40 (38%) of the 104 study patients contained HPV DNA, with such positivity being associated with tumors of the tonsils, lymph node metastasis, and nonsmoking. Overall survival was better for OPSCC patients with HPV DNA than for those without it (hazard ratio, 0.214; 95% confidence interval, 0.074-0.614; P = 0.002). Multivariate analysis revealed HPV DNA to be an independent prognostic factor for overall survival (P = 0.015). Expression of p16 was associated with HPV DNA positivity. However, 20% of HPV DNA-positive tumors were negative for p16, with most of these tumors manifesting DNA methylation at the p16 gene promoter. Radiation or cisplatin sensitivity did not differ between OPSCC cell lines positive or negative for HPV DNA. Thus, positivity for HPV DNA identifies a distinct clinical subset of OPSCC with a more favorable outcome in Japanese.
  • Junichi Shimizu; Fumihiko Hirai; Takeharu Yamanaka; Keni-chi Taguchi; Haruko Daga; Yoshihito Kogure; Tatsuo Kimura; Kaoru Tanaka; Yasuo Iwamoto; Akira Ono; Hidefumi Sasaki; Junya Fukuoka; Kenichi Nishiyama; Koji Takeda; Takashi Seto; Yukito Ichinose; Kazuhiko Nakagawa; Yoichi Nakanishi
    JOURNAL OF THORACIC ONCOLOGY 8 S270 - S270 2013年11月 [査読有り]
  • Takayasu Kurata; Yasuhito Fujisaka; Kaoru Tanaka; Toshihiro Kudo; Kunio Okamoto; Junji Tsurutani; Hiroyasu Kaneda; Isamu Okamoto; Masayuki Namiki; Chifumi Kitamura; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 8 S935 - S935 2013年11月 [査読有り]
  • Kunio Okamoto; Isamu Okamoto; Masaki Miyazaki; Kaoru Tanaka; Hiroyasu Kaneda; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 31 5 1364 - 1366 2013年10月 [査読有り]
     
    We report contemporaneous bronchoscopic findings for a case of bevacizumab-related pulmonary hemorrhage in a patient with advanced non-small cell lung cancer (NSCLC). Flexible bronchoscopy at diagnosis revealed abnormal capillary dilation that was suggestive of endobronchial involvement at the primary tumor location. The patient developed massive hemoptysis despite of marked tumor shrinkage achieved by bevacizumab-containing chemotherapy. Emergency flexible bronchoscopy for hemoptysis suggested that the location of the primary tumor was the source of bleeding. Subsequent follow-up flexible bronchoscopy revealed an ulcerative mucosal-like lesion associated with a white necrotic substance as well as attenuation of the dilation of submucosal vessels compared with that apparent at diagnosis. Our case report highlights the potential mechanistic insights into bevacizumab-related bleeding and importance of performing bronchoscopy at diagnosis in NSCLC patients, given that abnormal bronchoscopic findings may be a risk factor for bleeding.
  • Yoshihito Kogure; Fumihiko Hirai; Takeharu Yamanaka; Kenichi Taguchi; Koji Takeda; Haruko Daga; Tatsuo Kimura; Junichi Shimizu; Kaoru Tanaka; Yasuo Iwamoto; Akira Ono; Hidefumi Sasaki; Junya Fukuoka; Kenichi Nishiyama; Takashi Seto; Yukito Ichinose; Kazuhiko Nakagawa; Yoichi Nakanishi
    JOURNAL OF THORACIC ONCOLOGY 8 22 - 22 2013年09月 [査読有り]
  • Hiromichi Matsuoka; Takayasu Kurata; Isamu Okamoto; Hiroyasu Kaneda; Kaoru Tanaka; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 31 19 E322 - E323 2013年07月 [査読有り]
  • Yoshiko Urata; Isamu Okamoto; Masayuki Takeda; Yoshihiro Hattori; Keiko Okuno; Temiko Shimada; Takayasu Kurata; Hiroyasu Kaneda; Masaki Miyazaki; Masaaki Terashima; Kaoru Tanaka; Satoshi Morita; Kazuhiko Nakagawa; Shunichi Negoro; Miyako Satouchi
    CANCER 119 12 2275 - 2281 2013年06月 [査読有り]
     
    BACKGROUND A previous phase 3 trial demonstrated noninferiority in terms of overall survival for combined S-1 (an oral fluoropyrimidine) and carboplatin compared with combined paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC). In the current study, the authors evaluated the efficacy and safety of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab in chemotherapy-naive patients with advanced nonsquamous NSCLC. METHODS Patients received carboplatin (area under the concentration-time curve, 5 mg mL-1 per minute) and bevacizumab (15mg/kg) on day 1 plus oral S-1 (80 mg/m2 per day) on days 1 through 14 every 21 days for up to 6 cycles. For patients without disease progression, S-1 and bevacizumab were continued until disease progression or unacceptable toxicity developed. RESULTS Forty-eight patients were enrolled in the phase 2 study; of these, 35 patients (72.9%) completed at least 4 cycles. Most toxicities of grade 3 were hematologic, and no increase in relative incidence associated with maintenance with S-1 and bevacizumab was observed. The objective response rate was 54.2% (95% confidence interval, 39.2%-68.6%), and the median progression-free survival was 6.8 months (95% confidence interval, 4.3-8.2 months). CONCLUSIONS The regimen of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab was active and feasible as first-line treatment for advanced nonsquamous NSCLC. Cancer 2013;119:2275-2281. (c) 2013 American Cancer Society.
  • Tanizaki Junko; Okamoto Isamu; Okabe Takafumi; Sakai Kazuko; Tanaka Kaoru; Hayashi Hidetoshi; Kaneda Hiroyasu; Takezawa Ken; Nishio Kazuto; Nakagawa Kazuhiko
    CANCER RESEARCH 73 8 2013年04月 [査読有り]
  • Hidemi Kiyota; Isamu Okamoto; Masayuki Takeda; Haruko Daga; Tateaki Naito; Masaki Miyazaki; Hideaki Okada; Hidetoshi Hayashi; Kaoru Tanaka; Masaaki Terashima; Koichi Azuma; Haruyasu Murakami; Koji Takeda; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 71 4 859 - 865 2013年04月 [査読有り]
     
    A phase I dose-escalation study was performed to investigate the safety and pharmacokinetics of the combination of S-1 and gefitinib in patients with pulmonary adenocarcinoma who had failed previous chemotherapy. Patients received gefitinib at a fixed daily oral dose of 250 mg, and S-1 was administered on days 1-14 every 21 days at doses starting at 60 mg/m(2) (level 1) and escalating to 80 mg/m(2) (level 2). The primary end point of the study was determination of the recommended dose for S-1 given in combination with a fixed dose of gefitinib. Twenty patients were enrolled in the study. Two of the first six patients at dose level 2 experienced a dose-limiting toxicity (elevation of alkaline phosphatase of grade 3 in one patient; elevations of aspartate and alanine aminotransferases of grade 3 in the other). The recommended dose was thus determined as level 2, and an additional 11 patients were assigned to this level. All observed adverse events were well managed. The response rate was 50 % (10 of 20 patients), and the median progression-free survival (PFS) and overall survival times were 10.5 and 21.2 months, respectively. In EGFR mutation-positive patients (n = 9), seven patients achieved an objective response and the median PFS was 12.4 months, whereas none with wild-type EGFR (n = 6) responded. No pharmacokinetic interaction between S-1 and gefitinib was detected. The combination of S-1 and gefitinib is well tolerated and appears to possess activity against EGFR mutation-positive NSCLC.
  • Hidetoshi Hayashi; Takayasu Kurata; Yasuhito Fujisaka; Hisato Kawakami; Kaoru Tanaka; Takafumi Okabe; Masayuki Takeda; Taroh Satoh; Koji Yoshida; Takuya Tsunoda; Tokuzo Arao; Kazuto Nishio; Kazuhiko Nakagawa
    CANCER SCIENCE 104 1 98 - 104 2013年01月 [査読有り]
     
