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WATANABE Satomi

    Department of Medicine　Lecturer in Medical School
Last Updated :2024/04/23

Researcher Information

J-Global ID

Research Areas

  • Life sciences / Hematology and oncology

Education

  • 2014/04 - 2018/03  Kindai University  Graduate School of Medical Sciences
  • 2006/04 - 2012/03  Osaka city university

Association Memberships

  • American Society of Clinical Oncology   European Society of Medical Oncology   Japanese Society of Medical Oncology   THE JAPANESE SOCIETY OF INTERNAL MEDICINE   The Japan Lung Cancer Society   Japanese Breast Cancer Society   

Published Papers

  • Kana Fujimoto; Satomi Watanabe; Yuto Yasuda; Emi Date; Yasuhiro Kawabata; Hiroaki Kanemura; Takayuki Takahama; Kimio Yonesaka; Norishige Iizuka; Ken-Ichi Takahashi; Osamu Kawakami; Tomohiro Ozaki; Kazuhiko Nakagawa
    Thoracic cancer 14 (2) 214 - 217 2023/01 
    High-grade fetal lung adenocarcinoma (H-FLAC) is a rare tumor, with little known of its response to chemotherapy with or without an immune checkpoint inhibitor or of its molecular profile. We report the first case of a 56-year-old man with stage IV H-FLAC who was successfully treated with carboplatin plus nab-paclitaxel in combination with atezolizumab. In addition, the tumor was found to be positive for amplification of the human epidermal growth factor receptor 2 gene.
  • Toshio Shimizu; Kazuhiko Nakagawa; Hidetoshi Hayashi; Tsutomu Iwasa; Hisato Kawakami; Satomi Watanabe; Noboru Yamamoto; Kan Yonemori; Takafumi Koyama; Jun Sato; Kenji Tamura; Keiichi Kikuchi; Kenichiro Akaike; Shiho Takeda; Masayuki Takeda
    Investigational new drugs 41 (1) 1 - 12 2022/11 
    To determine the maximum tolerated dose (MTD) and recommended dose (RD) of orally-administered bendamustine in Japanese patients with advanced solid tumors. The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3 + 3 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21 days every 3 weeks as one cycle. The total dose per cycle was increased from 175 to 840 mg/m2. Eighteen patients were enrolled in this study. DLT occurred in one of six patients at 75 mg/m2/day × 7 days, and one of three patients at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days. However, the delayed recovery from a decrease in neutrophil or platelet count hampered the start of subsequent treatment cycles, and the trend was more prominent at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days than in 75 mg/m2/day × 7 days. MTD was determined as 75 mg/m2/day × 7 days to allow acceptable hematologic recovery. The pharmacokinetics of orally-administered bendamustine were generally dose-dependent; however, the inter-individual variability is relatively large. The major adverse events were hematologic toxicities; gastrointestinal disorders were generally mild. Adverse drug reactions did not lead to the discontinuation of the drug. A partial response was observed in two of six patients (prostatic small cell carcinoma and thymic carcinoma) at 75 mg/m2/day × 7 days. The RD and optimal dosing schedule of orally-administered bendamustine was 75 mg/m2 once daily for 7 days every 3 weeks for the treatment of advanced solid tumors. (Trial registration number ClinicalTrials.gov NCT03604679. Registration date July 27, 2018).
  • Kohsuke Isomoto; Koji Haratani; Satomi Watanabe; Masayuki Takeda; Tsutomu Iwasa; Kazuhiko Nakagawa
    Investigational new drugs 40 (1) 194 - 197 2022/02 
    Extramammary Paget disease (EMPD) is a rare cutaneous adenocarcinoma that usually is of epidermal origin and shows glandular differentiation and that is treated by wide local excision depending on the disease extent. For widely metastatic disease, however, a standard treatment remains to be established. Similar to breast cancer, EMPD has been found to overexpress human epidermal growth factor receptor 2 (HER2) or hormone receptors (HRs). Whereas HER2-directed therapy was recently shown to be effective for HER2-positive EMPD, the potential role of endocrine therapy for HR-positive EMPD has remained unknown. We here report a case of metastatic EMPD with HR positivity that was successfully treated with the selective estrogen receptor modulator tamoxifen. This first-line treatment of systemic metastasis resulted in durable tumor regression for > 20 months without any treatment-related toxicities. This is the first report to reveal the promise of tamoxifen as a safe and effective treatment for HR-positive metastatic EMPD.
