詳細

谷﨑　潤子 （タニザキ　ジュンコ）

  • 医学科　医学部講師
Last Updated :2024/04/23

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

    固形癌、特に肺癌、原発不明癌に対する薬物治療。

研究者情報

ホームページURL

J-Global ID

現在の研究分野（キーワード）

    固形癌、特に肺癌、原発不明癌に対する薬物治療。

研究分野

  • ライフサイエンス / 腫瘍診断、治療学

経歴

  • 2012年04月 - 現在  近畿大学医学部内科学腫瘍内科部門医学部講師
  • 2018年04月 - 2021年03月  市立岸和田市民病院腫瘍内科医長
  • 2015年04月 - 2018年03月  近畿大学医学部内科学腫瘍内科部門助教
  • 2012年08月 - 2015年03月  Dana－Farber Cancer InstitutePost-doctoral Fellow
  • 2009年04月 - 2012年07月  近畿大学医学部 内科学腫瘍内科部門助教
  • 2007年04月 - 2009年04月  近畿大学医学部附属病院臨床研修医

学歴

  • 2009年04月 - 2012年03月   近畿大学   大学院医学研究科 医学腫瘍生態制御学
  •         - 2007年03月   近畿大学   医学部   医学科

所属学協会

  • 日本肺癌学会   日本臨床腫瘍学会   日本内科学会   米国臨床腫瘍学会   

研究活動情報

論文

  • Hidetoshi Hayashi; Kenji Chamoto; Ryusuke Hatae; Takashi Kurosaki; Yosuke Togashi; Kazuya Fukuoka; Megumi Goto; Yasutaka Chiba; Shuta Tomida; Takayo Ota; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Takeshi Yoshida; Tsutomu Iwasa; Kaoru Tanaka; Masayuki Takeda; Tomoko Hirano; Hironori Yoshida; Hiroaki Ozasa; Yuichi Sakamori; Kazuko Sakai; Keiko Higuchi; Hitoshi Uga; Chihiro Suminaka; Toyohiro Hirai; Kazuto Nishio; Kazuhiko Nakagawa; Tasuku Honjo
    The Journal of clinical investigation 134 7 2024年04月 
    BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.
  • Koji Haratani; Atsushi Nakamura; Nobuaki Mamesaya; Kenji Sawa; Yoshimasa Shiraishi; Ryota Saito; Junko Tanizaki; Yosuke Tamura; Akito Hata; Kosuke Tsuruno; Tomohiro Sakamoto; Shunsuke Teraoka; Masahide Oki; Hiroshi Watanabe; Takaaki Tokito; Kenji Nagata; Takeshi Masuda; Yasushi Nakamura; Kazuko Sakai; Yasutaka Chiba; Akihiko Ito; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hidetoshi Hayashi
    British journal of cancer 2024年03月 
    BACKGROUND: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown. METHODS: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid. RESULTS: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration. CONCLUSIONS: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.
  • Satoru Hagiwara; Junko Tanizaki; Hidetoshi Hayashi; Yoriaki Komeda; Naoshi Nishida; Akihiro Yoshida; Tomoki Yamamoto; Takuya Matsubara; Masatoshi Kudo
    Cancer reports (Hoboken, N.J.) e1960  2024年01月 
    BACKGROUND: Immune checkpoint inhibitors have been reported to have excellent therapeutic effects on various malignant tumors. However, immune-related adverse events can occur, targeting various organs. CASE PRESENTATION: A 49-year-old male with lung carcinoma was started on carboplatin + pemetrexed + nivolumab (every 3 weeks) + ipilimumab (every 6 weeks), and nivolumab/ipilimumab was administered in the 3rd course. Subsequently, fever and fatigue developed, and grade 3 liver damage was also noted, so he was admitted to Kindai University Hospital. A bone marrow aspirate examination was performed on the third day of illness, and a definitive diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made. It was determined that immediate therapeutic intervention was necessary, and pulse therapy with methylprednisolone was started on the third day of illness. After 3 days of pulse treatment, a rapid recovery of platelet values, a decrease in ferritin levels, and a decrease in lactate dehydrogenase were observed. Subjective symptoms such as fever and fatigue also quickly improved. CONCLUSION: Early diagnosis and treatment for HLH resulted in a positive response. The number of HLH cases may increase in the future due to the expansion of immune checkpoint inhibitor indications.
  • Takeshi Masuda; Satoru Miura; Yuki Sato; Motoko Tachihara; Akihiro Bessho; Atsushi Nakamura; Taichi Miyawaki; Kohei Yoshimine; Masahide Mori; Hideaki Shiraishi; Kosuke Hamai; Koji Haratani; Sumiko Maeda; Eriko Tabata; Chiyoe Kitagawa; Junko Tanizaki; Takumi Imai; Shohei Nogami; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Noboru Hattori
    Scientific Reports 13 1 2023年11月 
    Abstract Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive for micro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.
  • Junko Tanizaki; Hiroaki Kuroda; Toshihide Yokoyama; Makoto Takahama; Hiroyasu Shoda; Atsushi Nakamura; Yoshitaka Kitamura; Nobuaki Mamesaya; Yoshihisa Kadota; Kenji Sawa; Kyoichi Okishio; Morihito Okada; Chihiro Suminaka; Kenta Noda; Kazuko Sakai; Yasutaka Chiba; Kazuto Nishio; Kenji Chamoto; Tasuku Honjo; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hidetoshi Hayashi
    JTO Clinical and Research Reports 100590 - 100590 2023年10月
  • 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.
  • Koji Haratani; Atsushi Nakamura; Nobuaki Mamesaya; Shigeki Mitsuoka; Yasuto Yoneshima; Ryota Saito; Junko Tanizaki; Yasuhito Fujisaka; Akito Hata; Kosuke Tsuruno; Tomohiro Sakamoto; Shunsuke Teraoka; Masahide Oki; Hiroshi Watanabe; Yuki Sato; Yusuke Nakano; Tomoyuki Otani; Kazuko Sakai; Shuta Tomida; Yasutaka Chiba; Akihiko Ito; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hidetoshi Hayashi
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 18 10 1334 - 1350 2023年06月 
    INTRODUCTION: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 (PD-L1) inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III non-small cell lung cancer (NSCLC). However, about half of treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L/SUBMARINE). METHODS: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue as well as flow cytometric analysis of circulating immune cells. Progression-free survival (PFS) was compared based on these biomarkers. RESULTS: The importance of preexisting effective adaptive immunity in tumors were revealed for treatment benefit regardless of genomic features. We also identified CD73-expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocytes (TILs) density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (HRs, 4.05 [95% CI, 1.17-14.04] for CD8+ TILs; 4.79 [95% CI, 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. CONCLUSIONS: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC, and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.
  • 切除可能非小細胞肺癌II-IIIA期における可溶性免疫因子の検討(WJOG12319LTR)
    谷崎 潤子; 黒田 浩章; 横山 俊秀; 高濱 誠; 庄田 浩康; 中村 敦; 北村 嘉隆; 豆鞘 伸昭; 門田 嘉久; 光岡 茂樹; 沖塩 協一; 岡田 守人; 坂井 和子; 千葉 康敬; 西尾 和人; 茶本 健司; 本庶 佑; 山本 信之; 中川 和彦; 林 秀敏
    肺癌 62 6 594 - 594 (NPO)日本肺癌学会 2022年11月
  • 進展型小細胞肺癌における免疫チェックポイント阻害薬の効果と腫瘍微小免疫環境の関連
    金村 宙昌; 林 秀敏; 原谷 浩司; 中川 和彦; 冨田 秀太; 谷崎 潤子; 鈴木 慎一郎; 川中 雄介; 津谷 あす香; 福田 泰; 金田 裕靖; 工藤 慶太; 高濱 隆幸; 今井 亮介; 千葉 康敬; 大谷 知之; 伊藤 彰彦; 坂井 和子; 西尾 和人
    肺癌 62 5 442 - 442 (NPO)日本肺癌学会 2022年10月
  • Yusuke Kawanaka; Yuto Yasuda; Junko Tanizaki; Daisuke Iwashima; Yoshikane Nonagase; Kiyoshi Uemasu; Yutaka Hirayama; Masakazu Ogura; Tomohiro Ozaki; Ken-Ichi Takahashi
    Respiratory investigation 60 5 667 - 673 2022年09月 