    OTS11101 is a novel peptide vaccine that acts as an angiogenesis inhibitor by inducing cytotoxic T lymphocyte (CTL) cells that specifically target vascular endothelial cells expressing vascular endothelial growth factor (VEGF) receptor 1. We conducted a phase I study to evaluate the safety, tolerability, maximum tolerated dose, and pharmacodynamic biomarker status of this vaccine. Nine patients with advanced solid tumors received 1.0, 2.0, or 3.0 similar to mg of OTS11101 subcutaneously, once a week in a 28-day cycle. Three patients experienced grade 1 injection site reactions, which were the most frequent adverse events. Grade 2 proteinuria and hypertension each occurred in one patient. As other toxicities were generally mild, the maximum tolerated dose was not reached. Furthermore, we explored the induction of specific activated CTLs, and biomarkers related to angiogenesis. A pharmacodynamics study revealed that induction of specific CTLs was observed for a dose of 2.0 and 3.0 similar to mg. The serum concentrations of soluble VEGF receptor 1 and 2 after vaccination increased significantly compared with baseline. A microarray was performed to give a comprehensive analysis of gene expression, suggesting that OTS11101 vaccination resulted in T cell activation in a clinical setting. In conclusion, OTS11101 was well tolerated in patients up to 3.0 similar to mg once weekly and our biomarker analysis suggested that this anti-angiogenesis vaccine is biologically active. (Cancer Sci 2013; 104: 98104)
  • Hidetoshi Hayashi; Takayasu Kurata; Yasuhito Fujisaka; Hisato Kawakami; Kaoru Tanaka; Takafumi Okabe; Masayuki Takeda; Taroh Satoh; Koji Yoshida; Takuya Tsunoda; Tokuzo Arao; Kazuto Nishio; Kazuhiko Nakagawa
    Cancer science 104 1 98 - 104 2013年01月 [査読有り]
     
    OTS11101 is a novel peptide vaccine that acts as an angiogenesis inhibitor by inducing cytotoxic T lymphocyte (CTL) cells that specifically target vascular endothelial cells expressing vascular endothelial growth factor (VEGF) receptor 1. We conducted a phase I study to evaluate the safety, tolerability, maximum tolerated dose, and pharmacodynamic biomarker status of this vaccine. Nine patients with advanced solid tumors received 1.0, 2.0, or 3.0 mg of OTS11101 subcutaneously, once a week in a 28-day cycle. Three patients experienced grade 1 injection site reactions, which were the most frequent adverse events. Grade 2 proteinuria and hypertension each occurred in one patient. As other toxicities were generally mild, the maximum tolerated dose was not reached. Furthermore, we explored the induction of specific activated CTLs, and biomarkers related to angiogenesis. A pharmacodynamics study revealed that induction of specific CTLs was observed for a dose of 2.0 and 3.0 mg. The serum concentrations of soluble VEGF receptor 1 and 2 after vaccination increased significantly compared with baseline. A microarray was performed to give a comprehensive analysis of gene expression, suggesting that OTS11101 vaccination resulted in T cell activation in a clinical setting. In conclusion, OTS11101 was well tolerated in patients up to 3.0 mg once weekly and our biomarker analysis suggested that this anti-angiogenesis vaccine is biologically active.
  • Junko Tanizaki; Isamu Okamoto; Takafumi Okabe; Kazuko Sakai; Kaoru Tanaka; Hidetoshi Hayashi; Hiroyasu Kaneda; Ken Takezawa; Kiyoko Kuwata; Haruka Yamaguchi; Erina Hatashita; Kazuto Nishio; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 18 22 6219 - 6226 2012年11月 [査読有り]
     
    Purpose: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib show marked efficacy in patients with non-small cell lung cancer positive for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown. Experimental Design: We established lines of EML4-ALK-positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay. We isolated EML4-ALK-positive lung cancer cells (K-3) from a patient who developed resistance to crizotinib and investigated their characteristics. Results: The expression of EML4-ALK was reduced at the transcriptional level, whereas phosphorylation of epidermal growth factor receptor (EGFR), HER2, and HER3 was upregulated, in H3122/TR cells compared with those in H3122 cells. This activation of HER family proteins was accompanied by increased secretion of EGF. Treatment with an EGFR-TKI induced apoptosis in H3122/TR cells, but not in H3122 cells. The TAE684-induced inhibition of extracellular signal-regulated kinase (ERK) and STAT3 phosphorylation observed in parental cells was prevented by exposure of these cells to exogenous EGF, resulting in a reduced sensitivity of cell growth to TAE684. K-3 cells also manifested HER family activation accompanied by increased EGF secretion. Conclusions: EGF-mediated activation of HER family signaling is associated with ALK-TKI resistance in lung cancer positive for EML4-ALK. Clin Cancer Res; 18(22); 6219-26. (C)2012 AACR.
  • Hiroyasu Kaneda; Shinya Ueda; Chihiro Makimura; Hidemi Kiyota; Hisato Kawakami; Isamu Okamoto; Kaoru Tanaka; Shinichi Nishina; Toshihiro Kudo; Junji Turutani; Masaki Miyazaki; Yasuhito Fujisaka; Wataru Okamoto; Takayasu Kurata; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 23 65 - 65 2012年06月 [査読有り]
  • Shinya Ueda; Hisato Kawakami; Wataru Okamoto; Shinichi Nishina; Toshihiro Kudo; Chihiro Makimura; Hidemi Kiyota; Kaoru Tanaka; Hiroyasu Kaneda; Yasuhito Fujisaka; Masaki Miyazaki; Junji Turutani; Isamu Okamoto; Takayasu Kurata; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 23 65 - 65 2012年06月 [査読有り]
  • Matsuoka H; Arao T; Makimura C; Takeda M; Kiyota H; Tsurutani J; Fujita Y; Matsumoto K; Kimura H; Otsuka M; Koyama A; Imamura CK; Tanigawara Y; Yamanaka T; Tanaka K; Nishio K; Nakagawa K
    Oncology reports 27 5 1393 - 1399 2012年05月 [査読有り]
     
    Genetic differences in individuals with regard to opioid-receptor signaling create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic and predictive biomarkers are needed. In this prospective study, we studied gene expression changes in peripheral blood leukocytes using a microarray and real-time RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect of morphine in a cohort of opioid-treatment-naive cancer patients. We also examined genetic variations in opioid receptor mu 1 (OPRMI, 118A -> G) and catechol-O-methyltransferase (COMT, 472G -> A) to evaluate predictive biomarkers of the treatment outcome of morphine. The plasma concentration of morphine was measured using a liquid chromatography-tandem mass spectrometry method. Microarray analysis revealed that the m RNA expression levels of arrestin beta 1 (ARRB1) were significantly down-regulated by morphine treatment. Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003) and changes during treatment were negatively correlated with the plasma morphine concentration (R=-0.42). No correlation was observed between the genotype of OPRMI and morphine treatrnent; however, the plasma concentration of morphine and the required dose of morphine were significantly lower for the A/A genotype of COMT (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1 may be a novel pharmacodynamic biomarker and the COMT 472G -> A genotype may be a predictive biomarker of the response to morphine treatment.
  • Hiroyasu Kaneda; Yoshiko Urata; Isamu Okamoto; Yoshihiro Hattori; Keiko Okuno; Temiko Shimada; Masayuki Takeda; Takayasu Kurata; Masaki Miyazaki; Masaaki Terashima; Kaoru Tanaka; Hidemi Kiyota; Hidetoshi Hayashi; Toshihiro Kudo; Takafumi Okabe; Koichi Azuma; Satoshi Morita; Kazuhiko Nakagawa; Shunichi Negoro; Miyako Satouchi
    JOURNAL OF CLINICAL ONCOLOGY 30 15 2012年05月 [査読有り]
  • Masayuki Takeda; Isamu Okamoto; Kazuko Sakai; Kaoru Tanaka; Masaaki Terashima; Kazuto Nishio; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 13 2 157 - 158 2012年03月 [査読有り]
  • Satoru Hagiwara; Toshiharu Sakurai; Shinichi Nishina; Kaoru Tanaka; Masafumi Ikeda; Kazuomi Ueshima; Yasunori Minami; Tatsuo Inoue; Norihisa Yada; Satoshi Kitai; Masahiro Takita; Tomoyuki Nagai; Sousuke Hayaishi; Tadaaki Arizumi; Ah-Mee Park; Hiroshi Munakata; Naoshi Nishida; Masatoshi Kudo
    DIGESTIVE DISEASES 30 6 541 - 546 2012年 [査読有り]
     