  • ベンダムスチン塩酸塩経口剤(SyB C-0501)の進行性固形がん患者に対する第1相臨床試験
    武田 真幸; 中川 和彦; 林 秀敏; 岩朝 勤; 川上 尚人; 渡邉 諭美; 山本 昇; 米盛 勧; 小山 隆文; 佐藤 潤; 田村 研治; 菊池 圭一; 赤池 健一郎; 竹田 志保; 清水 俊雄
    日本癌治療学会学術集会抄録集 (一社)日本癌治療学会 59回 O13 - 5 2021/10
  • Esuteru Hirokawa; Satomi Watanabe; Kazuko Sakai; Masayuki Takeda; Chihiro Sato; Takayuki Takahama; Kazuto Nishio; Kazuhiko Nakagawa
    Thoracic Cancer Wiley 12 (16) 2283 - 2287 1759-7706 2021/07 
    Epidermal growth factor receptor (EGFR) kinase domain duplication (KDD) has been identified as an oncogenic driver in 0.05% to 0.14% of non-small cell lung cancer (NSCLC) patients. However, little is known of the efficacy of EGFR tyrosine kinase inhibitors (TKIs) for such patients. Here, we report the case of a 45-year-old Japanese woman with NSCLC positive for EGFR-KDD (duplication of exons 18-25) who developed carcinomatous meningitis and showed a marked response to the EGFR-TKIs erlotinib and osimertinib. As far as we are aware, this is the first report of EGFR-TKI efficacy for carcinomatous meningitis in a NSCLC patient harboring EGFR-KDD.
  • Masayuki Takeda; Takayuki Takahama; Kazuko Sakai; Shigeki Shimizu; Satomi Watanabe; Hisato Kawakami; Kaoru Tanaka; Chihiro Sato; Hidetoshi Hayashi; Yoshikane Nonagase; Kimio Yonesaka; Naoki Takegawa; Tatsuya Okuno; Takeshi Yoshida; Soichi Fumita; Shinichiro Suzuki; Koji Haratani; Kazumasa Saigoh; Akihiko Ito; Tetsuya Mitsudomi; Hisashi Handa; Kazuya Fukuoka; Kazuhiko Nakagawa; Kazuto Nishio
    The oncologist 26 (4) e588-e596  2021/04 
    BACKGROUND: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. MATERIALS AND METHODS: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan. RESULTS: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. CONCLUSION: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. IMPLICATIONS FOR PRACTICE: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.
  • Satomi Watanabe; Masayuki Takeda; Tomoyuki Otani; Takeshi Yoshida; Kazuko Sakai; Elizabeth Olek; S Michael Rothenberg; Jennifer Kherani; Pearl P French; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    JCO precision oncology 5 2021
  • Hitomi Sakai; Atsuko Koyama; Kaoru Tanaka; Satomi Watanabe; Miki Nakura; Toshiko Yasuda; Makiko Hayashi; Miyuki Endo; Kazuhiko Nakagawa
    Asia-Pacific Journal of Clinical Oncology Wiley 16 (5) e185-e191  1743-7555 2020/10 
    PURPOSE: Cancer treatment can alter patient appearance, leading to psychological, social, and behavioral issues. This study aimed to investigate distress and difficulties related to appearance concerns in Japanese cancer patients and to identify information and support needs among them. METHODS: We conducted a questionnaire survey using the Derriford Appearance Scale 59 (DAS59) among cancer patients with a prior history of chemotherapy, molecular targeted therapy, or immunotherapy, who were recruited from the Departments of Medical Oncology and Psychosomatic Medicine, Kindai University Hospital. RESULTS: Participants were 114 patients with a mean age of 62.9 years; 70.2% were female, 86.0% had metastatic or locally advanced unresectable cancer, and 78.1% had concerns about some aspect of their appearance. Mean DAS59 full-scale score was 77.7 ± 36.4. Younger and female participants were found to have higher full-scale scores in univariate analysis (P < .05 for both), and younger participants were found to have higher full-scale scores in multivariate analysis (P < .05). CONCLUSIONS: DAS59 scores had a wide distribution, suggesting that psychological distress due to appearance changes showed large individual differences. Young and female patients tended to have high DAS59 full-scale scores, but some older and male patients also had high scores. Basic information regarding appearance changes should be provided to all patients before initiating cancer treatment. Both information provision prior to treatment and care at the time of actual appearance changes are important, and should be handled through a multidisciplinary approach.
  • 田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    気管支学 (NPO)日本呼吸器内視鏡学会 42 (Suppl.) S391 - S391 0287-2137 2020/06
  • 田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    肺癌 (NPO)日本肺癌学会 60 (2) 153 - 153 0386-9628 2020/04
  • 当院の非小細胞肺癌患者に対する遺伝子パネル検査の使用経験
    田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    肺癌 (NPO)日本肺癌学会 60 (2) 153 - 153 0386-9628 2020/04
  • 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 2019/12 [Refereed]
     
