Elucidation of refractory mechanism to the molecular targeted therapy for renal cell carcinoma

• Project/Area Number: 15H04977
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Keio University
• Principal Investigator: Oya Mototsugu 慶應義塾大学, 医学部(信濃町), 教授 (00213885)
• Co-Investigator(Kenkyū-buntansha): 菊地 栄次 慶應義塾大学, 医学部(信濃町), 准教授 (10286552) ; 三上 修治 慶應義塾大学, 医学部(信濃町), 講師 (20338180) ; 小坂 威雄 慶應義塾大学, 医学部, 助教 (30445407) ; 篠島 利明 慶應義塾大学, 医学部(信濃町), 講師 (60306777) ; 水野 隆一 慶應義塾大学, 医学部(信濃町), 講師 (60383824) ; 浅沼 宏 慶應義塾大学, 医学部(信濃町), 准教授 (70245570) ; 宮嶋 哲 慶應義塾大学, 医学部(信濃町), 准教授 (90245572)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 腎細胞癌 / 分子標的治療 / 治療抵抗性 / リスク分類 / 免疫チェックポイント阻害薬 / 癌 / 血管新生 / 耐性

Outline of Final Research Achievements

Aryl hydrocarbon receptor (AhR) was investigated in 120 patients with RCC using immunohistochemistry. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade.
Expression of VASH1 were immunohistochemically examined. Multivariate Cox analysis indicated that an elevated VASH1 density, but not microvascular density, was a significant and independent predictor of overall survival (odds ratio, 7.71; P=0.003). Blood samples were collected at baseline in 90 patients to analyze serum angiogenic and inflammatory markers together with peripheral blood immunological marker. Immunologic (myeloid-derived suppressor cells, percentage of T helper type 1 cells) markers at baseline predicted the response to sunitinib therapy and/or disease progression in patients with metastatic renal cell carcinoma.

Research Products

• [Journal Article] 特集 腎癌に対する薬物療法─最新エビデンスを実臨床に活かす 腎癌薬物療法におけるバイオマーカー開発の進歩 (2018)
  • Author(s): 水野隆一、浅沼宏、大家基嗣
  • Journal Title: 臨床泌尿器科 Volume: 72 Issue: 1 Pages: 64-69
  • DOI: 10.11477/mf.1413206172
  • ISSN: 0385-2393, 1882-1332
  • Year and Date: 2018-01-20
  • Peer Reviewed
• [Journal Article] 腎細胞がん分子標的治療の国際比較 (2018)
  • Author(s): 水野隆一、大家基嗣
  • Journal Title: 腎臓内科・泌尿器科 Volume: 7巻1号 Pages: 44-49
  • Peer Reviewed
• [Journal Article] 特集 泌尿器癌局所療法─局所を制する者は全身を制す 〈転移巣治療〉 腎細胞癌の転移巣に対する摘出術 (2017)
  • Author(s): 高松公晴、大家基嗣
  • Journal Title: 臨床泌尿器科 Volume: 71 Issue: 13 Pages: 1096-1100
  • DOI: 10.11477/mf.1413206155
  • ISSN: 0385-2393, 1882-1332
  • Year and Date: 2017-12-20
  • Peer Reviewed
• [Journal Article] Impact of baseline visceral fat accumulation on prognosis in patients with metastatic renal cell carcinoma treated with systemic therapy. (2017)
  • Author(s): Mizuno R, Miyajima A, Hibi T, Masuda A, Shinojima T, Kikuchi E, Jinzaki M, Oya M
  • Journal Title: Med Oncol. Volume: 34(4) Issue: 4 Pages: 47-47
  • DOI: 10.1007/s12032-017-0908-3
  • Peer Reviewed / Open Access
• [Journal Article] Overall survival of first-line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study. (2017)
  • Author(s): 5.Oya M, Tomita Y, Fukasawa S, Shinohara N, Habuchi T, Rini BI, Fujii Y, Kamei Y, Umeyama Y, Bair AH et al
  • Journal Title: Cancer science Volume: 108 Issue: 6 Pages: 1231-1239
  • DOI: 10.1111/cas.13232
  • Peer Reviewed / Open Access