    Objective: A number of studies have reported reactivation of hepatitis B during intensive immunosuppressive therapy such as cases of hematological malignancy, whereas little has been reported for characteristics of reactivation triggered by chemotherapy for solid cancer. Methods: A total of 130 patients underwent chemotherapy for treatments of common solid cancer between May 2011 and May 2012 at Kinki University Hospital. Among them, 27 patients were suspected for a past infection of hepatitis B virus (HBV), showing positive for hepatitis B core antibody or surface antibody but negative for hepatitis B surface antigen, and were eligible for this study. Results: Hepatitis B reactivation was observed in 2 of 27 cases (7.4%). The duration between the start of chemotherapy and increase of serum HBV load was 30 days in both cases. Conclusions: We reported the 2 cases of hepatitis B reactivation receiving chemotherapy for solid cancer in terms of patterns and characteristics of reactivation. Accumulation of such cases will help in clarifying the clinical importance of hepatitis B reactivation during treatment of solid malignancies. Copyright (C) 2012 S. Karger AG, Basel
  • Kaoru Tanaka; Tokuzo Arao; Daisuke Tamura; Keiichi Aomatsu; Kazuyuki Furuta; Kazuko Matsumoto; Hiroyasu Kaneda; Kanae Kudo; Yoshihiko Fujita; Hideharu Kimura; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    PLOS ONE 7 1 e27922  2012年01月 [査読有り]
     
    SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly posttranslational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand-glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.
  • Makimura C; Arao T; Matsuoka H; Takeda M; Kiyota H; Tsurutani J; Fujita Y; Matsumoto K; Kimura H; Otsuka M; Koyama A; Imamura CK; Yamanaka T; Tanaka K; Nishio K; Nakagawa K
    Anticancer research 31 12 4561 - 4568 2011年12月 [査読有り]
     
    Cytokine signaling is involved in pain and opioid-receptor signaling. In this prospective study, we studied the plasma cytokine levels in order to identify candidate biomarkers for predicting resistance to morphine treatment in a cohort of opioid-treatment-naïve cancer patients. We analyzed pain rating and the plasma concentrations of 26 cytokines at baseline and after morphine treatment using a multiplex immunoassay system for the following cytokines: eotaxin, colony stimulating factor, granulocyte (G-CSF), colony stimulating factor granulocyte-macrophage (GM-CSF), interferon α2 (IFN-α2), IFN-γ, interleukin 1α (IL-1α), IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, tumor necrosis factor-α (TNF-α) and TNF-β. No correlation was observed between the clinical characteristics and the numerical rating scale for pain at baseline or among patients who developed resistance to morphine treatment. Interestingly, the plasma concentration of MIP-1α significantly decreased during morphine treatment (day 8 vs. baseline, p=0.03). Regarding the baseline plasma cytokine concentrations, none of the cytokine levels were correlated with the numerical rating scale for pain at baseline; however, the baseline plasma concentrations of eotaxin, IL-8, IL-12 (p40), IL-12 (p70), MIP-1α and MIP-1β were significantly lower in patients who required a high dose of morphine or who developed resistance to morphine treatment. In conclusion, this is the first report revealing that the plasma concentrations of several cytokines were significantly modulated during treatment and were correlated with treatment outcome of morphine. Our results suggest that plasma cytokine levels may be promising biomarkers for morphine treatment and that they warrant further study.
  • H. Kaneda; T. Arao; K. Matsumoto; M. A. De Velasco; D. Tamura; K. Aomatsu; K. Kudo; K. Sakai; T. Nagai; Y. Fujita; K. Tanaka; K. Yanagihara; Y. Yamada; I. Okamoto; K. Nakagawa; K. Nishio
    BRITISH JOURNAL OF CANCER 105 8 1210 - 1217 2011年10月 
    BACKGROUND: Activin A is a multi-functional cytokine belonging to the transforming growth factor-beta (TGF-beta) superfamily; however, the effect of activin A on angiogenesis remains largely unclear. We found that inhibin beta A subunit (INHBA) mRNA is overexpressed in gastric cancer (GC) specimens and investigated the effect of activin A, a homodimer of INHBA, on angiogenesis in GC. METHODS: Anti-angiogenic effects of activin A via p21 induction were evaluated using human umbilical vein endothelial cells (HUVECs) in vitro and a stable INHBA-introduced GC cell line in vivo. RESULTS: Compared with TGF-beta, activin A potently inhibited the cellular proliferation and tube formation of HUVECs with induction of p21. A promoter assay and a chromatin immunoprecipitation assay revealed that activin A directly regulates p21 transcriptional activity through Smads. Stable p21-knockdown significantly enhanced the cellular proliferation of HUVECs. Notably, stable p21-knockdown exhibited a resistance to activin-mediated growth inhibition in HUVECs, indicating that p21 induction has a key role on activin A-mediated growth inhibition in vascular endothelial cells. Finally, a stable INHBA-introduced GC cell line exhibited a decrease in tumour growth and angiogenesis in vivo. CONCLUSION: Our findings highlight the suppressive role of activin A, unlike TGF-beta, on tumour growth and angiogenesis in GC. British Journal of Cancer (2011) 105, 1210-1217. doi:10.1038/bjc.2011.348 www.bjcancer.com Published online 6 September 2011 (C) 2011 Cancer Research UK
  • Wataru Okamoto; Isamu Okamoto; Kaoru Tanaka; Tokuzo Arao; Kazuto Nishio; Masahiro Fukuoka; Pasi Janne; Kazuhiko Nakagawa
    CANCER RESEARCH 71 2011年04月 [査読有り]
  • Aomatsu K; Arao T; Sugioka K; Matsumoto K; Tamura D; Kudo K; Kaneda H; Tanaka K; Fujita Y; Shimomura Y; Nishio K
    Investigative ophthalmology & visual science 52 5 2437 - 2443 2011年04月 [査読有り]
     