    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.
  • 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 (NPO)日本肺癌学会 59 (6) 694 - 694 0386-9628 2019/11
  • Tsutomu Iwasa; Junji Tsurutani; Satomi Watanabe; Ryoji Kato; Yutaka Mizuno; Yasuyuki Kojima; Tsutomu Takashima; Nobuki Matsunami; Takashi Morimoto; Jun Yamamura; Shoichiro Ohtani; Yuko Tanabe; Tetsuhiro Yoshinami; Toshimi Takano; Yoshifumi Komoike; Kazuhiko Nakagawa
    BMC cancer 19 (1) 962 - 962 2019/10 [Refereed]
     
    BACKGROUND: We previously reported the synergistic effect of S-1 and eribulin in preclinical models. In addition, our phase I study revealed the recommended dose for the phase II study of the combination therapy in advanced breast cancer (ABC) patients pre-treated with anthracycline and taxane. Our current study reports on the efficacy and safety of the combined use of eribulin and S-1 in patients with ABC and poor prognosis. METHODS: Patients with breast cancer who received prior anthracycline- and/or taxane-based therapy were assigned to receive a combination therapy of eribulin (1.4 mg/m2 on days 1 and 8, every 21 days) and S-1 (65 mg/m2, on days 1 to 14, every 21 days) for advanced/metastatic disease. All patients had at least one clinicopathological factor such as being oestrogen receptor negative, Human Epidermal Growth Factor Receptor 2 (HER2) receptor negative, presence of visceral involvement, presence of three or more metastatic sites, or having a disease-free interval shorter than 2 years. The primary endpoint was the independent-reviewer assessed objective response rate (ORR). Secondary endpoints were clinical benefit rate, disease control rate, progression-free survival (PFS), and overall survival (OS). RESULTS: This study enrolled 33 patients. Confirmed ORR was 33.3% (95% CI: 17.3 to 52.8). Median PFS was 7.5 months (95% CI: 4.0 to 14.3). Median OS time was not reached during the current experimental periods. The most common grade 3/4 adverse event was neutropenia (68.8%). CONCLUSIONS: The combination of eribulin and S-1 is safe and effective for treatment in patients with ABC and poor prognosis. TRIAL REGISTRATION: Current Controlled Trials UMIN000015049 , date of registration: September 5th 2014.
  • Satomi Watanabe; Tomoyuki Otani; Tsutomu Iwasa; Takayuki Takahama; Masayuki Takeda; Kazuko Sakai; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    Clinical breast cancer 19 (5) e589-e592  1526-8209 2019/10 [Refereed]
  • Kazuko Sakai; Masayuki Takeda; Shigeki Shimizu; Takayuki Takahama; Takeshi Yoshida; Satomi Watanabe; Tsutomu Iwasa; Kimio Yonesaka; Shinichiro Suzuki; Hidetoshi Hayashi; Hisato Kawakami; Yoshikane Nonagase; Kaoru Tanaka; Junji Tsurutani; Kazumasa Saigoh; Akihiko Ito; Tetsuya Mitsudomi; Kazuhiko Nakagawa; Kazuto Nishio
    Scientific reports 9 (1) 11340 - 11340 2019/08 [Refereed]
     
