Development of a novel therapy for colorectal cancers based on the gene mutation profiles.

Research Project

Project/Area Number	18K07218
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 50010:Tumor biology-related
Research Institution	Japanese Foundation for Cancer Research
Principal Investigator	Nagayama Satoshi 公益財団法人がん研究会, 有明病院消化器外科, 医長 (70362499)
Co-Investigator(Kenkyū-buntansha)	片山量平公益財団法人がん研究会, がん化学療法センター基礎研究部, 部長 (60435542)
Project Period (FY)	2018-04-01 – 2021-03-31
Project Status	Completed (Fiscal Year 2020)
Budget Amount *help	¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000) Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords	大腸癌 / 癌細胞株 / 薬剤感受性 / 大腸癌細胞株 / 薬効評価 / プロテオゲノムプロファイリング / 化学療法 / 遺伝子変異
Outline of Final Research Achievements	About 10% of colorectal cancer (CRC) patients harbor BRAF V600E mutation, which confers poor prognosis. Recently the combinational therapy of BRAF inhibitor with anti-EGFR antibody was approved for patients with CRC harboring BRAF V600E mutation. However, clinical benefit in the combination treatment is limited by the existence of intrinsic resistance. Therefore, new therapeutic strategies for BRAF V600E CRCs showing intrinsic resistance to the combination therapy are needed. In this study, we established more than 20 BRAF V600E CRC patient-derived cells (PDCs) from surgical specimens and examined drug sensitivity using a focused inhibitor library. More than 1/3 of BRAF-V600E PDCs showed highly resistance to BRAF and EGFR inhibition, but showed sensitivity to a kind of CDK inhibitor specifically. Our study proposed new potential therapeutic strategies to overcome the intrinsic resistance to BRAF and EGFR inhibition in BRAF V600E-mutated CRCs.
Academic Significance and Societal Importance of the Research Achievements	本研究では、患者由来の癌幹細胞様細胞株を樹立し、各種阻害剤に対する薬剤感受性を評価し、遺伝子変異状況に基づいた薬剤感受性群の選出を行ってきた。さらにプロテオーム解析も加えて、ゲノミクス・プロテオミクスデータと薬剤感受性・抵抗性データを統合して、主要なシグナル伝達系を深く解析することで、KRAS変異型およびBRAF変異型大腸癌では、なぜ標的遺伝子がありながら効果的な薬剤が見出されていないのかという問いを解明してきており、本研究は新規薬物療法の開発にも大きく貢献すると考えている。