    PURPOSE. The aim of this study was to investigate the expression changes of epithelial mesenchymal transition (EMT)-related molecules induced by TGF-beta signaling in a human corneal epithelial cell line (HCECs). METHODS. The cellular response to TGF-beta was evaluated by immunoblotting, quantitative real-time RT-PCR, and immunofluorescence microscopy in HCECs. RESULTS. TGF-beta significantly increased mRNA expression of SNAI1, SNAI2, VIM, and FN1, but not TWIST1 through Smad and non-Smad pathways in HCECs. Protein expression of a mesenchymal marker N-cadherin was dose-dependently increased and that of an epithelial marker of E-cadherin was decreased by TGF-beta. TGF-beta, but not EGF, mediated the EMT-like morphologic changes. Both TGF-beta and EGF were capable of upregulating SNAI1 and SNAI2 by about two-fold within a short response time. However, a detailed time course analysis revealed drastically different expression patterns, with TGF-beta mediating a sustained upregulation of SNAI1 and SNAI2 for at least for 6 days and EGF allowing a return to the baseline expression values after 8 similar to 12 h. These data indicate that TGF-beta, but not EGF, induces sustained upregulation of SNAI1 and SNAI2 in HCECs. CONCLUSIONS. TGF-beta induces sustained upregulation of SNAI1 and SNAI2 through Smad and non-Smad pathways, EMT-like morphologic changes, downregulation of E-cadherin, and upregulation of N-cadherin in HCECs. The authors' findings provide insight into the TGF-beta signaling and the temporal expression patterns of EMT-inducible transcription factors in HCECs. (Invest Ophthalmol Vis Sci. 2011; 52: 2437-2443) DOI: 10.1167/iovs.10-5635
  • Kanae Kudo; Tokuzo Arao; Kaoru Tanaka; Tomoyuki Nagai; Kazuyuki Furuta; Kazuko Sakai; Hiroyasu Kaneda; Kazuko Matsumoto; Daisuke Tamura; Keiichi Aomatsu; Marco A. De Velasco; Yoshihiko Fujita; Nagahiro Saijo; Masatoshi Kudo; Kazuto Nishio
    CLINICAL CANCER RESEARCH 17 6 1373 - 1381 2011年03月 
    Purpose: BIBF 1120 is a potent, orally available triple angiokinase inhibitor that inhibits VEGF receptors (VEGFR) 1, 2, and 3, fibroblast growth factor receptors, and platelet-derived growth factor receptors. This study examined the antitumor effects of BIBF 1120 on hepatocellular carcinoma (HCC) and attempted to identify a pharmacodynamic biomarker for use in early clinical trials. Experimental Design: We evaluated the antitumor and antiangiogenic effects of BIBF 1120 against HCC cell line both in vitro and in vivo. For the pharmacodynamic study, the phosphorylation levels of VEGFR2 in VEGF-stimulated peripheral blood leukocytes (PBL) were evaluated in mice inoculated with HCC cells and treated with BIBF 1120. Results: BIBF 1120 (0.01 mu mol/L) clearly inhibited the VEGFR2 signaling in vitro. The direct growth inhibitory effects of BIBF 1120 on four HCC cell lines were relatively mild in vitro (IC50 values: 2-5 mu mol/L); however, the oral administration of BIBF 1120 (50 or 100 mg/kg/d) significantly inhibited the tumor growth and angiogenesis in a HepG2 xenograft model. A flow cytometric analysis revealed that BIBF 1120 significantly decreased the phosphotyrosine (pTyr) levels of VEGFR2(+)CD45(dim) PBLs and the percentage of VEGFR2(+)pTyr(+) PBLs in vivo; the latter parameter seemed to be a more feasible pharmacodynamic biomarker. Conclusions: We found that BIBF 1120 exhibited potent antitumor and antiangiogenic activity against HCC and identified VEGFR2(+)pTyr(+) PBLs as a feasible and noninvasive pharmacodynamic biomarker in vivo. Clin Cancer Res; 17(6); 1373-81. (C)2010 AACR.
  • Kanae Kudo; Tokuzo Arao; Kaoru Tanaka; Tomoyuki Nagai; Kazuyuki Furuta; Kazuko Sakai; Hiroyasu Kaneda; Kazuko Matsumoto; Daisuke Tamura; Keiichi Aomatsu; Marco A. De Velasco; Yoshihiko Fujita; Nagahiro Saijo; Masatoshi Kudo; Kazuto Nishio
    CLINICAL CANCER RESEARCH 17 6 1373 - 1381 2011年03月 [査読有り]
     
    Purpose: BIBF 1120 is a potent, orally available triple angiokinase inhibitor that inhibits VEGF receptors (VEGFR) 1, 2, and 3, fibroblast growth factor receptors, and platelet-derived growth factor receptors. This study examined the antitumor effects of BIBF 1120 on hepatocellular carcinoma (HCC) and attempted to identify a pharmacodynamic biomarker for use in early clinical trials. Experimental Design: We evaluated the antitumor and antiangiogenic effects of BIBF 1120 against HCC cell line both in vitro and in vivo. For the pharmacodynamic study, the phosphorylation levels of VEGFR2 in VEGF-stimulated peripheral blood leukocytes (PBL) were evaluated in mice inoculated with HCC cells and treated with BIBF 1120. Results: BIBF 1120 (0.01 mu mol/L) clearly inhibited the VEGFR2 signaling in vitro. The direct growth inhibitory effects of BIBF 1120 on four HCC cell lines were relatively mild in vitro (IC50 values: 2-5 mu mol/L); however, the oral administration of BIBF 1120 (50 or 100 mg/kg/d) significantly inhibited the tumor growth and angiogenesis in a HepG2 xenograft model. A flow cytometric analysis revealed that BIBF 1120 significantly decreased the phosphotyrosine (pTyr) levels of VEGFR2(+)CD45(dim) PBLs and the percentage of VEGFR2(+)pTyr(+) PBLs in vivo; the latter parameter seemed to be a more feasible pharmacodynamic biomarker. Conclusions: We found that BIBF 1120 exhibited potent antitumor and antiangiogenic activity against HCC and identified VEGFR2(+)pTyr(+) PBLs as a feasible and noninvasive pharmacodynamic biomarker in vivo. Clin Cancer Res; 17(6); 1373-81. (C)2010 AACR.
  • Kunio Okamoto; Isamu Okamoto; Wataru Okamoto; Kaoru Tanaka; Ken Takezawa; Kiyoko Kuwata; Haruka Yamaguchi; Kazuto Nishio; Kazuhiko Nakagawa
    CANCER RESEARCH 70 24 10402 - 10410 2010年12月 [査読有り]
     
    The molecular mechanism by which epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) induce apoptosis in non-small cell-lung cancer (NSCLC) cells that are positive for activating mutations of the EGFR remains unclear. In this study, we report the effects of the EGFR-TKI gefitinib on expression of the antiapoptotic protein survivin that have functional consequences in EGFR mutation-positive NSCLC cells. Immunoblot analysis revealed that gefitinib downregulated survivin expression, likely through inhibition of the PI3K-AKT signaling pathway, in NSCLC cells positive for EGFR mutation. Stable overexpression of survivin attenuated gefitinib-induced apoptosis and also inhibited the antitumor effect of gefitinib in human tumor xenografts. Furthermore, the combination of survivin overexpression with inhibition of the gefitinib-induced upregulation of the proapoptotic protein BIM attenuated gefitinib-induced apoptosis to a greater extent than either approach alone. Our results indicate that downregulation of survivin plays a pivotal role in gefitinib-induced apoptosis in EGFR mutation-positive NSCLC cells. Furthermore, they suggest that simultaneous interruption of the PI3K-AKT-survivin and MEK-ERK-BIM signaling pathways is responsible for EGFR-TKI-induced apoptotic death in these cells. Cancer Res; 70(24); 10402-10. (C)2010 AACR.
  • Junji Tsurutani; Kunio Okamoto; Chihior Makimura; Koichi Azuma; Masayuki Takeda; Ken Takezawa; Wataru Okamoto; Hidemi Kiyota; Hidetoshi Hayashi; Kaoru Tanaka; Junko Tanizaki; Isamu Okamoto; Nagahiro Saijoh; Masahiro Fukuoka; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 21 38 - 39 2010年11月 [査読有り]
  • Ken Takezawa; Isamu Okamoto; Kaoru Tanaka; Hidetoshi Hayashi; Kunio Okamoto; Kimio Yonesaka; Masahiro Fukuoka; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 21 20 - 20 2010年11月 [査読有り]
  • Kunio Okamoto; Isamu Okamoto; Ken Takezawa; Kaoru Tanaka; Junko Tanizaki; Chihiro Makimura; Hidetoshi Hayashi; Izumi Tachibana; Yasumasa Nishimura; Masahiro Fukuoka; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 21 27 - 27 2010年11月 [査読有り]
  • Hidetoshi Hayashi; Isamu Okamoto; Masaki Miyazaki; Yasuko Ichikawa; Hiroshige Yoshioka; Kei Kunimasa; Kaoru Tanaka; Kunio Okamoto; Chihiro Makimura; Masahiro Iwasaku; Akihiro Nisiyama; Yohhei Korogi; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 21 26 - 26 2010年11月 [査読有り]
  • Wataru Okamoto; Isamu Okamoto; Kaoru Tanaka; Erina Hatashita; Yuki Yamada; Kiyoko Kuwata; Haruka Yamaguchi; Tokuzo Arao; Kazuto Nishio; Masahiro Fukuoka; Pasi A. Jaenne; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 10 2785 - 2792 2010年10月 [査読有り]
     