• [Journal Article] Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study (2017)
  • Author(s): 6.Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Kimura G, Yonese J, Yao M et al
  • Journal Title: apanese journal of clinical oncology Volume: 47 Issue: 7 Pages: 639-646
  • DOI: 10.1093/jjco/hyx049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Angiogenic, inflammatory and immunologic markers in predicting response to sunitinib in metastatic renal cell carcinoma. (2017)
  • Author(s): Mizuno R, Kimura G, Fukasawa S, Ueda T, Kondo T, Hara H, Shoji S, Kanao K, Nakazawa H, Tanabe K, Horie S, Oya M
  • Journal Title: Cancer Sci. Volume: 108(9) Issue: 9 Pages: 1858-1863
  • DOI: 10.1111/cas.13320
  • Peer Reviewed / Open Access
• [Journal Article] Baseline risk stratification or duration of prior therapy predicts prognosis in patients with metastatic renal cell carcinoma treated with axitinib. (2017)
  • Author(s): Mizuno R, Mikami S, Takamatsu K, Shinojima T, Kikuchi E, Oya M
  • Journal Title: Clin Oncol. Volume: 47(12) Issue: 12 Pages: 1170-1174
  • DOI: 10.1093/jjco/hyx134
  • Peer Reviewed / Open Access
• [Journal Article] Factors influencing the operating time for single-port laparoscopic radical nephrectomy: focus on the anatomy and distribution of the renal artery and vein. (2017)
  • Author(s): Matsumoto K, Miyajima A, Fukumoto K, Komatsuda A, Niwa N, Hattori S, Takeda T, Kikuchi E, Asanuma H, Oya M
  • Journal Title: Jpn J Clin Oncol. Volume: 47(10) Issue: 10 Pages: 976-980
  • DOI: 10.1093/jjco/hyx105
  • Peer Reviewed / Open Access
• [Journal Article] Increased vasohibin-1 expression is associated with metastasis and poor prognosis of renal cell carcinoma patients. (2017)
  • Author(s): Mikami S, Oya M, Kosaka T, Mizuno R, Miyazaki Y, Sato Y, Okada Y.
  • Journal Title: Lab Invest. Volume: － Issue: 7 Pages: 854-862
  • DOI: 10.1038/labinvest.2017.26
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 腎癌 腎癌の分子生物学と発癌機序 発症・進展メカニズム (2017)
  • Author(s): 水野隆一、大家基嗣
  • Journal Title: 日本臨床 Volume: 75巻増刊6 新腎・泌尿器癌(上) Pages: 35-38
  • Peer Reviewed
• [Journal Article] 腎癌 小児の腎癌 Wilms腫瘍(腎芽腫) (2017)
  • Author(s): 浅沼宏、大家基嗣
  • Journal Title: 日本臨床 Volume: 75巻増刊6 新腎・泌尿器癌(上) Pages: 387-390
  • Peer Reviewed
• [Journal Article] 腎癌 小児の腎癌 腎細胞癌 (2017)
  • Author(s): 浅沼宏、水野隆一、大家基嗣
  • Journal Title: 日本臨床 Volume: 75巻増刊6 新腎・泌尿器癌(上) Pages: 391-395
  • Peer Reviewed
• [Journal Article] がん転移学の基礎研究 がんの発生進展の分子機構 腎癌の分子生物学と発がん機序 (2017)
  • Author(s): 高松公晴、大家基嗣
  • Journal Title: 日本臨床 Volume: 75巻増刊8 がん転移学(上) Pages: 203-207
  • Peer Reviewed
• [Journal Article] Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma treated with first-line and subsequent second-line targeted therapy: A proposal of the modified-IMDC risk model. (2016)
  • Author(s): Tanaka N, Mizuno R, Yasumizu Y, Ito K, Shirotake S, Masunaga A, Ito Y, Miyazaki Y, Hagiwara M, Kanao K, Mikami S, Nakagawa K, Momma T, Masuda T, Asano T, Oyama M, Oya M
  • Journal Title: Urol Oncol Volume: 35(2) Issue: 2 Pages: 19-39