    Medical oncologists are challenged to personalize medicine with scientific evidence, drug approvals, and treatment guidelines based on sequencing of clinical samples using next generation sequencer (NGS). Knowledge-based curation systems have the potential to help address this challenge. We report here the results of examining the level of evidence regarding treatment approval and clinical trials between recommendations made by Watson for Genomics (WfG), QIAGEN Clinical Insight Interpret (QCII), and Oncomine knowledge-based reporter (OKR). The tumor samples obtained from the solid cancer patients between May to June 2018 at Kindai University Hospital. The formalin-fixed paraffin-embedded tumor samples (n = 31) were sequenced using Oncomine Comprehensive Assay v3. Variants including copy number alteration and gene fusions identified by the Ion reporter software were used commonly on three curation systems. Curation process of data were provided for 25 solid cancers using three curation systems independently. Concordance and distribution of curated evidence levels of variants were analyzed. As a result of sequencing analysis, nonsynonymous mutation (n = 58), gene fusion (n = 2) or copy number variants (n = 12) were detected in 25 cases, and subsequently subjected to knowledge-based curation systems (WfG, OKR, and QCII). The number of curated information in any systems was 51/72 variants. Concordance of evidence levels was 65.3% between WfG and OKR, 56.9% between WfG and QCII, and 66.7% between OKR and QCII. WfG provided great number of clinical trials for the variants. The annotation of resistance information was also observed. Larger differences were observed in clinical trial matching which could be due to differences in the filtering process among three curation systems. This study demonstrates knowledge-based curation systems (WfG, OKR, and QCII) could be helpful tool for solid cancer treatment decision making. Difference in non-concordant evidence levels was observed between three curation systems, especially in the information of clinical trials. This point will be improved by standardized filtering procedure and enriched database of clinical trials in Japan.
  • 渡邉 諭美; 川上 尚人
    臨床腫瘍プラクティス (株)ヴァンメディカル 15 (1) 45 - 50 1880-3083 2019/02 
    ＜View Points!＞▼DNAミスマッチ修復機構欠損(dMMR)/マイクロサテライト不安定(MSI-H)大腸がんに対しては、抗PD-1抗体薬単剤が奏効することが明らかとなっている。米国に引き続き、本邦でも2018年12月にペムブロリズマブが保険承認された。▼DNAミスマッチ修復機構欠損がない(pMMR)/マイクロサテライト安定(MSS)大腸がんに対する免疫チェックポイント阻害薬はその効果がまだ示されておらず、臨床応用には至っていない。▼pMMR/MSS大腸がんに対しては抗PD-1抗体薬と他剤併用療法の試験が進行中であり、今後の治療開発が期待される。(著者抄録)
  • Watanabe Satomi; Hayashi Hidetoshi; Haratani Koji; Shimizu Shigeki; Tanizaki Junko; Sakai Kazuko; Kawakami Hisato; Yonesaka Kimio; Tsurutani Junji; Togashi Yosuke; Nishio Kazuto; Ito Akihiko; Nakagawa Kazuhiko
    Cancer Science John Wiley & Sons Australia, Ltd 110 (1) 52 - 60 1347-9032 2019/01 
    非小細胞肺癌の細胞株や患者由来検体を実験材料とし、上皮成長因子受容体(EGFR)チロシンキナーゼ阻害薬(TKI)がMHCクラスIの発現に及ぼす影響について調査した。EGFR遺伝子にT790M二次的突然変異などの変異がある細胞株を適切なEGFR-TKIで処理するとMHCクラスIのmRNA/蛋白質発現は亢進した。細胞外シグナル調節キナーゼ(ERK)キナーゼであるMEKの阻害薬で処理した場合もMHCクラスI発現が亢進したことから、EGFR活性化に応答してみられるMHCクラスI発現の下方制御はMEK-ERK経路が媒介していることが示唆された。EGFR-TKI治療を施行したEGFR変異非小細胞肺癌患者から得た検体の免疫組織化学解析からも、疾患進行後においては、リン酸化EGFRやリン酸化ERKの下方制御が、MHC-Iの上方制御、CD8+浸潤T細胞の増加、およびPD-1リガンド1発現亢進と関連していることが明らかになった。これらの結果から、非小細胞癌においてEGFRが変異活性化するとMEK-ERK経路を通じてMHCクラスI発現が阻害され、免疫療法に不応となるのに寄与することが示唆された。
  • Suzuki S; Haratani K; Takahama T; Watanabe S; Takegawa N; Hayashi H; Takeda M; Yonesaka K; Nakagawa K
    J Thorac Oncol 14 (3) e50 - e52 2019 [Refereed]
  • 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 [Refereed]
     