    Most non-small cell lung cancer (NSCLC) tumors with an activating mutation of the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (TKI) such as gefitinib but ultimately develop resistance to these drugs. Hepatocyte growth factor (HGF) induces EGFR-TKI resistance in NSCLC cells with such a mutation. We investigated strategies to overcome gefitinib resistance induced by HGF. Human NSCLC cells with an activating EGFR mutation (HCC827 cells) were engineered to stably express HGF (HCC827-HGF cells). HCC827-HGF cells secreted large amounts of HGF and exhibited resistance to gefitinib in vitro to an extent similar to that of HCC827 GR cells, in which the gene for the HGF receptor MET is amplified. A MET-TKI reversed gefitinib resistance in HCC827-HGF cells as well as in HCC827 GR cells, suggesting that MET activation induces gefitinib resistance in both cell lines. TAK-701, a humanized monoclonal antibody to HGF, in combination with gefitinib inhibited the phosphorylation of MET, EGFR, extracellular signal-regulated kinase, and AKT in HCC827-HGF cells, resulting in suppression of cell growth and indicating that autocrine HGF-MET signaling contributes to gefitinib resistance in these cells. Combination therapy with TAK-701 and gefitinib also markedly inhibited the growth of HCC827-HGF tumors in vivo. The addition of TAK-701 to gefitinib is a promising strategy to overcome EGFR-TKI resistance induced by HGF in NSCLC with an activating EGFR mutation. Mol Cancer Ther; 9(10); 2785-92. (C) 2010 AACR.
  • Daisuke Tamura; Tokuzo Arao; Kaoru Tanaka; Hiroyasu Kaneda; Kazuko Matsumoto; Kanae Kudo; Keiichi Aomatsu; Yoshihiko Fujita; Takashi Watanabe; Nagahiro Saijo; Yoshikazu Kotani; Yoshihiro Nishimura; Kazuto Nishio
    CANCER SCIENCE 101 6 1403 - 1408 2010年06月 [査読有り]
     
    Bortezomib, a selective 26S proteasome inhibitor, has shown clinical benefits against refractory multiple myeloma. The indirect anti-angiogenic activity of bortezomib has been widely recognized; however, the growth-inhibitory mechanism of bortezomib on vascular endothelial cells remains unclear, especially on the cell cycle. Here, we showed that bortezomib (2 nM of the IC(50) value) potently inhibited the cellular growth of human umbilical vascular endothelial cells (HUVECs) via a vascular endothelial growth factor receptor (VEGFR)-independent mechanism resulting in the induction of apoptosis. Bortezomib significantly increased the vascular permeability of HUVECs, whereas a VEGFR-2 tyrosine kinase inhibitor decreased it. Interestingly, a cell cycle analysis using flow cytometry, the immunostaining of phospho-histone H3, and Giemsa staining revealed that bortezomib suppressed the G2/M transition of HUVECs, whereas the mitotic inhibitor paclitaxel induced M-phase accumulation. A further analysis of cell cycle-related proteins revealed that bortezomib increased the expression levels of cyclin B1, the cdc2/cyclin B complex, and the phosphorylation of all T14, Y15, and T161 residues on cdc2. Bortezomib also increased the ubiquitination of cyclin B1 and wee1, but inhibited the kinase activity of the cdc2/cyclin B complex. These protein modifications support the concept that bortezomib suppresses the G2/M transition, rather than causing M-phase arrest. In conclusion, we demonstrated that bortezomib potently inhibits cell growth by suppressing the G2/M transition, modifying G2/M-phase-related cycle regulators, and increasing the vascular permeability of vascular endothelial cells. Our findings reveal a cell cycle-related mode of action and strongly suggest that bortezomib exerts an additional unique vascular disrupting effect as a vascular targeting drug. (Cancer Sci 2010).
  • Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Kazuko Sakai; Marco Antonio De Velasco; Kazuko Matsumoto; Fujita Yoshihiko; Yasuhide Yamada; Junji Tsurutani; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio; Tomoyuki Nagai; Kazuyuki Furuta
    CANCER RESEARCH 70 2010年04月 [査読有り]
  • Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Kazuko Sakai; Marco A. De Velasco; Kazuko Matsumoto; Yoshihiko Fujita; Yasuhide Yamada; Junji Tsurutani; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    CANCER RESEARCH 70 5 2053 - 2063 2010年03月 [査読有り]
     
    Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family, and it has recently been proposed to participate in gastric acid secretion and mucin gene expression in mice. However, the role of FOXQ1 in humans and especially in cancer cells remains unknown. We found that FOXQ1 mRNA is overexpressed in clinical specimens of colorectal cancer (CRC; 28-fold/colonic mucosa). A microarray analysis revealed that the knockdown of FOXQ1 using small interfering RNA resulted in a decrease in p21(CIP1/WAF1) expression, and a reporter assay and a chromatin immunoprecipitation assay showed that p21 was one of the target genes of FOXQ1. Stable FOXQ1-overexpressing cells (H1299/FOXQ1) exhibited elevated levels of p21 expression and inhibition of apoptosis induced by doxorubicin or camptothecin. Although cellular proliferation was decreased in H1299/FOXQ1 cells in vitro, H1299/FOXQ1 cells significantly increased tumorigenicity [ enhanced green fluorescent protein (EGFP): 2/15, FOXQ1: 7/15] and enhanced tumor growth (437 +/- 301 versus 1735 +/- 769 mm(3), P < 0.001) in vivo. Meanwhile, stable p21 knockdown of H1299/FOXQ1 cells increased tumor growth, suggesting that FOXQ1 promotes tumor growth independent of p21. Microarray analysis of H1299/EGFP and H1299/FOXQ1 revealed that FOXQ1 overexpression upregulated several genes that have positive roles for tumor growth, including VEGFA, WNT3A, RSPO2, and BCL11A. CD31 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining of the tumor specimens showed that FOXQ1 overexpression mediated the angiogenic and antiapoptotic effect in vivo. In conclusion, FOXQ1 is overexpressed in CRC and enhances tumorigenicity and tumor growth presumably through its angiogenic and antiapoptotic effects. Our findings show that FOXQ1 is a new member of the cancer-related FOX family. Cancer Res; 70(5); 2053-63. (C) 2010 AACR.
  • 胃がんに対する分子標的治療
    田中 薫; 佐藤 太郎
    腫瘍内科 4 6 506 - 511 2009年12月
  • Kazuko Matsumoto; Tokuzo Arao; Kaoru Tanaka; Hiroyasu Kaneda; Kanae Kudo; Yoshihiko Fujita; Daisuke Tamura; Keiichi Aomatsu; Tomohide Tamura; Yasuhide Yamada; Nagahiro Saijo; Kazuto Nishio
    CANCER RESEARCH 69 18 7160 - 7164 2009年09月 [査読有り]
     