  • DOI: 10.1016/j.urolonc.2016.10.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impact of Second-Line Targeted Therapy Dose Intensity on Patients With Metastatic Renal Cell Carcinoma (2016)
  • Author(s): Shirotake S, Yasumizu Y, Ito K, Masunaga A, Ito Y, Miyazaki Y, Hagiwara M, Kanao K, Mikami S, Nakagawa K, Momma T, Masuda T, Asano T, Oyama M, Tanaka N, Mizuno R, Oya M
  • Journal Title: Clin Genitourin Cancer Volume: Epub ahead of print Issue: 6 Pages: e575-e583
  • DOI: 10.1016/j.clgc.2016.03.014
  • Peer Reviewed / Open Access
• [Journal Article] Effect of reclassification of the IMDC model in patients with metastatic renal cell carcinoma treated with targeted therapy in the first-line and second-line settings (2016)
  • Author(s): Tanaka N, Mizuno R, Shirotake S, Ito K, Yasumizu Y, Masunaga A, Ito Y, Miyazaki Y, Hagiwara M, Kanao K, Mikami S, Nakagawa K, Momma T, Masuda T, Asano T, Oyama M, Oya M
  • Journal Title: Urol Oncol Volume: Epub ahead of print Issue: 7 Pages: 293.e17-293.e25
  • DOI: 10.1016/j.urolonc.2016.02.023
  • Peer Reviewed / Open Access
• [Journal Article] Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer. (2016)
  • Author(s): Hashimoto, S,. Mikami, S., Sugino, H., Yoshikawa, A., Hashimoto, A., Onodera, Y., Furukawa, S., Handa, H., Oikawa, T., Okada, Y., Oya, M. and Sabe, H.
  • Journal Title: Nat. Commun. Volume: 7 Issue: 1 Pages: 10656-10656
  • DOI: 10.1038/ncomms10656
  • NAID: 120005743066
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Plasma fibrinogen level: An independent prognostic factor for disease-free survival and cancer-specific survival in patients with localized renal cell carcinoma (2016)
  • Author(s): Obata J, Tanaka N, Mizuno R, Kanao K, Mikami S, Matsumoto K, Kosaka T, Kikuchi E, Jinzaki M, Oya M
  • Journal Title: BJU Int Volume: Epub ahead of print Issue: 4 Pages: 598-603
  • DOI: 10.1111/bju.13414
  • Peer Reviewed / Open Access
• [Journal Article] How does visceral obesity affect surgical performance in laparoscopic radical nephrectomy? (2015)
  • Author(s): Yuge K, Miyajima A, Jinzaki M, Kaneko G, Hagiwara M, Hasegawa M, Takeda T, Kikuchi E, Nakagawa K, Oya M
  • Journal Title: Jpn J Clin Oncol Volume: 45(4) Issue: 4 Pages: 373-7
  • DOI: 10.1093/jjco/hyv001
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic Impact of Renin-Angiotensin System Blockade on Renal Cell Carcinoma After Surgery. (2015)
  • Author(s): Miyajima A, Yazawa S, Kosaka T, Tanaka N, Shirotake S, Mizuno R, Kikuchi E, Oya M.
  • Journal Title: Ann Surg Oncol Volume: 22 Issue: 11 Pages: 3751-3759
  • DOI: 10.1245/s10434-015-4436-0
  • Peer Reviewed / Open Access
• [Journal Article] Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke. (2014)
  • Author(s): Ishida M, Mikami S, Shinojima T, Kosaka T, Mizuno R, Kikuchi E, Miyajima A, Okada Y, Oya M
  • Journal Title: Int J Cancer Volume: Epub ahead of print Issue: 2 Pages: 299-310
  • DOI: 10.1002/ijc.29398
  • Peer Reviewed / Open Access
• [Presentation] Real-world data analysis of patients treated with immune checkpoint inhibitors in Japan. (2017)
  • Author(s): Oya M