    BACKGROUND: Some lung cancer patients have preexisting interstitial lung disease (ILD), which is considered a risk factor for lung cancer treatment. This study investigated the safety and efficacy of durvalumab consolidation therapy for patients with stage III non-small-cell lung cancer (NSCLC) and preexisting ILD. METHODS: Fifty consecutive patients who were judged to be tolerable to concurrent chemoradiotherapy (CCRT) for stage III NSCLC were enrolled. Differences in the incidence rate of radiation pneumonitis (RP) and progression-free survival (PFS) were assessed in patients with or without ILD of which CT showed non-usual interstitial pneumonia pattern between the durvalumab consolidation group and chemotherapy (combination of carboplatin and paclitaxel [CP]) consolidation group. RESULTS: The incidence of RP was higher in patients with preexisting ILD (40% and 20% in the durvalumab and CP groups, respectively) than in those without ILD (26% and 8% in the durvalumab and CP groups, respectively). Univariate analysis showed that durvalumab therapy tended to increase the incidence of RP; however, preexisting ILD did not significantly increase the incidence of RP. The condition of all patients who developed RP improved with the administration of oral prednisolone. Among patients without ILD, the median PFS was 17 and 16 months in the durvalumab and CP groups, respectively. Among patients with preexisting ILD, median PFS was not achieved in the durvalumab group and was 8 months in the CP group. CONCLUSIONS: Although durvalumab consolidation therapy tended to increase the incidence of RP, it might be tolerable in stage III NSCLC patients with preexisting ILD.
  • Hiroaki Kanemura; Hidetoshi Hayashi; Shuta Tomida; Junko Tanizaki; Shinichiro Suzuki; Yusuke Kawanaka; Asuka Tsuya; Yasushi Fukuda; Hiroyasu Kaneda; Keita Kudo; Takayuki Takahama; Ryosuke Imai; Koji Haratani; Yasutaka Chiba; Tomoyuki Otani; Akihiko Ito; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    JTO clinical and research reports 3 8 100373 - 100373 2022年08月 
    Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.
  • Hidetoshi Hayashi; Shunichi Sugawara; Yasushi Fukuda; Daichi Fujimoto; Satoru Miura; Keiichi Ota; Yuichi Ozawa; Satoshi Hara; Junko Tanizaki; Koichi Azuma; Shota Omori; Motoko Tachihara; Kazumi Nishino; Akihiro Bessho; Yasutaka Chiba; Koji Haratani; Kazuko Sakai; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 28 5 893 - 902 2022年03月 
    PURPOSE: Although the efficacy of programmed cell death-1 (PD-1) blockade is generally poor for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) gene, EGFR tyrosine kinase inhibitors (TKIs) may improve the tumor immune microenvironment. We performed a randomized study to assess whether nivolumab improves outcome compared with chemotherapy in such patients previously treated with EGFR-TKIs. PATIENTS AND METHODS: Patients with EGFR-mutated NSCLC who acquired EGFR-TKI resistance not due to a secondary T790M mutation of EGFR were randomized 1:1 to nivolumab (n = 52) or carboplatin-pemetrexed (n = 50). The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS and 1-year PFS probability were 1.7 months and 9.6% for nivolumab versus 5.6 months and 14.0% for carboplatin-pemetrexed [log-rank P < 001; hazard ratio (HR) of 1.92, with a 60% confidence interval (CI) of 1.61-2.29]. Overall survival was 20.7 and 19.9 months [HR, 0.88 (95% CI, 0.53-1.47)], and response rate was 9.6% and 36.0% for nivolumab and carboplatin-pemetrexed, respectively. No subgroup including patients with a high tumor mutation burden showed a substantially longer PFS with nivolumab than with carboplatin-pemetrexed. The T-cell-inflamed gene expression profile score (0.11 vs. -0.17, P = 0.036) and expression of genes related to cytotoxic T lymphocytes or their recruitment were higher in tumors that showed a benefit from nivolumab. CONCLUSIONS: Nivolumab did not confer a longer PFS compared with carboplatin-pemetrexed in the study patients. Gene expression profiling identified some cases with a favorable tumor immune microenvironment that was associated with nivolumab efficacy.
  • Daichi Fujimoto; Satoru Miura; Kenichi Yoshimura; Kazushige Wakuda; Yuko Oya; Koji Haratani; Shoichi Itoh; Takehiro Uemura; Ryotaro Morinaga; Takayuki Takahama; Kazuhisa Nakashima; Motoko Tachihara; Go Saito; Junko Tanizaki; Kohei Otsubo; Satoshi Ikeda; Hirotaka Matsumoto; Satoshi Hara; Akito Hata; Takeshi Masuda; Nobuyuki Yamamoto
    JTO clinical and research reports 3 2 100265 - 100265 2022年02月 
    INTRODUCTION: The real-world effectiveness of combination treatment with cytotoxic chemotherapy and programmed cell death protein-1 or programmed death-ligand 1 inhibitor for NSCLC, especially for the elderly (aged ≥75 y) or those with poor performance status (≥2), has not been fully elucidated. We investigated the real-world effectiveness and safety of this combination therapy in these populations. METHODS: This multicenter retrospective study evaluated patients who are chemo-naïve with advanced NSCLC who received a combination of platinum, pemetrexed, and pembrolizumab between December 2018 and June 2019. This was an updated prespecified secondary analysis with the primary objective of investigating the safety and effectiveness in this cohort. RESULTS: Overall, 299 patients were included. Multivariate analysis identified performance status (0-1) and programmed death-ligand 1 tumor proportion score (≥50%) as significant independent predictors of progression-free survival (p = 0.007, and p = 0.003, respectively). The incidence of severe adverse events (AEs) was higher in the elderly and those with poor performance status than in their younger and good performance status counterparts. A total of 71 patients developed AEs that led to treatment discontinuation, and AE-related treatment discontinuation occurred at a significantly higher rate in older patients (median [range]) (70 [46-82] y) than in younger patients (68 [31-84] y) (p <0.001). CONCLUSIONS: Combination treatment with pembrolizumab plus chemotherapy had low real-world effectiveness for poor performance status patients. Severe AEs occurred at a higher rate in the elderly and poor performance status patients, and the AE-related treatment discontinuation rate increased with age. Physicians should be cautious about using this regimen, especially in the elderly and poor performance status patients.
  • J Tanizaki; K Yonemori; K Akiyoshi; H Minami; H Ueda; Y Takiguchi; Y Miura; Y Segawa; S Takahashi; Y Iwamoto; Y Kidera; K Fukuoka; A Ito; Y Chiba; K Sakai; K Nishio; K Nakagawa; H Hayashi
    Annals of oncology : official journal of the European Society for Medical Oncology 33 2 216 - 226 2022年02月 
    BACKGROUND: Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. PATIENTS AND METHODS: Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. RESULTS: Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. CONCLUSIONS: Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.
  • 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; Kimio Yonesaka; Takeshi Teramura; Toshiyuki Takehara; Ryoji Kato; Hitomi Sakai; Koji Haratani; Junko Tanizaki; Hisato Kawakami; Hidetoshi Hayashi; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 28 2 428 - 428 2022年01月
  • Shinya Sakata; Kohei Otsubo; Hisako Yoshida; Kentaro Ito; Atsushi Nakamura; Shunsuke Teraoka; Naohisa Matsumoto; Yoshimasa Shiraishi; Koji Haratani; Motohiro Tamiya; Satoshi Ikeda; Satoru Miura; Junko Tanizaki; Shota Omori; Hiroshige Yoshioka; Akito Hata; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Cancer science 113 1 221 - 228 2022年01月 
    Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non-small-cell lung cancer (NSCLC). Next-generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real-world clinical data using the Oncomine Dx Target Test Multi-CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%-83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36-6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings.
  • 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
  • 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
  • 鈴木 慎一郎; 米阪 仁雄; 寺村 岳士; 竹原 俊幸; 加藤 了資; 酒井 瞳; 原谷 浩司; 谷崎 潤子; 川上 尚人; 林 秀敏; 坂井 和子; 西尾 和人; 中川 和彦