    The underlying mechanism regulating the expression of the cancer stem cell/tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. Here, we found that the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA and protein levels in a CD133-overexpressing cancer cell line. This effect was canceled by a rapamycin-competitor, tacrolimus, and was not modified by conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1 alpha (HIF-1 alpha), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1 alpha. Hypoxic conditions up-regulated HIF-1 alpha expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1 alpha activator deferoxamine mesylate dose-dependently down-regulated CD133 expression, consistent with the effects of hypoxic conditions. Finally, the correlations between CD133 and the expressions of HIF-1 alpha and HIF-1 beta were examined using clinical gastric cancer samples. A strong inverse correlation (r = -0.68) was observed between CD133 and HIF-1 alpha, but not between CD133 and HIF-1 beta. In conclusion, these results indicate that HIF-1 alpha down-regulates CD133 expression and suggest that mTOR signaling is involved in the expression of CD133 in cancer cells. Our findings provide a novel insight into the regulatory mechanisms of CD133 expression via mTOR signaling and HIF-1 alpha in cancer cells and might lead to insights into the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in the maintenance of stemness in cancer stem cells. [Cancer Res 2009;69(1,8):7 7160-4]
  • Daisuke Tamura; Tokuzo Arao; Kaoru Tanaka; Yasuhiro Kaneda; Kazuko Matsumoto; Kanae Kudo; Keiichi Aomatsu; Mari Maegawa; Yoshihiko Fujita; Takashi Watanabe; Yoshikazu Kotani; Yoshihiro Nishimura; Kazuto Nishio
    CANCER RESEARCH 69 2009年05月 [査読有り]
  • Kaoru Tanaka; Tokuzo Arao; Mari Maegawa; Kazuko Matsumoto; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Hiroyasu Kaneda; Yoshihiko Fujita; Eiko Honda; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    CANCER RESEARCH 69 2009年05月 [査読有り]
  • Kanae Kudo; Tokuzo Arao; Kaoru Tanaka; Hiroyasu Kaneda; Mari Maegawa; Kazuko Matsumoto; Daisuke Tamura; Keiichi Aomatsu; Yoshihiko Fujita; Masatoshi Kudo; Kazuto Nishio
    CANCER RESEARCH 69 2009年05月 [査読有り]
  • Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Mari Maegawa; Kazuko Matsumoto; Kanae Kudo; Daisuke Tamura; Keiichi Aomatsu; Yoshihiko Fujita; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    CANCER RESEARCH 69 2009年05月 [査読有り]
  • Yoshihiko Fujita; Kazuko Matsumoto; Kaoru Tanaka; Hiroyasu Kaneda; Kanae Kudo; Mari Maegawa; Daisuke Tamura; Keiichi Aomatsu; Marco DeVelasco; Tokuzo Arao; Kazuto Nishio
    CANCER RESEARCH 69 2009年05月 [査読有り]
  • Kazuko Matsumoto; Tokuzo Arao; Kaoru Tanaka; Hiroyasu Kaneda; Kanae Kudo; Mari Maegawa; Daisuke Tamura; Keiichi Aomatsu; Yoshihiko Fujita; Yasuhide Yamada; Kazuto Nishio
    CANCER RESEARCH 69 2009年05月 [査読有り]
  • Mari Maegawa; Tokuzo Arao; Hideyuki Yokote; Kazuko Matsumoto; Kanae Kudo; Kaoru Tanaka; Hiroyasu Kaneda; Yoshihiko Fujita; Fumiaki It; Kazuto Nishio
    ANTICANCER RESEARCH 29 4 1111 - 1117 2009年04月 [査読有り]
     
    Background: DelE746_A750-type EGFR is a constitutively active type of mutation that enhances EGFR signaling. However, the changes in gene expression that occur in mutant EGFR-harboring cells has not been fully studied. Materials and Methods: A gene expression analysis of HEK293 cells transfected with wild-type or mutant EGFR was performed focusing on the significant gene. Results: Early growth response 1 (EGR1), a transcription factor, was the most strongly up-regulated gene in mutant EGFR-transfected cells among the genes examined. An increase in EGR1 expression in the mutant EGFR cells was confirmed using RTPCR or immunoblotting. The expression was up-regulated by EGF stimulation and down-regulated by EGFR-tyrosine kinase inhibitor. In addition, the MEK inhibitor U0126 inhibited EGR1 expression, while the phosphatidylinositol 3-kinase inhibitor LY294002 did not. Conclusion: Mutant EGFR constitutively up-regulates EGR1 through the ERK pathway, and its expression is correlated with EGFR signal activation. Findings provide an insight into a target gene of mutant EGFR and further improve the understanding of the oncogenic properties of EGFR.
  • Kaoru Tanaka; Tokuzo Arao; Mari Maegawa; Kazuko Matsumoto; Hiroyasu Kaneda; Kanae Kudo; Yoshihiko Fujita; Hideyuki Yokote; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    INTERNATIONAL JOURNAL OF CANCER 124 5 1072 - 1080 2009年03月 [査読有り]
     
    SRPX2 (Sushi repeat containing protein, X-linked 2) was first identified as a downstream molecule of the E2A-HLF fusion gene in t(17;19)-positive leukemia cells and the biological function of this gene remains unknown. We found that SRPX2 is overexpressed in gastric cancer and the expression and clinical features showed that high mRNA expression levels were observed in patients with unfavorable outcomes using real-time RT-PCR. The cellular distribution of SRPX2 protein showed the secretion of SRPX2 into extracellular regions and its localization in the cytoplasm. The introduction of the SRPX2 gene into HEK293 cells did not modulate the cellular proliferative activity but did enhance the cellular migration activity, as shown using migration and scratch assays. The conditioned-medium obtained from SRPX2-overexpressing cells increased the cellular migration activity of a gastric cancer cell line, SNU-16. In addition, SRPX2 protein remarkably enhanced the cellular adhesion of SNU-16 and HSC-39 and increased the phosphorylation levels of focal adhesion kinase (FAK), as shown using western blotting, suggesting that SRPX2 enhances cellular migration and adhesion through FAK signaling. In conclusion, the overexpression of SRPX2 enhances cellular migration and adhesion in gastric cancer cells. Here, we report that the biological functions of SRPX2 include cellular migration and adhesion to cancer cells. (c) 2008 Wiley-Liss, Inc.
  • Mari Maegawa; Tokuzo Arao; Hideyuki Yokote; Kazuko Matsumoto; Kanae Kudo; Kaoru Tanaka; Hiroyasu Kaneda; Yoshihiko Fujita; Fumiaki Ito; Kazuto Nishio
    CANCER SCIENCE 100 3 552 - 557 2009年03月 [査読有り]
     
    Constitutively active mutations of epidermal growth factor receptor (EGFR) (delE746_A750) activate downstream signals, such as ERK and Akt, through the phosphorylation of tyrosine residues in the C-terminal region of EGFR. These pathways are thought to be important for cellular sensitivity to EGFR tyrosine kinase inhibitors (TKI). To examine the correlation between phosphorylation of the tyrosine residues in the C-terminal region of EGFR and cellular sensitivity to EGFR TKI, we used wild-type (wt) EGFR, as well as the following constructs: delE746_A750 EGFR; delE746_A750 EGFR with substitution of seven tyrosine residues to phenylalanine in the C-terminal region; and delE746_A750 EGFR with a C-terminal truncation at amino acid 980. These constructs were transfected stably into HEK293 cells and designated HEK293/Wt, HEK293/D, HEK293/D7F, and HEK293/D-Tr, respectively. The HEK293/D cells were found to be 100-fold more sensitive to EGFR TKI (AG1478) than HEK293/Wt. Surprisingly, the HEK293/D7F and HEK293/D-Tr cells, transfected with EGFR lacking the C-terminal autophosphorylation sites, retained high sensitivity to EGFR TKI. In these three high-sensitivity cells, the ERK pathway was activated without ligand stimulation, which was inhibited by EGFR TKI. In addition, although EGFR in the HEK293/D7F and HEK293/D-Tr cells lacked significant tyrosine residues for EGFR signal transduction, phosphorylation of Src homology and collagen homology (Shc) was spontaneously activated in these cells. Our results indicate that tyrosine residues in the C-terminal region of EGFR are not required for cellular sensitivity to EGFR TKI, and that an as-yet-unknown signaling pathway of EGFR may exist that is independent of the C-terminal region of EGFR. (Cancer Sci 2009; 100: 552-557).
  • Kazuko Matsumoto; Hideyuki Yokote; Tokuzo Arao; Mari Maegawa; Kaoru Tanaka; Yoshihiko Fujita; Chikako Shimizu; Toshiaki Hanafusa; Yasuhiro Fujiwara; Kazuto Nishio
    CANCER SCIENCE 99 8 1611 - 1617 2008年08月 [査読有り]
     
    The glycosylation of cell surface proteins is important for cancer biology processes such as cellular proliferation or metastasis. alpha 1,6-Fucosyltransferase (FUT8) transfers a fucose residue to n-linked oligosaccharides on glycoproteins. Herein, we study the effect of fucosylation on epidermal growth factor receptor (EGFR) activity and sensitivity to an EGFR-specific tyrosine kinase inhibitor (EGFR-TKI). The increased fucosylation of EGFR significantly promoted EGF-mediated cellular growth, and the decreased fucosylation by stable FUT8 knockdown weakened the growth response in HEK293 cells. The overexpression of FUT8 cells were more sensitive than the control cells to the EGFR-TKI gefitinib, and FUT8 knockdown decreased the sensitivity to gefitinib. Finally, to examine the effects in a human cancer cell line, we constructed stable FUT8 knockdown A549 cells, and found that these cells also decreased EGF-mediated cellular growth and were less sensitive than the control cells to gefitinib. In conclusion, we demonstrated that the modification of EGFR fucosylation affected EGF-mediated cellular growth and sensitivity to gefitinib. Our results provide a novel insight into how the glycosylation status of a receptor may affect the sensitivity of the cell to molecular target agents. (Cancer Sci 2008; 99: 1611-1617)
  • Ken Takezawa; Isamu Okamoto; Junya Fukuoka; Kaoru Tanaka; Hiroyasu Kaneda; Hisao Uejima; Hyung-Eun Yoon; Masami Imakita; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 3 2 187 - 189 2008年02月 [査読有り]
     
