Exploration of biomarkers for the choice of chemotherapy in colorectal cancer patients

• Project/Area Number: 17K07204
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnostics
• Research Institution: Kindai University
• Principal Investigator: FUJITA Yoshihiko 近畿大学, 医学部, 講師 (80192730)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 進行性大腸がん / irinotecan / oxaliplatin / bevacizumab / CGH アレイ法 / 遺伝子コピー数増加 / FOLFOX 療法 / FOLFIRI療法 / バイオマーカー

Outline of Final Research Achievements

Among patients of metastatic colorectal cancer (mCRC) with copy number gain (CNG) at chromosome 8q24.1-q24.2 (~ 40% of the patients), response rate and prognosis factors (OS and PFS) were better for those treated with irinotecan(iri)-based than those with oxaliplatin(ox)-based combination chemotherapy. Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either iri- or ox-based chemotherapy in combination with bevacizumab for treatment of mCRC patients. Myc-knocked down Colo320 cells (with a CNG at 8q24.1-24.2) reduced sensitivity to SN38, but Myc-overexpressed DLD1 cells (without CNG at 8q24.1-24.2) did not, suggesting that Myc is not indispensable factor for iri sensitivity. Fam84B-overexpressed DLD1 cells increase sensitivity to SN38, suggesting that this gene that resides in the 8q24.1-24.2 region could be a critical factor to choose ox- or iri-based chemotherapy in combination with bevacizumab for treatment of mCRC patients.

Academic Significance and Societal Importance of the Research Achievements

これまで大腸がん患者へのベバシズマブの併用療法としてFOLFOX療法またはFOLFIRI療法のどちらを選択するか決まった指針がなかった。今回の結果から、がん部DNAにおける8q24.1-q24.2染色体領域に遺伝子増幅がある患者は全体の約40%を占め、そのような患者ならばFOLFOX療法よりFOLFIRI療法を採用するのが良いことが示された。また、この染色体上におけるMYC、FAM84B遺伝子が薬剤感受性に関与することから、効果予測バイオマーカーの特定のみならず大腸がん患者の分子標的治療への道が拓けた。これらのことは臨床的にはたいへん意義深いことである。

Research Products

• [Journal Article] Clinical and immune profiling for cancer of unknown primary site. (2019)
  • Author(s): 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 Title: Journal for immunotherapy of cancer Volume: 7 Issue: 1 Pages: 251-251
  • DOI: 10.1186/s40425-019-0720-z
  • Peer Reviewed / Open Access
• [Journal Article] aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer. (2019)
  • Author(s): Fujita Y, Taguri M, Yamazaki K, Tsurutani J, Sakai K, Tsushima T, Nagase M, Tamagawa H, Ueda S, Tamura T, Tsuji Y, Murata K, Taira K, Denda T, Moriwaki T, Funai S, Nakajima TE, Muro K, Tsuji A, Yoshida M, Suyama K, Kurimoto T, Sugimoto N, Baba E, Seki N, Sato M, Shimura T, Boku N, Hyodo I, Yamanaka T, Nishio K.
  • Journal Title: Oncologist. Volume: 24 Issue: 3 Pages: 327-337
  • DOI: 10.1634/theoncologist.2018-0119
  • Peer Reviewed / Open Access
• [Journal Article] Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site (2019)
  • Author(s): Hayashi Hidetoshi、Kurata Takayasu、Takiguchi Yuichi、Arai Makoto、Takeda Koji、Akiyoshi Kohei、Matsumoto Koji、Onoe Takuma、Mukai Hirofumi、Matsubara Nobuaki、Minami Hironobu、Toyoda Masanori、Onozawa Yusuke、Ono Akira、Fujita Yoshihiko、Sakai Kazuko、et al.
  • Journal Title: Journal of Clinical Oncology Volume: 37 Issue: 7 Pages: 570-579
  • DOI: 10.1200/jco.18.00771
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Selection of opioids for cancer-related pain using a biomarker: a randomized, multi-institutional, open-label trial (RELIEF study). (2017)
  • Author(s): Matsuoka H, Tsurutani J, Chiba Y, Fujita Y, Terashima M, Yoshida T, Sakai K, Otake Y, Koyama A, Nishio K, Nakagawa K
  • Journal Title: BMC Cancer Volume: 17 Issue: 1 Pages: 674-674
  • DOI: 10.1186/s12885-017-3664-z
  • Peer Reviewed / Open Access
• [Journal Article] Prospective replication study implicates the catechol-O-methyltransferase Val158Met polymorphism as a biomarker for the response to morphine in patients with cancer. (2017)
  • Author(s): Matsuoka H, Makimura C, Koyama A, Fujita Y, Tsurutani J, Sakai K, Sakamoto R, Nishio K, Nakagawa K.
  • Journal Title: Biomed Rep Volume: 7 Issue: 4 Pages: 380-384
  • DOI: 10.3892/br.2017.963
  • Peer Reviewed
• [Journal Article] Expectation of a Decrease in Pain Affects the Prognosis of Pain in Cancer Patients: a Prospective Cohort Study of Response to Morphine. (2017)
  • Author(s): Matsuoka H, Yoshiuchi K, Koyama A, Makimura C, Fujita Y, Tsurutani J, Sakai K, Sakamoto R, Nishio K, Nakagawa K.
  • Journal Title: Int J Behav Med Volume: 24 Pages: 535-541
  • Peer Reviewed
• [Presentation] 大腸がん治療法選択のためのバイオマーカーの探索的研究 (2019)
  • Author(s): 藤田 至彦、坂井 和子、山崎 健太郎、西尾 和人
  • Organizer: 日本がん分子標的治療学会学術集会
• [Presentation] Exploration of biomarkers for the choice of chemotherapy in colorectal cancer patients (2019)
  • Author(s): 藤田 至彦
  • Organizer: 日本臨床腫瘍学会学術集会
• [Presentation] Novel target molecules for treatment of cancer of unknown primary (2018)
  • Author(s): Yoshihiko Fujita
  • Organizer: 109th AACR Annual Meeting
• [Presentation] Target molecules for treatment of cancer of unknown primary site (2018)
  • Author(s): Yoshihiko Fujita
  • Organizer: 第22回日本がん分子標的治療学会
• [Presentation] Novel target molecules for treatment of cancer of unknown primary (2018)
  • Author(s): Yoshihiko Fujita, Kazuko Sakai, Marco De Velasco,Takayasu Kurata, Hidetoshi Hayashi, Kazuhiko Nakagawa, Kazuto Nishio
  • Organizer: 米国癌学会年会
  • Int'l Joint Research