    肺癌 61 6 629 - 629 (NPO)日本肺癌学会 2021年10月
  • 福田 泰; 林 秀敏; 菅原 俊一; 佐藤 悠城; 三浦 理; 大田 恵一; 小澤 雄一; 原 聡志; 谷崎 潤子; 東 公一; 大森 翔太; 立原 素子; 西野 和美; 別所 昭宏; 原谷 浩司; 坂井 和子; 西尾 和人; 山本 信之; 中川 和彦
    肺癌 61 6 677 - 677 (NPO)日本肺癌学会 2021年10月
  • 金村 宙昌; 林 秀敏; 大谷 知之; 冨田 秀太; 鈴木 慎一郎; 原谷 浩司; 谷崎 潤子; 津谷 あす香; 福田 泰; 金田 裕靖; 工藤 慶太; 高濱 隆幸; 今井 亮介; 千葉 康敬; 西尾 和人; 伊藤 彰彦; 中川 和彦
    肺癌 61 6 499 - 499 (NPO)日本肺癌学会 2021年10月
  • 小細胞癌のICI(Treatment of SCLC) 進展型小細胞肺癌における腫瘍微小免疫環境の網羅的解析
    金村 宙昌; 林 秀敏; 大谷 知之; 冨田 秀太; 鈴木 慎一郎; 原谷 浩司; 谷崎 潤子; 津谷 あす香; 福田 泰; 金田 裕靖; 工藤 慶太; 高濱 隆幸; 今井 亮介; 千葉 康敬; 西尾 和人; 伊藤 彰彦; 中川 和彦
    肺癌 61 6 499 - 499 (NPO)日本肺癌学会 2021年10月
  • EGFR阻害剤によるHER3の発現亢進及び抗HER3パトリツマブデルクステカンの抗腫瘍効果の増強
    米阪 仁雄; 谷崎 潤子; 前西 修; 坂井 和子; 後藤 大輝; 小林 真季; 吉本 龍人; 大塚 絵里; 沖田 弘明; 船橋 賢記; 橋本 悠里; 廣谷 賢志; 明松 隆志; 西尾 和人; 中川 和彦
    日本癌学会総会記事 80回 [E14 - 4] 2021年09月
  • Shinichiro Suzuki; Kimio Yonesaka; Takeshi Teramura; Toshiyuki Takehara; Ryoji Kato; Hitomi Sakai; Koji Haratani; Junko Tanizaki; Hisato Kawakami; Hidetoshi Hayashi; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 27 20 5697 - 5707 2021年08月 
    PURPOSE: Treatment with KRAS G12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRAS G12C NSCLC cells. EXPERIMENTAL DESIGN: Clones of sotorasib-sensitive KRAS G12C NSCLC H23 cells exposed to different concentrations of sotorasib were examined using whole-genomic transcriptome analysis, multiple receptor kinase phosphorylation analysis, and gene copy number evaluation. The underlying mechanisms of resistance were investigated using immunological examination, and a treatment aimed at overcoming resistance was tested in vitro and in vivo Results: Unbiased screening detected subclonal evolution of MET amplification in KRAS G12C NSCLC cells that had developed resistance to sotorasib in vitro MET knockdown using siRNA restored susceptibility to sotorasib in these resistant cells. MET activation by its amplification reinforced RAS cycling from its inactive form to its active form. In addition to RAS-mediated MEK-ERK induction, MET induced AKT activation independently of RAS. Crizotinib, a MET inhibitor, restored sensitivity to sotorasib by eliminating RAS-MEK-ERK as well as AKT signaling. MET/KRAS G12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice. CONCLUSIONS: MET amplification leads to the development of resistance to KRAS G12C inhibitors in NSCLC. Dual blockade of MET and KRAS G12C could be a treatment option for MET amplified, KRAS G12C-mutated NSCLC.
  • 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 2021年06月
  • Osamu Nishiyama; Shigeki Shimizu; Koji Haratani; Kosuke Isomoto; Junko Tanizaki; Hidetoshi Hayashi; Ryo Yamazaki; Takashi Oomori; Yusaku Nishikawa; Akiko Sano; Kazuhiko Nakagawa; Yuji Tohda
    BMC pulmonary medicine 21 1 155 - 155 2021年05月 
    BACKGROUND: The utility of bronchoscopy for patients with suspected immune checkpoint inhibitor (ICI)-related pneumonitis is currently debatable. The purpose of this study was to examine the findings of bronchoalveolar lavage (BAL) analysis and transbronchial lung biopsy (TBLB) in non-small cell lung cancer (NSCLC) patients with ICI-related pneumonitis, and to elucidate the clinical significance of bronchoscopy for this health condition. PATIENTS AND METHODS: Consecutive NSCLC patients treated with ICIs, diagnosed with ICI-related pneumonitis after undergoing bronchoscopy between October 2015 and March 2019 were retrospectively screened. Findings of BAL fluid analysis and/or TBLB specimen histology were reviewed. RESULTS: Twelve patients underwent bronchoscopy for the diagnosis of ICI-related pneumonitis, ten of whom underwent BAL. An increase in the proportion of lymphocytes higher than 20% was observed in all ten patients. An increase in the proportion of neutrophils (> 10%) and eosinophils (> 10%) was observed in two and one patient, respectively. TBLB specimens were analyzed for eight patients. Major histologic findings included alveolitis in seven (87.5%) and organizing pneumonia (OP) in five (62.5%) patients. Other findings included acute lung injury and fibrosis. All twelve patients demonstrated favorable outcomes. CONCLUSION: A major characteristic of BAL analysis in ICI-related pneumonitis with NSCLC was an increased proportion of lymphocytes. The histologic features of lung tissue included alveolitis and/or OP. Acute lung injury and fibrosis were observed. Although the necessity of bronchoscopy should be determined on a case-by-case basis, it is necessary to assess these parameters when proper differential diagnosis is needed.
  • Kiichiro Ninomiya; Shunsuke Teraoka; Yoshitaka Zenke; Hirotsugu Kenmotsu; Yukiko Nakamura; Yusuke Okuma; Akihiro Tamiya; Kaname Nosaki; Masahiro Morise; Keiju Aokage; Yuko Oya; Toshiyuki Kozuki; Tomohiro Sakamoto; Kentaro Tanaka; Hisashi Tanaka; Junko Tanizaki; Satoru Miura; Hideaki Mizutani; Eisaku Miyauchi; Ou Yamaguchi; Noriyuki Ebi; Yasushi Goto; Takaaki Sasaki; Haruko Daga; Satoshi Morita; Takeharu Yamanaka; Shinsuke Amano; Kazuo Hasegawa; Chiyo K Imamura; Kenichi Suzuki; Kazuko Nakajima; Hitomi Nishimoto; Satoshi Oizumi; Toyoaki Hida; Katsuyuki Hotta; Yuichi Takiguchi
    JTO clinical and research reports 2 1 100107 - 100107 2021年01月 
    Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.
  • 鈴木 慎一郎; 原谷 浩司; 林 秀敏; 加藤 了資; 川中 雄介; 谷崎 潤子; 尾崎 智博; 黒崎 隆; 長谷川 喜一; 岡部 崇記; 明石 雄策; 千葉 康敬; 伊藤 彰彦; 中川 和彦
    肺癌 60 6 635 - 635 (NPO)日本肺癌学会 2020年10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
    ONCOLOGIST 2020年09月 
    Lessons LearnedThe 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/m(2)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/m(2), one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m(2), 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/m(2)and cisplatin at 75 mg/m(2)every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.
  • 鈴木 慎一郎; 原谷 浩司; 加藤 了資; 林 秀敏; 中川 和彦; 谷崎 潤子; 尾崎 智博; 岡部 崇記; 明石 雄策; 長谷川 喜一; 西尾 和人; 伊藤 彰彦
    肺癌 60 2 155 - 156 (NPO)日本肺癌学会 2020年04月
  • 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 60 2 148 - 148 (NPO)日本肺癌学会 2020年04月
  • 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 60 2 149 - 149 (NPO)日本肺癌学会 2020年04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01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.
  • 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.
  • 西山 理; 佐野 安希子; 林 秀敏; 西川 裕作; 谷崎 潤子; 原谷 浩司; 中川 和彦; 東田 有智
    肺癌 59 6 547 - 547 (NPO)日本肺癌学会 2019年11月
  • 横山 俊秀; 丹羽 崇; 林 秀敏; 小倉 昌和; 谷崎 潤子; 尾崎 智博; 吉岡 弘鎮; 倉田 宝保; 田村 洋輔; 藤阪 保仁; 田中 薫; 長谷川 喜一; 千葉 康敬; 中川 和彦
    肺癌 59 6 672 - 672 (NPO)日本肺癌学会 2019年11月
  • 田中 薫; 谷崎 潤子; 野長瀬 祥兼; 原谷 浩司; 酒井 瞳; 加藤 了資; 渡邉 諭美; 吉田 健史; 佐藤 千尋; 林 秀敏; 坂井 和子; 西尾 和人; 中川 和彦
    肺癌 59 6 694 - 694 (NPO)日本肺癌学会 2019年11月
  • 鈴木 慎一郎; 加藤 了資; 原谷 浩司; 林 秀敏; 谷崎 潤子; 尾崎 智博; 長谷川 喜一; 大田 隆代; 千葉 康敬; 伊藤 彰彦; 坂井 和子; 西尾 和人; 中川 和彦
    肺癌 59 6 800 - 800 (NPO)日本肺癌学会 2019年11月
  • 米阪 仁雄; 岩間 映二; 林 秀敏; 高濱 隆幸; 谷崎 潤子; 武田 真幸; 東 公一; 安宅 信二; 岡本 勇; 中川 和彦
    肺癌 59 6 723 - 723 (NPO)日本肺癌学会 2019年11月
  • 磯本 晃佑; 原谷 浩司; 林 秀敏; 清水 重喜; 富田 秀太; 丹羽 崇; 横山 俊秀; 福田 泰; 千葉 康敬; 加藤 了資; 谷崎 潤子; 田中 薫; 武田 真幸; 小倉 高志; 石田 直; 伊藤 彰彦; 中川 和彦
    肺癌 59 6 567 - 567 (NPO)日本肺癌学会 2019年11月
  • Haratani K; Hayashi H; Takahama T; Nakamura Y; Tomida S; Yoshida T; Chiba Y; Sawada T; Sakai K; Fujita Y; Togashi Y; Tanizaki J; Kawakami H; Ito A; Nishio K; Nakagawa K
    Journal for immunotherapy of cancer 7 1 251  2019年09月 [査読有り]
  • Watanabe S; Yonesaka K; Tanizaki J; Nonagase Y; Takegawa N; Haratani K; Kawakami H; Hayashi H; Takeda M; Tsurutani J; Nakagawa K
    Cancer Med 8 1258 1268 - 1268 2019年 [査読有り]
     