    Large cell neuroendocrine carcinoma (LCNEC) is a relatively new category of pulmonary neuroendocrine tumor. Although it was first detected in the lung, LCNEC has since been found in a variety of extrapulmonary sites. We now describe a patient who was diagnosed with LCNEC originating from the mediastinum, an extremely rare disorder. An increased serum concentration of alpha-fetoprotein (AFP) in the patient was reduced by chemotherapy in association with tumor shrinkage. Furthermore, the tumor was confirmed immuno-histochemically to produce AFP. To our knowledge, this is the first report of a LCNEC that produces AFP.
  • EGFR変異の高感度検出法
    田中 薫; 西尾和人
    Mook 肺癌の臨床 28 - 31 2007年03月

講演・口頭発表等

  • 『がん免疫療法実用化の時代』〜あなたが抱く基礎・臨床の課題を皆で考える2020〜 再発転移頭頸部癌に対する免疫チェックポイント阻害剤を用いた化学療法
    田中 薫
    日本がん免疫学会総会プログラム・抄録集 2020年09月 日本がん免疫学会
  • 持続する上部消化管出血と高度直腸狭窄を伴うも経口摂取を継続した若年の原発不明癌症例
    酒井 瞳; 川中 雄介; 田中 薫; 武田 真幸; 前田 宗之; 中川 和彦
    Palliative Care Research 2020年08月 (NPO)日本緩和医療学会
  • 頭頸部癌における免疫チェックポイント阻害薬後のセツキシマブ使用の有効性および安全性
    三谷 誠一郎; 田中 薫; 鈴木 慎一郎; 原谷 浩司; 文田 壮一; 川上 尚人; 吉田 健史; 林 秀敏; 北野 睦三; 土井 勝美; 石川 一樹; 西村 恭昌; 中川 和彦
    頭頸部癌 2020年07月 (一社)日本頭頸部癌学会
  • 当院における分化型甲状腺癌および未分化癌に対するレンバチニブの使用経験
    吉田 健史; 田中 薫; 中川 和彦
    頭頸部癌 2020年07月 (一社)日本頭頸部癌学会
  • 当院での進行頭頸部癌に対するニボルマブの有効性と安全性
    鈴木 慎一郎; 田中 薫; 佐藤 千尋; 金村 宙昌; 磯本 晃佑; 加藤 了資; 原谷 浩司; 三谷 誠一郎; 林 秀敏; 北野 睦三; 石川 一樹; 土井 勝美; 西村 恭昌; 中川 和彦
    頭頸部癌 2020年07月 (一社)日本頭頸部癌学会
  • 頭頸部癌における臓器温存療法は本当に機能温存につながっているのか 導入化学療法による臓器機能温存と生命予後改善への取り組み
    田中 薫
    頭頸部癌 2020年07月 (一社)日本頭頸部癌学会
  • 田中 薫
    癌と化学療法 2020年07月 (株)癌と化学療法社
  • 田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    気管支学 2020年06月 (NPO)日本呼吸器内視鏡学会
  • 鈴木 慎一郎; 田中 薫; 金村 宙昌; 磯本 晃佑; 原谷 浩二; 林 秀敏; 武田 真幸; 中川 和彦
    気管支学 2020年06月 (NPO)日本呼吸器内視鏡学会
  • 肺線維症をもつ悪性胸膜中皮腫患者へのニボルマブ使用報告  [通常講演]
    岩朝 勤; 黒崎 隆; 鈴木 慎一郎; 田中 薫; 武田 真幸; 中川 和彦
    肺癌 2020年04月 (NPO)日本肺癌学会
  • 免疫チェックポイント阻害薬奏効後に転移巣増大を来した肺癌症例の遺伝子的検討  [通常講演]
    佐藤 千尋; 林 秀敏; 田中 薫; 武田 真幸; 中川 和彦; 坂井 和子; 西尾 和人
    肺癌 2020年04月 (NPO)日本肺癌学会
  • 当院の非小細胞肺癌患者に対する遺伝子パネル検査の使用経験  [通常講演]
    田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    肺癌 2020年04月 (NPO)日本肺癌学会
  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌の腫瘍微小環境への影響  [通常講演]
    磯本 晃佑; 原谷 浩司; 林 秀敏; 加藤 了資; 田中 薫; 武田 真幸; 中川 和彦; 清水 重喜; 伊藤 彰彦; 冨田 秀太; 丹羽 崇; 小倉 高志; 横山 俊秀; 福田 泰; 石田 直; 千葉 康敬; 谷崎 潤子
    肺癌 2020年04月 (NPO)日本肺癌学会
  • CAPP-Seqを用いたLiquid biopsyによるT790M陽性非小細胞肺癌のオシメルチニブ耐性因子の検討  [通常講演]
    加藤 了資; 林 秀敏; 原谷 浩司; 高濱 隆幸; 谷崎 潤子; 野長瀬 祥兼; 田中 薫; 吉田 健史; 武田 真幸; 米阪 仁雄; 中川 和彦; 坂井 和子; 西尾 和人; 金田 裕靖
    肺癌 2020年04月 (NPO)日本肺癌学会
  • 岩朝 勤; 黒崎 隆; 鈴木 慎一郎; 田中 薫; 武田 真幸; 中川 和彦
    肺癌 2020年04月 (NPO)日本肺癌学会
  • 佐藤 千尋; 林 秀敏; 田中 薫; 武田 真幸; 中川 和彦; 坂井 和子; 西尾 和人
    肺癌 2020年04月 (NPO)日本肺癌学会
  • 田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    肺癌 2020年04月 (NPO)日本肺癌学会
  • 磯本 晃佑; 原谷 浩司; 林 秀敏; 加藤 了資; 田中 薫; 武田 真幸; 中川 和彦; 清水 重喜; 伊藤 彰彦; 冨田 秀太; 丹羽 崇; 小倉 高志; 横山 俊秀; 福田 泰; 石田 直; 千葉 康敬; 谷崎 潤子
    肺癌 2020年04月 (NPO)日本肺癌学会
  • 加藤 了資; 林 秀敏; 原谷 浩司; 高濱 隆幸; 谷崎 潤子; 野長瀬 祥兼; 田中 薫; 吉田 健史; 武田 真幸; 米阪 仁雄; 中川 和彦; 坂井 和子; 西尾 和人; 金田 裕靖
    肺癌 2020年04月 (NPO)日本肺癌学会
  • 田中 薫; 中川 和彦
    薬局 2020年03月 (株)南山堂
  • 血管破壊剤（VDA) オンブラリンの３週間隔投与時の日本人進行固形がん患者に対する第Ⅰ相臨床試験  [通常講演]
    倉田 宝保; 藤阪 保仁; 清田秀美; 林 秀敏; 田中 薫; 中川 和彦; 他; 他, 他; 静岡県立がんセンター
    第10回日本臨床腫瘍学会学術集会 2012年07月 大阪 第10回日本臨床腫瘍学会学術集会
  • 進行肺腺癌を対象としたゲフィチニブ／S-1併用療法第１層臨床試験  [通常講演]
    清田 秀美; 岡本 勇; 田中 薫; 林 秀敏; 寺嶋応顕; 東 公一; 武田真幸; 米阪 仁雄; 藤阪 保仁; 鶴谷 純司; 宮﨑 昌樹; 佐藤 太郎; 倉田 宝保; 中川 和彦
    第51回日本肺癌学会総会 2010年11月 広島 第51回日本肺癌学会総会
  • 進行肺腺癌を対象としたゲフェチニブ／S-1 併用療法第１相臨床試験  [通常講演]
    清田 秀美; 岡本 勇; 谷﨑 潤子; 文田 壮一; 岡本 邦男; 牧村 ちひろ; 竹澤 健; 田中 薫; 林 秀敏; 岡本 渉; 寺嶋応顕; 東 公一; 金田裕靖; 武田真幸; 上田 眞也; 米阪 仁雄; 藤阪 保仁; 鶴谷 純司; 宮﨑 昌樹; 佐藤 太郎; 倉田 宝保; 中川 和彦
    第92回日本肺癌学会関西支部会 2010年07月 大阪 第92回日本肺癌学会関西支部会
  • ソラフェニブは肺癌細胞においてＫＲＡＳ野生型に対しては  [通常講演]
    竹澤 健; 岡本 勇; 田中 薫; 林 秀敏; 岡本 邦男; 米阪 仁雄; 福岡正博; 中川 和彦
    第8回日本臨床腫瘍学会総会 2010年03月 東京 第8回日本臨床腫瘍学会総会
  • 角膜上皮細胞に対するTGF-βシグナル経路を介した上皮間葉移行の検討  [通常講演]
    青松 圭一; 荒尾 徳三; 松本 和子; 金田 裕靖; 田中 薫; 藤田 至彦; 下村 嘉一; 西尾 和人
    第13回日本がん分子標的治療学会学術集会 2009年06月 徳島 第13回日本がん分子標的治療学会学術集会
  • Inhibition of phospho-tyrosine in VEGFR2+CD45dim population as a biomarker for VEGFR2 tyrosine kinase inhibitors.  [通常講演]
    工藤 可苗; 荒尾 徳三; 松本 和子; 田中 薫; 金田 裕靖; 藤田 至彦; 工藤 正俊; 西尾 和人
    第67回日本癌学会学術総会 2008年10月 名古屋国際会議場, 愛知 第67回日本癌学会学術総会
  • 胃癌細胞におけるＩＭＰ-3 遺伝子の機能解析  [通常講演]
    田中 薫; 荒尾徳三; 前川麻里; 松本和子; 工藤可苗; 金田裕靖; 藤田至彦; 柳原五吉; 山田康秀; 岡本 勇; 中川 和彦; 西尾和人
    第67回日本癌学会学術総会 2008年10月 名古屋 第67回日本癌学会学術総会
  • Inhibitation of phospho-tyrosine in VEGFR2+D45dim population as a biomaker for VEGFR2 tyrosine kinase inhibitors.  [通常講演]
    工藤 可苗; 荒尾 徳三; 田中 薫; 金田 裕靖; 松本 和子; 藤田 至彦; 工藤 正俊; 西尾 和人
    The 67th Annual Meeting of the Japanese Cnacer Association 2008年10月 Nagoya, Japan The 67th Annual Meeting of the Japanese Cnacer Association
  • ＩＭＰ-3 promotes cellular proliferation activity in gastric cancer  [通常講演]
    田中 薫; 荒尾徳三; 前川麻里; 松本和子; 工藤可苗; 金田裕靖; 藤田至彦; 柳原五吉; 山田康秀; 岡本 勇; 中川 和彦; 西尾和人
    A.A.C.R 2008年04月 San Diego (U.S.A) A.A.C.R
  • Suppression of SRPX2 mRNA expression inhibits cellular growth and adhesion in gastric cancer cells  [通常講演]
    田中 薫; 荒尾徳三; 前川麻里; 松本和子; 金田裕靖; Abe Y; 藤田至彦; 横手秀行; 柳原五吉; 山田康秀; 岡本 勇; 中川 和彦; 西尾和人
    66th Annual Meeting of the Japanese Cancer Association 2007年10月 横浜 66th Annual Meeting of the Japanese Cancer Association
  • 胃癌高発現遺伝子SRPX2の生物学的検討  [通常講演]
    田中 薫; 荒尾徳三; 前川麻里; 松本和子; 藤田至彦; 横手秀行; 柳原五吉; 山田康秀; 岡本 勇; 中川 和彦; 福岡正博; 西尾和人
    第11回がん分子標的治療研究会総会 2007年07月 大阪 第11回がん分子標的治療研究会総会