    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.
  • Satomi Watanabe; Hidetoshi Hayashi; Koji Haratani; Shigeki Shimizu; Junko Tanizaki; Kazuko Sakai; Hisato Kawakami; Kimio Yonesaka; Junji Tsurutani; Yosuke Togashi; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    Cancer science 110 (1) 52 - 60 1347-9032 2019/01 [Refereed]
     
    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. .
  • Yonesaka K; Takegawa N; Watanabe S; Haratani K; Kawakami H; Sakai K; Chiba Y; Maeda N; Kagari T; Hirotani K; Nishio K; Nakagawa K
    Oncogene 38 (9) 1398 - 1409 0950-9232 2018/10 [Refereed]
     
    EGFR tyrosine kinase inhibitors (TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC); however, these tumours eventually acquire chemoresistance. U3-1402 is an anti-HER3 antibody-drug conjugate with a novel topoisomerase I inhibitor, DXd. In the current study, we evaluated the anticancer efficacy of U3-1402 in EGFR-mutant NSCLC cells with acquired resistance to EGFR-TKIs. HCC827GR5 and PC9AZDR7 are EGFR-TKI-resistant clones for gefitinib and osimertinib, respectively. U3-1402 alone or in combination with the EGFR-TKI erlotinib demonstrated potent anticancer efficacy in HCC827GR5 cells using an in vitro growth inhibition assay and in vivo xenograft mouse model. U3-1402 induced apoptosis in HCC827GR5 cells accompanying phosphorylation of histone H2A.X, a marker of DNA damage, but did not block HER3/PI3K/AKT signalling. Further, we found using flow cytometry that the cell surface HER3 expression level in HCC827GR5 cells was twice that found in HCC827 cells, indicating internalization of U3-1402 was increased in resistant cells. In addition, administration of U3-1402 notably repressed growth of EGFR-TKI osimertinib-resistant PC9AZDR7 xenograft tumours, and that PC9AZDR7 cells expressed five times greater cell surface HER3 than PC9 cells. Furthermore, using immunofluorescent microscopy, HER3 was observed predominantly in the nucleus of PC9 cells, but was localized in the cytoplasm of PC9AZDR7 cells. This finding indicates that altered trafficking of the HER3-U3-1402 complex may accelerate linker payload cleavage by cytoplasmic lysosomal enzymes, resulting in DNA damage. Our results indicate that administration of U3-1402 alone or in combination with an EGFR-TKI may have potential as a novel therapy for EGFR-TKI-resistant EGFR-mutant NSCLC.
  • 進行性/再発性乳癌に対するeribulin/S-1併用療法の第II相試験(Phase II trial of Eribulin/S-1 combination therapy for advanced/recurrent breast cancer)
    鶴谷 純司; 岩朝 勤; 水野 豊; 小島 康幸; 高島 勉; 松並 展輝; 森本 卓; 山村 順; 大谷 彰一郎; 田辺 裕子; 渡邉 諭美; 加藤 了資; 高野 利美; 菰池 佳史; 中川 和彦
    日本乳癌学会総会プログラム抄録集 (一社)日本乳癌学会 26回 334 - 334 2018/05
  • 当院における高齢者への化学療法施行の現状に関して
    岩朝 勤; 鶴谷 純司; 酒井 瞳; 渡邊 諭美; 新崎 亘; 安積 達也; 橋本 幸彦; 菰池 佳史
    日本乳癌学会総会プログラム抄録集 (一社)日本乳癌学会 26回 532 - 532 2018/05
  • Satomi Watanabe; Takeshi Yoshida; Hisato Kawakami; Naoki Takegawa; Junko Tanizaki; Hidetoshi Hayashi; Masayuki Takeda; Kimio Yonesaka; Junji Tsurutani; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS AMER ASSOC CANCER RESEARCH 16 (11) 2563 - 2571 1535-7163 2017/11 [Refereed]
     