  • Organizer: Asia Urological Oncology Forum
  • Int'l Joint Research / Invited
• [Presentation] The efficacy and safety of sorafenib in patients with renal insufficiency of advanced renal cell carcinoma: Real- world data of sorafenib in Japan. (2017)
  • Author(s): Tatsugami K, Oya M, Kabu K, Akaza H
  • Organizer: ESMO Congress
  • Int'l Joint Research
• [Presentation] 分子標的薬～Real World Dataの衝撃～ (2017)
  • Author(s): 大家基嗣
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] 当院における腹腔鏡下副腎部分切除術の術式確立の試み (2017)
  • Author(s): 勝井政博、宮嶋哲、森田伸也、松本一宏、篠田和伸、小坂威雄、水野隆一、篠島利明、菊地栄次、浅沼宏、大家基嗣
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] 転移性淡明型腎細胞癌に対する1次分子標的薬開始後の血液マーカーの変化を加味した無増悪生存期間の予測 (2017)
  • Author(s): 伊藤敬一、升永綾子、水野隆一、田中伸之、城武卓、安水洋太、伊藤祐二郎、宮崎保匡、荻原正幸、金尾健人、三上修治、門間哲雄、中川健、増田毅、小山政史、浅野友彦、大家基嗣
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] 血管新生阻害薬に対して初期耐性を示した進行性腎細胞癌症例の特徴 (2017)
  • Author(s): 篠島利明、水野隆一、松本一宏、森田伸也、篠田和伸、小坂威雄、菊地栄次、浅沼宏、宮嶋哲、大家基嗣
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] 免疫チェックポイント阻害剤の現状と今後の展望 (2017)
  • Author(s): 水野隆一、三上修治、大家基嗣
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] 進行性腎細胞がん治療における免疫チェックポイント阻害薬の現状と今後の展望 (2017)
  • Author(s): 水野隆一、大家基嗣
  • Organizer: 第26回日本腎泌尿器疾患予防医学研究会
• [Presentation] ニボルマブ関連間質性肺炎に対してステロイドが有効であった転移性腎細胞癌の1例 (2017)
  • Author(s): 岩佐俊、水野隆一、寺西悠、森田伸也、篠田和伸、小坂威雄、篠島利明、菊地栄次、浅沼宏、秋田大宇、陣崎雅弘、額賀重成、大家基嗣
  • Organizer: 第82回日本泌尿器科学会東部総会
• [Presentation] 腎細胞癌治療におけるTKIの意義と今後の課題 (2017)
  • Author(s): 大家基嗣
  • Organizer: 日本泌尿器腫瘍学会第3回学術集会
• [Presentation] Keynote lecture：腎癌薬物療法：発展の軌跡と今後 (2017)
  • Author(s): 大家基嗣
  • Organizer: 第67回日本泌尿器科学会中部総会
• [Presentation] 腎細胞癌とはどのような癌か？-臨床的特徴から迫る腎細胞癌の最新トピックス- (2016)
  • Author(s): 大家基嗣
  • Organizer: 第54回日本癌治療学会学術集会
  • Place of Presentation: パシフィコ横浜（横浜市西区）
  • Year and Date: 2016-10-20
• [Presentation] 進行性腎細胞癌に対してチロシンキナーゼ阻害薬後にエベロリムスを用いた症例の腎機能変化の検討 (2016)
  • Author(s): 早川望、水野隆一、森田伸也、篠田和伸、平橋淳一、吉田理、宮嶋哲、林松彦、大家基嗣
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市西区）
  • Year and Date: 2016-06-17
• [Presentation] 維持血液透析患者に生じた腎細胞癌組織を用いた遺伝子変異解析 (2016)
  • Author(s): 水野隆一、森田伸也、篠田和伸、大家基嗣、平橋淳一、吉田理、林松彦
  • Organizer: 第61回日本透析医学会学術集会・総会
  • Place of Presentation: 大阪国際会議場（大阪市北区）
  • Year and Date: 2016-06-09
• [Presentation] Metastatic renal cell carcinoma to the bladder: systematic review of 113 reported cases (2016)
  • Author(s): Matsumoto K, Hayakawa N, Mizuno R, Kikuchi E, Miyajima A, Oya M
  • Organizer: 2016 AUA Annual Meeting
  • Place of Presentation: サンディエゴ（アメリカ）
  • Year and Date: 2016-05-06
  • Int'l Joint Research
• [Presentation] Clinical outcomes in patients with metastatic papillary renal cell carcinoma: A Japanese multi-institutional study (2016)
  • Author(s): Ito K, Mikami S, Tatsugami K, Masumori N, Shinohara N, Kondo T, Nakanishi S, Nagashima Y, Eto M, Kamba T, Kuroda N, Tomita Y, Matsuyama H, Onishi T, Tsushima T, Nakazawa H, Oya M, Ozono S, Naito S, Asano T
  • Organizer: 2016 AUA Annual Meeting
  • Place of Presentation: サンディエゴ（アメリカ）
  • Year and Date: 2016-05-06
  • Int'l Joint Research