MISC

共同研究・競争的資金等の研究課題

  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 米阪 仁雄; 坂井 和子; 土井 勝美; 北野 睦三; 田中 薫
     
    本研究の目的は、頭頚部癌の治療薬である抗EGFR抗体セツキシマブの耐性機序を明らかにし、同腫瘍の治療の改善につなげる事である。まず頭頸部癌細胞株FaDuに同剤を継続暴露し、セツキシマブ耐性株FaDuCRを樹立した。耐性機序の解明のため網羅的ゲノム解析を行うが、新たな遺伝子変異を認めなかった。一方、全トランスクリプトーム解析では耐性株においてHER3リガンドのヘレグリンの過剰発現を認め、定量的PCR法により親株に比べおよそ10倍亢進していた。免疫ブロッティング解析の結果、耐性株ではHER3及びその下流に存在するAktの活性化がみられ、siRNA法によるヘレグリンのノックダウンはこれらの活性化を抑制した。さらに同ノックダウンは耐性株のセツキシマブ感受性を回復した。従ってヘレグリンによるHER3-Aktの活性化がセツキシマブ耐性をもたらすと考えられた。 次に耐性株FaDuCRのpan-HERファミリー阻害剤アファチニブへの感受性をマウス試験で調べ、同耐性株はアファチニブへの感受性を認めた。また免疫ブロッティング解析ではアファチニブはHER3-Aktのリン酸化を阻害することを確認した。アファチニブによるEGFR及びHER3阻害がFaDuCRへの抗癌作用をもたらすと考えられる。 さらに頭頚部癌症例の腫瘍組織を用いてヘレグリンmRNAの発現をin situ ハイブリダイズ法で定量した。28腫瘍中、2腫瘍でヘレグリンの発現が耐性株FaDuCRと同程度に亢進していた。またこれらの症例はセツキシマブ治療に対し耐性であった。 以上より頭頚部癌においてヘレグリンの過剰発現に依存したHER3-Aktの活性化がセツキシマブ治療への耐性化をもたらすことが考えられる。しかしpan-HERファミリー阻害剤のアファチニブにはヘレグリン過剰発現頭頚部癌への抗腫瘍効果が期待できる。
  • 日本学術振興会：科学研究費助成事業 若手研究(B)
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 田中 薫
     
    本研究は、ALK融合遺伝子陽性進行再発非扁平上皮非小細胞肺癌患者を対象にALK阻害剤での治療後の腫瘍組織および血液検体を用いて薬剤耐性機序を分子生物学的に解明し、薬剤耐性克服のための新たな治療標的を同定することを目的とし行っている。また、新たな耐性機序を示唆する分子学的変化が検出されれば、in vitro、in vivoにおいて生物学的な特性を確認し、その克服のための治療戦略を検討する予定である。平成30年度末までに15例のALK-TKIに耐性を獲得したEML4-ALK融合遺伝子陽性肺癌患者から本研究への参加同意を取得し、治療前後の腫瘍組織検体及び血液検体を可能な限り収集した。EML4-ALK融合遺伝子陽性肺癌患者では、治療効果により治療後の再生検を行うことが困難な症例が多くみられるが当院では12例において治療後の再生検が施行され、収集した検体から抽出したDNAを用いて体細胞遺伝子変異解析を行っている。29年度は残念ながら治療前の保存検体で十分な試料が回収できた症例が少なかったが、出来る限り検体の収集を進めた結果、30年度末までに10例の治療前後両方の腫瘍組織検体が収集できた。治療後の再生検検体を用いた検討では、L1196M、G1202R、V1180Lの3つの既知のALK遺伝子の2次変異が検出されており、本研究の経過並びに得られた知見については第16回日本臨床腫瘍学会、第59回日本肺癌学会で学会発表も行った。対象症例が少ないことから思うように症例集積が進まないため、同一症例で複数回の再生検を行うなど新たなアプローチで耐性機序解明に向けて研究を進めている。31年度中に論文発表に向けた最終解析を行う予定である。

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