Towards the personalized medicine for metastatic renal cell cancer

• Project/Area Number: 16K11035
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: YUASA Takeshi 公益財団法人がん研究会, 有明病院 泌尿器科, 副部長 (00314162)
• Research Collaborator: YONESE junichi ; ISHIKAWA yuichi ; ISONO takahiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 腎癌 / 分子標的治療 / 予後因子 / 血管新生阻害剤 / バイオマーカー / 糖枯渇 / HIF-2 / ミトコンドリア機能 / VHL / 治療耐性 / 次世代シーケンサー / 遺伝子発現 / 遺伝子変異

Outline of Final Research Achievements

One of the most important efficacies of angiogenesis inhibitors is glucose deprivation for RCC cells. We investigated the mechanism of resistance against glucose deprivation of cancer cell. We found that the resistant type possessed higher activities for both mitochondrial oxidative phosphorylation and glycolysis than the sensitive types. These higher activities were supported by the stored carbon, lipid and carbohydrate sources, and by a low level of mitochondrial ROS due to sustained SOD2 expression in the resistant RCC cells. Next, deprivation-resistant RCC, that had lost von Hippel-Lindau (VHL) tumor suppressor expression, expressed hydroxyl-HIF2-alpha in the nucleus, but not sensitive- RCCs. Hydroxyl-HIF2-alpha might be a potential therapeutic target for RCCs. At last, by global transcriptome analysis, ARL4C was shown to be a predictive biomarker for poor prognosis in patients with RCC and may be a novel target in the treatment of RCC.

Academic Significance and Societal Importance of the Research Achievements

転移性腎細胞癌に対して、血管新生阻害剤治療時においてHIF-2(hypoxia inducible factor)シグナルによる治療耐性をあきらかにし、新規の予後不良遺伝子ADP-ribosylation factor-like 4Cを同定することによって将来的に新たな治療戦略の基礎になる可能性がある。さらにInternational Metastatic renal cell cancer database Consortium (IMDC)国際共同研究は後方視的研究ではあるが、現時点の実臨床における様々な問題点を解決するヒントになっていると思う。

