Development of the novel therapy for renal cell carcinoma resistance to molecular targeting therapy using the assessment by FDG PET/CT

• Project/Area Number: 16K11021
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Yokohama City University
• Principal Investigator: Nakaigawa Noboru 横浜市立大学, 医学部, 准教授 (00237207)
• Co-Investigator(Kenkyū-buntansha): 矢尾 正祐 横浜市立大学, 医学研究科, 教授 (00260787) ; 近藤 慶一 横浜市立大学, 附属病院, 准教授 (80363836)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 腎細胞癌 / 分子標的治療薬 / 抵抗性獲得機序 / ブドウ糖集積 / FDG PET/CT / 腎癌 / バイオマーカー / 免疫チェックポイント阻害剤 / j腎細胞癌 / 血液マーカー / ＦＤＧ ＰＥＴ／ＣＴ / プロテオミクス解析 / 薬物効果判定 / 抵抗性獲得 / 新規治療

Outline of Final Research Achievements

We identified the candidates of the blood biomarker which assess the anti-tumor effect of tyrosine kinase inhibitor for vascular endothelial growth factor receptor (VEGFr-TKI) to renal cell carcinoma (RCC) in real time, using the blood samples gained from the patients who were monitored by FDG PET/CT. This biomarker could predict not only the progression free survival of VEGFr-TKI, but also the response to mTOR inhibitor of RCC. Based on the sequential FDG PET/CT monitoring of RCC treated by VEGFr-TKI, we clarified the resistance acquisition mechanism of RCC to VEGFr-TKI which was regulated by mTOR protein signal. Additionally, we revealed that the early assessment using FDG PET/CT was useful for predicting the anti-tumor effect of immune checkpoint inhibitor to RCC.

Academic Significance and Societal Importance of the Research Achievements

病態を評価する血液バイオマーカーが確立されていない腎細胞癌において腫瘍径の著明な変化を来さずに抗腫瘍効果を発揮することのある血管新生阻害剤、mTOR阻害剤、免疫チェックポイント阻害剤の効果判定は従来のCT画像評価だけでは困難であり、治療の切り替えのタイミングが臨床上大きな課題となっている。我々が同定した血液バイオマーカーとFDG PET/CTによって治療中の腎細胞癌をモニタリングすることにより効率の高い治療体系を確立できれば、進行性腎細胞癌患者さんの生命予後の延長が期待できるだけでなく、無効な治療を継続することで生じる副作用による生活の質の低下や医療費の高騰を防ぐことが可能と思われた。

Research Products

• [Journal Article] Early assessment with 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography to predict short-term outcome in clear cell renal carcinoma treated with nivolumab (2019)
  • Author(s): Tabei T, Nakaigawa N, Kaneta T, Ikeda I, Kondo K, Makiyama K, Hasumi H, Hayashi N, Kawahara T, Izumi K, Osaka K, Muraoka K, Teranishi JI, Miyoshi Y, Yumura Y, Uemura H, Kobayashi K, Inoue T, Yao M.
  • Journal Title: BMC Cancer Volume: 19 Issue: 1 Pages: 298-298
  • DOI: 10.1186/s12885-019-5510-y
  • Peer Reviewed / Open Access
• [Journal Article] FDG PET/CT after first molecular targeted therapy predicts survival of patients with renal cell carcinoma. (2018)
  • Author(s): Nakaigawa N, Kondo K, Kaneta T, Tateishi U, Minamimoto R, Namura K, Ueno D, Kobayashi K, Kishida T, Ikeda I, Hasumi H, Makiyama K, Hayashi N, Osaka K, Muraoka K, Izumi K, Kawahara T, Teranishi JI, Miyoshi Y, Yumura Y, Uemura H, Inoue T, Yao M.
  • Journal Title: Cancer Chemother Pharmacol. Volume: 81 Issue: 4 Pages: 739-744
  • DOI: 10.1007/s00280-018-3542-7
  • Peer Reviewed
• [Journal Article] The acceleration of glucose accumulation in renal cell carcinoma assessed by FDG PET/CT demonstrated acquisition of resistance to tyrosine kinase inhibitor therapy. (2017)
  • Author(s): Nakaigawa N, Kondo K, Ueno D, Namura K, Makiyama K, Kobayashi K, Shioi K, Ikeda I, Kishida T, Kaneta T, Minamimoto R, Tateishi U, Inoue T, Yao M.
  • Journal Title: BMC Cancer. Volume: １７ Issue: 1 Pages: 39-39
  • DOI: 10.1186/s12885-016-3044-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 3. One-month assessment of renal cell carcinoma treated by everolimus using FDG PET/CT predicts progression-free and overall survival. (2017)
  • Author(s): Ito H, Kondo K, Kawahara T, Kaneta T, Tateishi U, Ueno D, Namura K, Kobayashi K, Miyoshi Y, Yumura Y, Makiyama K, Hayashi N, Hasumi H, Osaka K, Yokomizo Y, Teranishi JI, Hattori Y, Inoue T, Uemura H, Yao M, Nakaigawa N.
  • Journal Title: Cancer Chemother Pharmacol Volume: ７９ Issue: 5 Pages: 855-861
  • DOI: 10.1007/s00280-017-3275-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] FDG PET/CT to predict short-term outcome in clear cell renal carcinoma treated with nivolumab. (2019)
  • Author(s): Nakaigawa N, Tabei T, Kondo K, Kaneta T, Kobayashi K, Ikeda I, Inoue T, Yao M.
  • Organizer: American Society of Clinical Oncology Annual meeting
  • Int'l Joint Research
• [Presentation] Immuno-Oncological therapy for renal carcinoma: the current state of Japan (2019)
  • Author(s): Nakaigawa N
  • Organizer: The 35th Korea-Japan Urological Congress
  • Int'l Joint Research / Invited
• [Presentation] Japan multicenter prospective study: FDG PET/CT in the assessment of advanced renal cell carcinoma treated with sorafenib (2018)
  • Author(s): Nakaigawa N, Tateishi U, Kato T, Kaneta T, Kondo K, Sugimoto M, Yao M, Inoue T, Kakehi Y, Kubota Y
  • Organizer: ASCO GU