    HER2-targeted therapy, especially the anti-HER2 antibody trastuzumab, is standard for HER2-positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)-dependent HER2-HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2-positive breast cancer. The anti-HER2 antibody pertuzumab and anti-HER3 antibody patritumab both target this heregulin-HER3-HER2 complex in different ways. This study examined the anticancer efficacy of dual HER2 and HER3 blockade in trastuzumab-resistant HER2-positive breast cancer. HER2-positive SKBR3 or BT474 cells overexpressing heregulin (SKBR3-HRG, BT474-HRG) were used to evaluate the efficacy of trastuzumab, pertuzumab, and patritumab in vitro by performing cell viability, immunoblotting, and clonogenic assays. The effects of these agents were then evaluated in vivo using BT474-HRG and an intrinsic heregulin-expressing and HER2-positive JIMT-1 xenograft models. SKBR3-HRG and BT474-HRG cells lost sensitivity to trastuzumab, which was accompanied by Akt activation. Unexpectedly, trastuzumab in combination with pertuzumab or patritumab also showed limited efficacy toward these cells. In contrast, trastuzumab/pertuzumab/patritumab triple treatment demonstrated potent anticancer efficacy, concomitant with strong repression of Akt. Finally, in heregulin-expressing BT474-HRG and JIMT-1 xenograft models, the addition of pertuzumab and patritumab to trastuzumab also enhanced antitumor efficacy leading to tumor regression. The current study found that triple blockade of HER2 and HER3 using trastuzumab, pertuzumab, and patritumab could overcome resistance to trastuzumab therapy in heregulin-expressing and HER2-positive breast cancer, which could be exploited clinically.
  • Watanabe S; Hayashi H; Haratani K; Shimizu S; Tanizaki J; Sakai K; Kawakami H; Yonesaka K; Tsurutani J; Togashi Y; Nishio K; Ito A; Nakagawa K
    Cancer science 110 1 52 - 60 2018年11月 [査読有り]
     