Research Products

• [Journal Article] Hydroxyl-HIF2-alpha is potential therapeutic target for renal cell carcinomas. (2019)
  • Author(s): Isono T, Chano T, Yoshida T, Kageyama S, Kawauchi A, Suzaki M, Yuasa T:
  • Journal Title: Am J Cancer Res Volume: 9 Pages: 415-423
  • Peer Reviewed / Open Access
• [Journal Article] Checkpoint inhibitors in patients with metastatic renal cell carcinoma: Results from the international metastatic renal cell carcinoma database consortium. (2018)
  • Author(s): Yip SM, Wells C, Moreira R, Wong A, Srinivas S, Beuselinck B, Porta C, Sim HW, Ernst DS, Rini BI, Yuasa T, Basappa NS, Kanesvaran R, Wood LA, Canil C, Kapoor A, Fu SYF, Choueiri TK, Heng DYC.
  • Journal Title: Cancer Volume: 124 Issue: 18 Pages: 3677-3683
  • DOI: 10.1002/cncr.31595
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Abundance of TRAIL attenuated by HIF2α and c-FLIP affects malignancy in renal cell carcinomas. (2018)
  • Author(s): Isono T, Chano T, Yoshida T, Kageyama S, Kawauchi A, Yonese J, Yuasa T
  • Journal Title: Oncotarget. Volume: 9 Issue: 33 Pages: 23091-23101
  • DOI: 10.18632/oncotarget.25214
  • Peer Reviewed / Open Access
• [Journal Article] Superoxide dismutase 2 expression can predict prognosis of renal cell carcinoma patients (2018)
  • Author(s): Yoshida Tetsuya、Kageyama Susumu、Isono Takahiro、Yuasa Takeshi、Kushima Ryoji、Kawauchi Akihiro、Chano Tokuhiro
  • Journal Title: Cancer Biomarkers Volume: 22 Issue: 4 Pages: 755-761
  • DOI: 10.3233/cbm-181308
  • Peer Reviewed
• [Journal Article] Preliminary Kidney Parenchymal Ligation Using Endoloop Ligatures-A Simple Method to Achieve a Trifecta in Laparoscopic Partial Nephrectomy Without Hilar Clamping for Polar Complex Tumors. (2018)
  • Author(s): Komai Y, Gotohda N, Matsubara N, Takeda H, Yuasa T, Inoue M, Yamamoto S, Yonese J.
  • Journal Title: Urology. Volume: 121 Pages: 182-188
  • DOI: 10.1016/j.urology.2018.08.023
  • Peer Reviewed
• [Journal Article] Recent advances in medical therapy for metastatic urothelial cancer. (2018)
  • Author(s): Yuasa T, Urakami S, Yonese J.
  • Journal Title: Int J Clin Oncol. Volume: 23 Issue: 4 Pages: 599-607
  • DOI: 10.1007/s10147-018-1260-0
  • Peer Reviewed / Open Access
• [Journal Article] Editorial comment to Prognostic impact of the pretreatment aspartate transaminase/alanine transaminase ratio in patients treated with tyrosine kinase inhibitors as a first-line therapy for metastatic renal cell carcinoma. (2018)
  • Author(s): Yuasa T.
  • Journal Title: Int J Urol Volume: in press
  • Peer Reviewed
• [Journal Article] Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations. (2018)
  • Author(s): Albiges L, Hakimi AA, Xie W, McKay RR, Simantov R, Lin X, Lee JL, Rini BI, Srinivas S, Bjarnason GA, Ernst S, Wood LA, Vaishamayan UN, Rha SY, Agarwal N, Yuasa T, Pal SK, Bamias A, Zabor EC, Skanderup AJ, Furberg H, Fay AP, de Velasco G, Preston MA, Wilson KM, Cho E, McDermott DF, Signoretti S, Heng DY, Choueiri TK.
  • Journal Title: J Clin Oncol. Volume: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Biomarkers to predict prognosis and response to checkpoint inhibitors. (2017)
  • Author(s): Yuasa T, Masuda H, Yamamoto S, Numao N, Yonese J.
  • Journal Title: Int J Clin Oncol. Volume: 22 Issue: 4 Pages: 629-634
  • DOI: 10.1007/s10147-017-1122-1
  • Peer Reviewed / Open Access
• [Journal Article] A case of gastric metastasis from renal cell cancer during the sequential targeted therapy. (2017)
  • Author(s): Uehara S, Yuasa T, Fujisaki J, Fujii Y, Yamamoto S, Masuda H, Fukui I, Yonese J.
  • Journal Title: Int Cancer Conf J. Volume: 6 Issue: 3 Pages: 114-117
  • DOI: 10.1007/s13691-017-0286-x
  • Peer Reviewed / Open Access
• [Journal Article] Editorial comment to Identification of risk factors predicting febrile neutropenia in patients with metastatic germ cell tumors receiving cisplatin-based combination chemotherapy. (2017)
  • Author(s): Yuasa T.
  • Journal Title: Int J Urol Volume: 24 Issue: 6 Pages: 453-453
  • DOI: 10.1111/iju.13365
  • Peer Reviewed
• [Journal Article] Early response of C-reactive protein as a predictor of survival in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. (2017)
  • Author(s): Yasuda Y, Saito K, Yuasa T, Uehara S, Kawamura N, Yokoyama M, Ishioka J, Matsuoka Y, Yamamoto S, Okuno T, Yonese J, Kihara K, Fujii Y.
  • Journal Title: Int J Clin Oncol. Volume: 22 Issue: 6 Pages: 1081-1086
  • DOI: 10.1007/s10147-017-1166-2
  • Peer Reviewed
• [Journal Article] Stepwise algorithm using computed tomography and magnetic resonance imaging for diagnosis of fat-poor angiomyolipoma in small renal masses: Development and external validation. (2017)
  • Author(s): Tanaka H, Fujii Y, Tanaka H, Ishioka J, Matsuoka Y, Saito K, Uehara S, Numao N, Yuasa T, Yamamoto S, Masuda H, Yonese J, Kihara K.