• [Presentation] 血管新生阻害薬に対して内因性耐性を示した進行性腎細胞癌症例の転帰 (2016)
  • Author(s): 篠島利明、水野隆一、松本一宏、森田伸也、篠田和伸、小坂威雄、菊地栄次、浅沼宏、宮嶋哲、大家基嗣
  • Organizer: 第104回日本泌尿器科学会総会
  • Place of Presentation: 仙台国際センター（仙台市青葉区）
  • Year and Date: 2016-04-23
• [Presentation] Clinical impact of the dose modification of second-line targeted therapy for patients with metastatic renal cell carcinoma (2016)
  • Author(s): Shirotake S, Yasumizu Y, Tanaka N, Mizuno R, Ito Y, Miyazaki Y, Masunaga A, Ito K, Hagiwara M, Asano T, Oya M, Oyama M
  • Organizer: 31th Annual EAU Congress
  • Place of Presentation: ミュンヘン（ドイツ）
  • Year and Date: 2016-03-11
  • Int'l Joint Research
• [Presentation] A prospective multicentre biomarker identification trial for sunitinib in Japanese patients with metastatic RCC (2016)
  • Author(s): Mizuno R, Kimura G, Ueda T, Kondo T, Hara H, Shoji S, Kanao K, Nakazawa H, Tanabe K, Horie S, Oya M
  • Organizer: 31th Annual EAU Congress
  • Place of Presentation: ミュンヘン（ドイツ）
  • Year and Date: 2016-03-11
  • Int'l Joint Research
• [Presentation] Renal function in advanced renal cell carcinoma patients treated with sorafenib: Subset analyses of post-marketing surveillance in Japan with over 3,200 consecutive cases (2016)
  • Author(s): Oya M, Kabu K, Adachi M, Ito Y, Akaza H
  • Organizer: 2016 Genitourinary Cancers Symposium
  • Place of Presentation: サンフランシスコ（アメリカ）
  • Year and Date: 2016-01-07
  • Int'l Joint Research
• [Presentation] Impact of precise quantitative assessment of visceral obesity on outcomes of patients with metastatic renal cell carcinoma treated with systemic therapy (2016)
  • Author(s): Mizuno R, Miyajima A, Hayakawa N, Kikuchi E, Mikami S, Jinzaki M, Oya M
  • Organizer: 2016 Genitourinary Cancers Symposium
  • Place of Presentation: サンフランシスコ（アメリカ）
  • Year and Date: 2016-01-07
  • Int'l Joint Research
• [Presentation] Role of TNF-α and CD44 in resistance to sunitinib treatment in clear cell renal cell carcinomas (2015)
  • Author(s): Oya M
  • Organizer: 35th CONGRESS OF THE SOCIETE INTERNATIONALE D’ UROLOGIE
  • Place of Presentation: メルボルン（オーストラリア）
  • Year and Date: 2015-10-15
  • Int'l Joint Research
• [Presentation] Predictors of renal dysfunction during everolimus treatment in patients with metastatic renal cell carcinoma (2015)
  • Author(s): Mizuno R, Takahashi R, Shinojima T, Kosaka T, Miyajima A, Oya M
  • Organizer: 2015 ASCO Annual Meeting
  • Place of Presentation: シカゴ（アメリカ）
  • Year and Date: 2015-05-29
  • Int'l Joint Research
• [Presentation] Plasma fibrinogen level independently predicts the prognosis of patients with non-metastatic renal cell carcinoma (2015)
  • Author(s): Obata J, Tanaka N, Mizuno R, Morita S, Shinoda K, Kosaka T, Shinojima T, Kikuchi E, Asanuma H, Miyajima A, Oya M
  • Organizer: The 110th American Urological Association Annual Meeting
  • Place of Presentation: ニューオーリンズ（アメリカ）
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Book] Year Book of RCC 2017 (2018)
  • Author(s): 冨田 善彦、金山 博臣、植村 天受、篠原 信雄
  • Total Pages: 148
  • Publisher: メディカルレビュー社
  • ISBN: 9784779219962