    The efficacy of programmed cell death-1 (PD-1) blockade in patients with non-small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutations has been found to be limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I (MHC-I) molecules is essential for an antitumor immune response, we examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on MHC-I expression in NSCLC cell lines. Appropriate EGFR-TKIs increased MHC-I expression at the mRNA and cell surface protein levels in NSCLC cells positive for EGFR mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK, also increased MHC-I expression, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib did not, suggesting that the MEK-ERK pathway mediates the down-regulation of MHC-I expression in response to EGFR activation. Immunohistochemical analysis of EGFR-mutated NSCLC specimens obtained before and after EGFR-TKI treatment also revealed down-regulation of phosphorylated forms of EGFR and ERK in association with up-regulation of MHC-I, an increased number of infiltrating CD8(+) T cells, and increased PD-1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of EGFR inhibits MHC-I expression through the MEK-ERK pathway in NSCLC and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between EGFR-MEK-ERK signaling in and the immune response to EGFR-mutated NSCLC.
  • Jang J; Son J; Park E; Kosaka T; Saxon JA; De Clercq DJH; Choi HG; Tanizaki J; Eck MJ; Jänne PA; Gray NS
    Angewandte Chemie (International ed. in English) 57 36 11629 - 11633 2018年09月 [査読有り]
  • Junko Tanizaki; Yasutaka Chiba; Koji Haratani; Hidetoshi Hayashi; Kazuhiko Nakagawa
    Journal of Thoracic Oncology 13 5 e86 - e87 2018年05月 [査読有り]
  • 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]
     
    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
  • 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.
  • Satomi Watanabe; Takeshi Yoshida; Hisato Kawakami; Naoki Takegawa; Junko Tanizaki; Hidetoshi Hayashi; Masayuki Takeda; Kimio Yonesaka; Junji Tsurutani; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 16 11 2563 - 2571 2017年11月 [査読有り]
     
    T790M mutation-selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non-small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, we evaluated the efficacy of dasatinib combined with the clinically relevant T790M-selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation-positive NSCLC with or without T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M positive cells and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the Annexin-V binding assay; this was associated with down-regulation of the antiapoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFRTKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M. (C) 2017 AACR.
  • 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.
  • Takayuki Kosaka; Junko Tanizaki; Raymond M. Paranal; Hideki Endoh; Christine Lydon; Marzia Capelletti; Claire E. Repellin; Jihyun Choi; Atsuko Ogino; Antonio Calles; Dalia Ercan; Amanda J. Redig; Magda Bahcall; Geoffrey R. Oxnard; Michael J. Eck; Pasi A. Janne
    CANCER RESEARCH 77 10 2712 - 2721 2017年05月 [査読有り]
     
    Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. (C) 2017 AACR.
  • Kato R; Hayashi H; Tanizaki J; Tanaka K; Takeda M; Nakagawa K
    ESMO open 2 1 e000145  2017年 [査読有り]
  • Haratani K; Hayashi H; Tanaka T; Kaneda H; Togashi Y; Sakai K; Hayashi K; Tomida S; Chiba Y; Yonesaka K; Nonagase Y; Takahama T; Tanizaki J; Tanaka K; Yoshida T; Tanimura K; Takeda M; Yoshioka H; Ishida T; Mitsudomi T; Nishio K; Nakagawa K
    Ann Oncol 28 7 1532 - 1539 2017年 [査読有り]
     
    Background: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR. Patients and methods: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B). Results: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden. Conclusion: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
  • Nonagase Y; Yonesaka K; Kawakami H; Watanabe S; Haratani K; Takahama T; Takegawa N; Ueda H; Tanizaki J; Hayashi H; Yoshida T; Takeda M; Chiba Y; Tamura T; Nakagawa K; Tsurutani J
    Oncotarget. 7 51 84860 - 84871 2016年12月 [査読有り]
     
    BACKGROUND: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. RESULTS: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. MATERIALS AND METHODS: SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. CONCLUSIONS: mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.
  • 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.
  • Hibi M; Kaneda H; Tanizaki J; Sakai K; Togashi Y; Terashima M; De Velasco MA; Fujita Y; Banno E; Nakamura Y; Takeda M; Ito A; Mitsudomi T; Nakagawa K; Okamoto I; Nishio K
    Cancer Sci 107 11 1667 - 1676 2016年11月 [査読有り]
     
    Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1–ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.
  • Junko Tanizaki; Eri Banno; Yosuke Togashi; Hidetoshi Hayashi; Kazuko Sakai; Masayuki Takeda; Hiroyasu Kaneda; Kazuto Nishio; Kazuhiko Nakagawa
    LUNG CANCER 101 11 - 15 2016年11月 [査読有り]
     