    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.
  • 吉田 健史; 渡邉 諭美; 武川 直樹; 川上 尚人; 中川 和彦
    肺癌 (NPO)日本肺癌学会 57 (5) 377 - 377 0386-9628 2017/09
  • Yoshikane Nonagase; Kimio Yonesaka; Hisato Kawakami; Satomi Watanabe; Koji Haratani; Takayuki Takahama; Naoki Takegawa; Hiroto Ueda; Junko Tanizaki; Hidetoshi Hayashi; Takeshi Yoshida; Masayuki Takeda; Yasutaka Chiba; Takao Tamura; Kazuhiko Nakagawa; Junji Tsurutani
    ONCOTARGET IMPACT JOURNALS LLC 7 (51) 84860 - 84871 1949-2553 2016/12 [Refereed]
     
    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.
  • Satomi Watanabe; Hidetoshi Hayashi; Kunio Okamoto; Kimiko Fujiwara; Yoshikazu Hasegawa; Hiroyasu Kaneda; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER CIG MEDIA GROUP, LP 17 (6) 528 - 534 1525-7304 2016/11 [Refereed]
     
    We identified 11 patients with ALK-rearranged non-small cell lung cancer treated with sequential crizotinib and alectinib. The median combined progression-free survival and overall survival in the present study was 18.2 and 48.6 months, respectively. These findings suggest that this regimen produces durable survival and therefore warrants further investigation. Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4-ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first-and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK-rearranged NSCLC. Materials and Methods: Eleven patients with ALK-rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records. Results: The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 020.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively. Conclusion: Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK-rearranged NSCLC.
  • Satomi Watanabe; Hidetoshi Hayashi; Kazuhiko Nakagawa
    Annals of Translational Medicine AME Publishing Company 4 (11) 225 - 225 2305-5847 2016/06 [Refereed]
  • Satomi Watanabe; Masayuki Takeda; Takayuki Takahama; Tsutomu Iwasa; Junji Tsurutani; Junko Tanizaki; Toshio Shimizu; Kazuko Sakai; Yoshitaka Wada; Noritaka Isogai; Kazuto Nishio; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS SPRINGER 34 (3) 394 - 396 0167-6997 2016/06 [Refereed]
     