  • Journal Title: Int J Urol. Volume: 24 Issue: 7 Pages: 511-517
  • DOI: 10.1111/iju.13354
  • Peer Reviewed
• [Journal Article] Diagnostic performance of a computer-assisted diagnosis system for bone scintigraphy of newly developed skeletal metastasis in prostate cancer patients: search for low-sensitivity subgroups. (2017)
  • Author(s): Koizumi M, Motegi K, Koyama M, Terauchi T, Yuasa T, Yonese J.
  • Journal Title: Ann Nucl Med. Volume: 31 Issue: 7 Pages: 521-528
  • DOI: 10.1007/s12149-017-1175-2
  • Peer Reviewed
• [Journal Article] Efficacy of Second-line Targeted Therapy for Renal Cell Carcinoma According to Change from Baseline in International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Category. (2017)
  • Author(s): Davis ID, Xie W, Pezaro C, Donskov F, Wells JC, Agarwal N, Srinivas S, Yuasa T, Beuselinck B, Wood LA, Ernst DS, Kanesvaran R, Knox JJ, Pantuck A, Saleem S, Alva A, Rini BI, Lee JL, Choueiri TK, Heng DY.
  • Journal Title: Eur Urol. Volume: 71 Issue: 6 Pages: 970-978
  • DOI: 10.1016/j.eururo.2016.09.047
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Therapeutic inhibition of mitochondrial function induces cell death in starvation-resistant renal cell carcinomas. (2016)
  • Author(s): Isono T, Chano T, Yonese J, Yuasa T.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 25669-25669
  • DOI: 10.1038/srep25669
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Long-term complete response of antiandrogen withdrawal syndrome in a patient with metastatic prostate cancer: A case report. (2016)
  • Author(s): Sano M, Yamamoto S, Uehara S, Yuasa T, Masuda H, Fukui I, Yonese J.
  • Journal Title: Mol Clin Oncol. Volume: 5 Issue: 3 Pages: 208-210
  • DOI: 10.3892/mco.2016.946
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and Safety Profile of Enzalutamide for Japanese Patients with Castration-resistant Prostate Cancer. (2016)
  • Author(s): Yamasaki M, Yuasa T, Yamamoto S, Hayashi T, Ogawa M, Sakura M, Masuda H, Fukui I, Yonese J.
  • Journal Title: Anticancer Res. Volume: 36 Pages: 361-5
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Improvement of renal function by changing the bone-modifying agent from zoledronic acid to denosumab. (2016)
  • Author(s): Yamasaki M, Yuasa T, Uehara S, Fujii Y, Yamamoto S, Masuda H, Fukui I, Yonese J.
  • Journal Title: Int J Clin Oncol. Volume: unknown
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Editorial Comment to Role of routine computed tomography scan in the oncological follow up of patients treated by radical cystectomy for bladder cancer. (2016)
  • Author(s): Yuasa T.
  • Journal Title: Int J Urol. Volume: unknown Issue: 10 Pages: 846-847
  • DOI: 10.1111/iju.13178
  • Peer Reviewed
• [Journal Article] Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations (2016)
  • Author(s): Albiges L, Hakimi AA, Xie W, McKay RR, Simantov R, Lin X, Lee JL, Rini BI, Srinivas S, Bjarnason GA, Ernst S, Wood LA, Vaishamayan UN, Rha SY, Agarwal N, Yuasa T, Pal SK, Bamias A, Zabor EC, Skanderup AJ, Furberg H, Fay AP, de Velasco G, Preston MA, Wilson KM, Cho E, McDermott DF, Signoretti S, Heng DY, Choueiri TK.
  • Journal Title: J Clin Oncol. Volume: unknown
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology. (2016)
  • Author(s): Shibata H, Kato S, Sekine I, Abe K, Araki N, Iguchi H, Izumi T, Inaba Y, Osaka I, Kato S, Kawai A, Kinuya S, Kodaira M, Kobayashi E, Kobayashi T, Sato J, Shinohara N, Takahashi S, Takamatsu Y, Takayama K, Takayama K, Tateishi U, Nagakura H, Hosaka M, Morioka H, Moriya T, Yuasa T, Yurikusa T, Yomiya K, Yoshida M.
  • Journal Title: ESMO Open. Volume: 1 Pages: 37-37
  • Peer Reviewed
• [Journal Article] Hydroxyl-HIF2-alpha is potential therapeutic target for renal cell carcinomas. (2016)
  • Author(s): Isono T, Chano T, Yoshida T, Kageyama S, Kawauchi A, Suzaki M, Yuasa T:
  • Journal Title: Am J Cancer Res Volume: 6 Pages: 2263-2276
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] First-line sunitinib versus pazopanib in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. (2016)
  • Author(s): Ruiz-Morales JM, Swierkowski M, Wells JC, Fraccon AP, Pasini F, Donskov F, Bjarnason GA, Lee JL, Sim HW, Sliwczynsk A, Ptak-Chmielewska A, Teter Z, Beuselinck B, Wood LA, Yuasa T, Pezaro C, Rini BI, Szczylik C, Choueiri TK, Heng DY.
  • Journal Title: Eur J Cancer. Volume: 65 Pages: 102-8
  • DOI: 10.1016/j.ejca.2016.06.016
  • Peer Reviewed
• [Journal Article] Clinical Value of F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Upper Tract Urothelial Carcinoma: Impact on Detection of Metastases and Patient Management. . . (2016)
  • Author(s): Tanaka H, Yoshida S, Komai Y, Sakai Y, Urakami S, Yuasa T, Yamamoto S, Masuda H, Koizumi M, Kohno A, Fukui I, Yonese J, Fujii Y, Kihara K.
  • Journal Title: Urol Int Volume: 96 Issue: 1 Pages: 65-72
  • DOI: 10.1159/000381269
  • Peer Reviewed