    Comprehensive genomic profiling for non-small cell lung cancer (NSCLC) is likely to identify more patients with rare genetic alterations including uncommon epidermal growth factor receptor gene (EGFR) mutations. It remains unclear how such patients should be treated, however. We here report a case of NSCLC positive for two uncommon mutations of EGFR and a KRAS mutation, including its treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI) afatinib. Tumor specimen obtained by a NSCLC patient with no smoking history was analyzed by next-generation sequencing. Comprehensive genomic profiling revealed that the patient harbored the EGFR mutations G719C and S768I as well as the E49K mutation of KRAS. Treatment with afatinib was clinically effective as confirmed by PET-CT scans of bone metastases and by a marked decrease in the serum concentration of carcinoembryonic antigen. Afatinib was the most effective among seven EGFR-TKIs tested in inhibiting the growth of Ba/F3 cells expressing EGFR(S768I), showing an efficacy similar to that apparent with cells expressing the common EGFR mutant L858R, whereas first- and third-generation EGFR-TKIs were markedly less effective against EGFR(S7681) than against EGFR(L858R). These data suggest that EGFR-TKIs differ in their activity toward cells expressing EGFR(S7681) in vitro. Consistently, afatinib was clinically effective for the treatment of NSCLC harboring G719C and S768I mutations of EGFR. Further studies are warranted to determine the most appropriate EGFR-TKI for treatment of NSCLC harboring uncommon EGFR mutations. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Watanabe S; Takeda M; Takahama T; Iwasa T; Tsurutani J; Tanizaki J; Shimizu T; Sakai K; Wada Y; Isogai N; Nishio K; Nakagawa K
    Invest New Drugs 34 3 396 - 404 2016年06月 [査読有り]
     
    Extramammary Paget's disease is a malignant intraepithelial carcinoma, which constitutes less than 1 % of all vulvar malignancies. Surgical resection is the first treatment of choice and standard chemotherapy has not been established for advanced or recurrent disease. Experimental and clinical studies have identified human epidermal growth receptor 2 as a potential therapeutic target. A 63-year-old male was referred for recurrent extramammary Paget's disease after surgery. Human epidermal growth receptor 2 was shown to be overexpressed and amplified by immunohistochemical analysis and fluorescence in situ hybridization analysis, respectively. After two cycles of trastuzumab monotherapy, all lymph node metastases decreased in size. However, he experienced recurrence in the lymph nodes during the seven courses of trastuzumab. As a subsequent treatment, trastuzumab was administered in combination with docetaxel and pertuzumab; clinical response was sustained for 12 months without significant adverse events.
  • Ota K; Azuma K; Kawahara A; Hattori S; Iwama E; Tanizaki J; Harada T; Matsumoto K; Takayama K; Takamori S; Kage M; Hoshino T; Nakanishi Y; Okamoto I
    Clinical cancer research : an official journal of the American Association for Cancer Research 21 17 4014 - 21 2015年09月 [査読有り]
     
    Purpose: Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in a subset of patients with non-small cell lung cancer (NSCLC). We have now examined PD-L1 expression and its regulation in NSCLC positive for the EML4-ALK fusion gene. Experimental Design: The expression of PD-L1 at the protein and mRNA levels in NSCLC cell lines was examined by flow cytometry and by reverse transcription and real-time PCR analysis, respectively. The expression of PD-L1 in 134 surgically resected NSCLC specimens was evaluated by immunohistochemical analysis. Results: The PD-L1 expression level was higher in NSCLC cell lines positive for EML4-ALK than in those negative for the fusion gene. Forced expression of EML4-ALK in Ba/F3 cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in EML4-ALK-positive NSCLC cells was attenuated by treatment with the specific ALK inhibitor alectinib or by RNA with ALK siRNAs. Furthermore, expression of PD-L1 was downregulated by inhibitors of the MEK-ERK and PI3K-AKT signaling pathways in NSCLC cells positive for either EML4-ALK or activating mutations of the EGFR. Finally, the expression level of PD-L1 was positively associated with the presence of EML4-ALK in NSCLC specimens. Conclusions: Our findings that both EML4-ALK and mutant EGFR upregulate PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression.
  • Junko Tanizaki; Dalia Ercan; Marzia Capelletti; Michael Dodge; Chunxiao Xu; Magda Bahcall; Erin M. Tricker; Mohit Butaney; Antonio Calles; Lynette M. Sholl; Peter S. Hammerman; Geoffrey R. Oxnard; Kwok-Kin Wong; Pasi A. Jaenne
    CANCER RESEARCH 75 15 3139 - 3146 2015年08月 [査読有り]
     
    The discovery of oncogenic driver mutations and the subsequent developments in targeted therapies have led to improved outcomes for subsets of lung cancer patients. The identification of additional oncogenic and drug-sensitive alterations may similarly lead to new therapeutic approaches for lung cancer. We identify and characterize novel FGFR2 extracellular domain insertion mutations and demonstrate that they are both oncogenic and sensitive to inhibition by FGFR kinase inhibitors. We demonstrate that the mechanism of FGFR2 activation and subsequent transformation is mediated by ligand-independent dimerization and activation of FGFR2 kinase activity. Both FGFR2-mutant forms are predominantly located in the endoplasmic reticulum and Golgi but nevertheless can activate downstream signaling pathways through their interactions with fibroblast growth factor receptor substrate 2 (FRS2). Our findings provide a rationale for therapeutically targeting this unique subset of FGFR2-mutant cancers as well as insight into their oncogenic mechanisms. (C)2015 AACR.
  • Tsurutani J; Kuroi K; Iwasa T; Miyazaki M; Nishina S; Makimura C; Tanizaki J; Okamoto K; Yamashita T; Aruga T; Shigekawa T; Komoike Y; Saeki T; Nakagawa K
    Cancer science 106 6 734 - 739 2015年06月 [査読有り]
     
    We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80 mg/m(2) ) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100 mg/m(2) nab-paclitaxel on days 1, 8, and 15 with 80 mg/m(2) S-1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy.
  • Li Tan; Jun Wang; Junko Tanizaki; Zhifeng Huang; Amir R. Aref; Maria Rusan; Su-Jie Zhu; Yiyun Zhang; Dalia Ercan; Rachel G. Liao; Marzia Capelletti; Wenjun Zhou; Wooyoung Hur; NamDoo Kim; Taebo Sim; Suzanne Gaudet; David A. Barbie; Jing-Ruey Joanna Yeh; Cai-Hong Yun; Peter S. Hammerman; Moosa Mohammadi; Pasi A. Jaenne; Nathanael S. Gray
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 111 45 E4869 - E4877 2014年11月 [査読有り]
     
    The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
  • Kawakami H; Okamoto I; Okamoto W; Tanizaki J; Nakagawa K; Nishio K
    Cancers 6 3 1540 - 1542 2014年07月 [査読有り]
     
    Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as "oncogene addiction". A new generation of drugs that selectively target such "driver oncogenes" manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an "oncogenic driver" and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.
  • Hayashi H; Okamoto I; Tanizaki J; Tanaka K; Okuda T; Kato A; Nishimura Y; Nakagawa K
    J Clin Oncol 32 36 e122 - 4 2014年02月 [査読有り]
  • Matsuoka H; Tsurutani J; Tanizaki J; Iwasa T; Komoike Y; Koyama A; Nakagawa K
    BMC research notes 6 541 - 541 2013年12月 [査読有り]
     