    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.
  • K. Haratani; H. Hayashi; S. Watanabe; H. Kaneda; T. Yoshida; M. Takeda; T. Shimizu; K. Nakagawa
    ANNALS OF ONCOLOGY OXFORD UNIV PRESS 27 (1) 200 - 202 0923-7534 2016/01 [Refereed]
  • Naoki Takegawa; Kimio Yonesaka; Kazuko Sakai; Hiroto Ueda; Satomi Watanabe; Yoshikane Nonagase; Tatsuya Okuno; Masayuki Takeda; Osamu Maenishi; Junji Tsurutani; Taroh Satoh; Isamu Okamoto; Kazuto Nishio; Takao Tamura; Kazuhiko Nakagawa
    ONCOTARGET IMPACT JOURNALS LLC 7 (3) 3443 - 3450 1949-2553 2016/01 [Refereed]
     
    Background: Patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS benefit from epidermal growth factor receptor (EGFR)-targeted therapy. However, patients who are treated with anti-EGFR antibodies will eventually develop the resistance to those agents. HER2 amplification is one of the mechanisms conferring resistance to anti-EGFR antibody therapy and could therefore be a potential therapeutic target. The aim of this study was to detect HER2 amplification in circulating tumor DNA (ctDNA) from patients with CRC and acquired resistance to anti-EGFR antibody therapy Results: Our data showed that 22% (4/18) of patients in the cohort exhibited HER2 amplification. One of these patients was found to be positive for HER2 amplification in matched tumor specimens collected after cetuximab therapy, at which point the patient had acquired cetuximab resistance, despite being negative for HER2 amplification prior to therapy. Methods: We analyzed plasma ctDNA using digital polymerase chain reaction (PCR) from 18 patients with CRC, who had been treated with anti-EGFR antibody-based therapy (cetuximab) and subsequently acquired resistant cetuximab. HER2 gene copy number was analyzed using fluorescence in situ hybridization in tumor samples before and after acquisition of resistance to cetuximab-based therapy. Conclusion: Analysis of plasma ctDNA by digital PCR could be useful for detecting HER2 amplification in patients with CRC who were resistant to anti-EGFR antibody therapy.
  • Kimio Yonesaka; Keita Kudo; Satomi Nishida; Takayuki Takahama; Tsutomu Iwasa; Takeshi Yoshida; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Isamu Okamoto; Kazuto Nishio; Kazuhiko Nakagawa
    ONCOTARGET IMPACT JOURNALS LLC 6 (32) 33602 - 33611 1949-2553 2015/10 [Refereed]
     
    Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non-small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF-TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulin-overexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulin-mediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance.
  • ホルモン陽性転移・再発乳癌に対するフルベストラントの治療成績 自験例51例の後ろ向き検討
    菰池 佳史; 久保田 倫代; 濱田 未佳; 新崎 亘; 安積 達也; 橋本 幸彦; 乾 浩己; 北條 敏也; 西田 諭美; 岩朝 勉; 鶴谷 純司; 藤島 成; 大和 宗久
    日本乳癌学会総会プログラム抄録集 (一社)日本乳癌学会 23回 637 - 637 2015/07

MISC

Research Grants & Projects

  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists
    Date (from‐to) : 2019/04 -2021/03 
    Author : WATANABE Satomi
     
    AAAWe analyzed 20 patients with metastatic or recurrent extramammary Paget’s disease (EMPD). Protein expressions and gene expression analysis were performed, and we evaluated the relationship between the tumor profile and the treatment outcome and the survival. HER2 gene alteration was observed in a fraction of patients with EMPD, furthermore, HER2 positive patients who have received anti-HER2 targeted therapies showed apparent survival benefit compared to those who have not. On the other hand, gene expression analysis revealed overexpression of several gene expression pathways in EMPD tumors when compared with breast cancer tumors, which should be further investigated as potential treatment targets. Regarding immune environment, CD274 (PD-L1) overexpression was observed in EMPD patients, which indicated the potency of therapeutical development using immune check point inhibitors.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2016/04 -2019/03 
    Author : YOSHIDA Takeshi; WATANABE satomi
     
    We evaluated the efficacy of dasatinib combined with the T790M-selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation-positive NSCLC with or 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 downregulation 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 EGFR-TKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M.

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