    BACKGROUND: Eribulin is a recently approved new therapeutic option for patients with metastatic breast cancer. According to several reports, eribulin has limited ability to cross the blood brain barrier. Recently, capecitabine and eribulin have been recognized as drugs with similar application for patients with advanced breast cancer. Although there have been several case reports describing the efficacy of capecitabine against brain metastases, no report of eribulin demonstrating efficacy for brain metastases exists today. CASE PRESENTATION: We describe a case of a 57-year-old Japanese woman who was diagnosed with breast cancer stage IV metastasized to multiple organs including liver and lung. After she received 3 regimens, she showed evidence of brain metastases, and whole brain radiation therapy was performed. Lapatinib and capecitabine was then administered as fourth-line chemotherapy, but the patient was hospitalized due to the exacerbation of interstitial pneumonitis and progression of brain and liver metastases. To control the systemic disease, eribulin was commenced as fifth-line chemotherapy. One month later, a significant response of brain metastases had been achieved, and this response has persisted for the last 4 months. We now describe a remarkable antitumor effect of eribulin against brain metastases from breast cancer. This case is the first report which indicates potential treatment of brain metastases using this medication. CONCLUSION: This report suggests that eribulin treatment may be beneficial for breast cancer patients with brain metastases progressing after whole brain radiation therapy. However, further clinical studies are warranted to determine the clinical effect of eribulin in brain metastases.
  • 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]
  • 転移性乳がん患者におけるエリブリンの臨床効果と安全性プロファイル
    崎山 勉; 鶴谷 純司; 谷崎 潤子; 松岡 弘道; 岡本 邦男; 清田 秀美; 倉田 宝保; 中川 和彦
    日本内科学会雑誌 102 Suppl. 195 - 195 (一社)日本内科学会 2013年02月
  • Regression of brain metastases from breast cancer with eribulin: a case report.
    Matsuoka H; Tsurutani J; Tanizaki J; Iwasa T; Komoike Y; Koyama A; Nakagawa K
    BMC Res Notes. 65 412  2013年 [査読有り]
  • 谷崎 潤子; 鶴谷 純司
    日本臨床 70 増刊8 分子標的薬 336 - 340 (株)日本臨床社 2012年11月
  • 谷崎潤子; 鶴谷純司
    日本臨床 70 Suppl 8 336 - 40 2012年11月
  • 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.
  • Kaneda H; Okamoto I; Sakai K; Tanizaki J; Takeda M; Nishio K; Nakagawa K
    Acta oncologica (Stockholm, Sweden) 51 7 942 - 944 2012年09月 [査読有り]
  • J. Tanizaki; I. Okamoto; K. Takezawa; K. Sakai; K. Azuma; K. Kuwata; H. Yamaguchi; E. Hatashita; K. Nishio; P. A. Janne; K. Nakagawa
    BRITISH JOURNAL OF CANCER 106 4 763 - 767 2012年02月 [査読有り]
     
    BACKGROUND: Although most non-small-cell lung cancer (NSCLC) patients with the echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene - benefit from ALK tyrosine kinase inhibitors (ALK-TKIs), the efficacy of these drugs varies greatly among individuals. METHODS: The antitumour action of ALK-TKIs in EML4-ALK-positive NSCLC cell lines was evaluated from their effects on cell proliferation, signal transduction, and apoptosis. RESULTS: The ALK-TKI TAE684 inhibited cell proliferation and induced apoptosis, in association with inhibition of STAT3 and ERK phosphorylation, in EML4-ALK-positive H3122 cells. TAE684 inhibited STAT3 phosphorylation, but not ERK phosphorylation, and it showed little effect on cell proliferation or apoptosis, in EML4-ALK-positive H2228 cells. The combination of TAE684 and a MEK inhibitor-induced marked apoptosis accompanied by inhibition of STAT3 and ERK pathways in H2228 cells. Such dual interruption of STAT3 and ERK pathways induced downregulation of the antiapoptotic protein survivin and upregulation of the proapoptotic protein BIM. CONCLUSION: Our results indicate that interruption of both STAT3-survivin and ERK-BIM pathways is required for induction of apoptosis in NSCLC harbouring EML4-ALK, providing a rationale for combination therapy with ALK and MEK inhibitors in EML4-ALK-positive NSCLC patients for whom ALK inhibitors alone are ineffective.
  • Junko Tanizaki; Isamu Okamoto; Kunio Okamoto; Ken Takezawa; Kiyoko Kuwata; Haruka Yamaguchi; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 6 10 1624 - 1631 2011年10月 [査読有り]
     
    Introduction: Tyrosine kinase inhibitors (TKIs) targeted to MET are undergoing clinical trials in patients with solid tumors, but the precise mechanism of the antitumor activity of these drugs remains unclear. We examined the antitumor action of the MET-TKI crizotinib (PF-02341066) in lung cancer cells that are positive or negative for MET amplification or mutation. Methods: The antitumor action of crizotinib was evaluated on the basis of signal transduction, cell proliferation, apoptosis, and progression of tumor xenografts. Results: Inhibition of MET signaling by crizotinib or by RNA interference-mediated MET depletion resulted in the induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in lung cancer cells with MET amplification but not in cells with a MET mutation or in those without amplification or mutation of MET. These results suggest that MET signaling is essential for the survival of cells with MET amplification but not for that of cells without this genetic change, including those with a MET mutation. Crizotinib up-regulated the expression of BIM, a proapoptotic member of the Bcl-2 family, and down-regulated that of survivin, a member of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM and expression of survivin each inhibited crizotinib-induced apoptosis, suggesting that both up-regulation of BIM and down-regulation of survivin contribute to the proapoptotic effect of crizotinib. Conclusions: Crizotinib shows a marked antitumor action in MET amplification-positive lung cancer cells but not in cells without MET amplification, including those with a MET mutation.
  • J. Tanizaki; I. Okamoto; S. Fumita; W. Okamoto; K. Nishio; K. Nakagawa
    ONCOGENE 30 39 4097 - 4106 2011年09月 [査読有り]
     
    Lapatinib, a dual tyrosine kinase inhibitor of the epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), is clinically active in patients with breast cancer positive for HER2 amplification. The mechanism of this anti-tumor action has remained unclear, however. We have now investigated the effects of lapatinib in HER2 amplification-positive breast cancer cells with or without an activating PIK3CA mutation. Lapatinib induced apoptosis in association with upregulation of the pro-apoptotic protein Bcl-2 interacting mediator of cell death (BIM) through inhibition of the MEK-ERK signaling pathway in breast cancer cells with HER2 amplification. RNA interference (RNAi)-mediated depletion of BIM inhibited lapatinib-induced apoptosis, implicating BIM induction in this process. The proapoptotic effect of lapatinib was less pronounced in cells with a PIK3CA mutation than in those without one. Lapatinib failed to inhibit AKT phosphorylation in PIK3CA mutant cells, likely because of hyperactivation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by the mutation. Depletion of PIK3CA (a catalytic subunit of PI3K) revealed that survivin expression is regulated by the PI3K pathway in these cells, suggesting that insufficient inhibition of PI3K-survivin signaling is responsible for the limited pro-apoptotic effect of lapatinib in HER2 amplification-positive cells with a PIK3CA mutation. Consistent with this notion, depletion of survivin by RNAi or treatment with a PI3K inhibitor markedly increased the level of apoptosis in PIK3CA mutant cells treated with lapatinib. Our results thus suggest that inhibition of both PI3K-survivin and MEK-ERK-BIM pathways is required for effective induction of apoptosis in breast cancer cells with HER2 amplification. Oncogene (2011) 30, 4097-4106; doi:10.1038/onc.2011.111; published online 18 April 2011
  • J. Tanizaki; I. Okamoto; K. Sakai; K. Nakagawa
    BRITISH JOURNAL OF CANCER 105 6 807 - 813 2011年09月 [査読有り]
     
    BACKGROUND: MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumour types. We investigated the roles and mechanisms of RTK heterodimerisation in lung cancer with MET amplification. METHODS: With the use of an RTK array, we identified phosphorylated RTKs in lung cancer cells with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays. RESULTS: We identified epidermal growth factor receptor (EGFR), human EGFR (HER) 2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signalling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signalling. CONCLUSION: Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET have differential roles in tumour development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerisation partners of MET in lung cancer with MET amplification. British Journal of Cancer (2011) 105, 807-813. doi: 10.1038/bjc.2011.322 www.bjcancer.com Published online 16 August 2011 (C) 2011 Cancer Research UK
  • Tsurutani Junji; Okamoto Kunio; Makimura Chihior; Azuma Koichi; Takeda Masayuki; Takezawa Ken; Okamoto Wataru; Kiyota Hidemi; Hayashi Hidetoshi; Tanaka Kaoru; Tanizaki Junko; Okamoto Isamu; Saijoh Nagahiro; Fukuoka Masahiro; Nakagawa Kazuhiko
    ANNALS OF ONCOLOGY 21 38 - 39 2010年11月 [査読有り]
  • Okamoto Kunio; Okamoto Isamu; Takezawa Ken; Tanaka Kaoru; Tanizaki Junko; Makimura Chihiro; Hayashi Hidetoshi; Tachibana Izumi; Nishimura Yasumasa; Fukuoka Masahiro; Nakagawa Kazuhiko
    ANNALS OF ONCOLOGY 21 27  2010年11月 [査読有り]
  • Takezawa K; Okamoto I; Tanizaki J; Kuwata K; Yamaguchi H; Fukuoka M; Nishio K; Nakagawa K
    Molecular cancer therapeutics 9 6 1647 - 1656 2010年06月 [査読有り]
     
    Most non-small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR. Mol Cancer Ther; 9(6); 1647-56. (C)2010 AACR.
  • Junko Tanizaki; Isamu Okamoto; Ken Takezawa; Sayaka Tsukioka; Junji Uchida; Mamoru Kiniwa; Masahiro Fukuoka; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 5 1198 - 1207 2010年05月 [査読有り]
     
    Amplification of human epidermal growth factor receptor 2 (HER2) has been detected in 20% to 30% of gastric cancers and is associated with a poor outcome. Combination therapies with HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for gastric cancer with HER2 amplification. We have now investigated the effects of combination treatment with the oral fluoropyrimidine S-1 and the HER2-targeting agents lapatinib or trastuzumab in gastric cancer cells with or without HER2 amplification. We used 5-fluorouracil (5FU) instead of S-1 for in vitro experiments, given that tegafur, a component of S-1, is metabolized to 5FU in the liver. The combination of 5FU and HER2-targeting agents synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect in gastric cancer cells with HER2 amplification, but not in those without it. Lapatinib or trastuzumab also induced downregulation of thymidylate synthase (TS) expression and activity only in cells with HER2 amplification. The combination of 5FU and TS depletion by RNA interference also exhibited an enhanced proapoptotic effect in cells with HER2 amplification. These observations thus suggest that lapatinib-induced or trastuzumab-induced downregulation of TS is responsible, at least in part, for the synergistic antitumor effect of combined treatment with 5FU and HER2-targeting agents. The antitumor effect of the combination of S-1 and HER2-targeting agents in vivo was also greater than that of either drug alone. Our preclinical findings thus indicate that the combination of S-1 and HER2-targeting agents is a promising treatment option for gastric cancer with HER2 amplification. Mol Cancer Ther; 9(5); 1198-207. (C) 2010 AACR.

講演・口頭発表等

  • EGFR-TKI 獲得耐性肺癌に対する BIBW2992 とＴＳ標的薬剤の併用効果の検討  [通常講演]
    竹澤 健; 岡本 勇; 谷﨑 潤子; 西尾和人; 福岡正博; 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
  • EGFR-TKI 耐性Ｔ790M 肺癌に対するB IBW2992 とTS標的薬剤の効用効果  [通常講演]
    竹澤 健; 岡本 勇; 谷﨑 潤子; 福岡正博; 西尾和人; 中川 和彦
    第69回日本癌学会学術総会 2010年09月 大阪 第69回日本癌学会学術総会
  • Ｔ７９０ＭによるＥＧＦＲ-ＴＫＩ獲得耐性に対するＢＩＢＷ2992+Ｓ-１併用療法の分子生物学的検討  [通常講演]
    竹澤 健; 岡本 勇; 谷﨑 潤子; 中川 和彦; 福岡正博
    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
  • 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

MISC

受賞

  • 2011年 上原記念生命科学財団 平成23年度ポストドクトラルフェローシップ
  • 2011年 近畿大学校友会長賞
  • 2010年 財団法人大阪難病研究財団 難病および精神疾患に関する医学研究助成金
  • 2007年 近畿大学学長賞

共同研究・競争的資金等の研究課題

委員歴

  • 2018年12月 - 現在   特定非営利活動法人 日本肺癌学会   ガイドライン検討委員会 薬物療法及び集学的治療小委員会
  • 2018年12月 - 2020年12月   特定非営利活動法人日本肺癌学会   国際委員会
  • 日本臨床腫瘍学会   がん免疫療法ガイドライン 改訂第3版ワーキンググループ委員

その他

  • 2011年 - 2011年  上原記念生命科学財団 平成23年度ポストドクトラルフェローシップ
  • 2010年 - 2010年  財団法人大阪難病研究財団 難病および精神疾患に関する医学研究助成金

その他のリンク

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