Classification of BRAF V600E mutated colorectal cancer based on microsatellite stability

• Project/Area Number: 19K16852
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: National Hospital Organization, Kyushu Cancer Center
• Principal Investigator: Nakano Michitaka 独立行政法人国立病院機構(九州がんセンター臨床研究センター), その他部局等, 消化管・腫瘍内科医師 (30839478)
• Project Period (FY): 2020-03-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: BRAF / MSI / colorectal cancer / immune checkpoint / BRAFV600E / 大腸がん / 微小環境 / 腫瘍免疫 / マイクロサテライト / 大腸癌 / ゲノム医療

Outline of Research at the Start

切除不能進行・再発大腸がんに対する薬物療法において、既存の分子標的薬に加えて、マイクロサテライト安定性に応じた免疫チェックポイント阻害薬の有効性が示され、さらに層別化されていくことが想定される。本研究において、BRAF変異大腸がんをマイクロサテライト安定性に基づいて分類し、①網羅的な遺伝子発現解析による治療標的のスクリーニング②独自に開発したCRISPR/CAS9網羅的遺伝子ノックアウトを用いた治療標的の同定③ヒト大腸がん組織における標的分子の発現の検証、を行うことによりMSI-H/MSS BRAF変異大腸がんに対する新たな治療標的を抽出し、新規治療法開発の基盤を構築する。

Outline of Final Research Achievements

The study aims to stratify BRAF V600E mutated colorectal cancer which shows dismal prognosis by classifying them with immunogenicity. Particularly, discovering therapeutic targets in microsatellite stabie (MSS) tumor which is known to be less responsive to microsatellite instability high (MSI-H) is crucial for the personalized cancer therapy. We identified specific gene expression profiles on each of the subgroup by using 2 cohort build through TCGA and GEO database. Furthermore, nCounter gene expression panel analysis in our cohort with clinical data shows consistent data. These results will stratify the responder to checkpoint blockade in BRAF V600E mutated colorectal cancer, and discover the optimal therapeutic targets for low immunogenic BRAF V600E colorectal cancer.

Academic Significance and Societal Importance of the Research Achievements

本研究は予後不良であるBRAFV600E変異陽性(BRAF-mt)大腸がんを免疫プロファイリングに基づき分類し、新たな治療標的を探索することを目的としている。BRAF変異陽性大腸がんにおいて、免疫チェックポイント阻害薬に対する奏効群を抽出し、さらに非奏効群における最適な治療選択候補を探索することができるため、同患者群における個別化医療の推進が期待される。

Research Products

• [Int'l Joint Research] Stanford University School of Medicine(米国)
• [Journal Article] RHAMM marks proliferative subpopulation of human colorectal cancer stem cells (2023)
  • Author(s): Nakano Michitaka、Taguchi Ryosuke、Kikushige Yoshikane、Isobe Taichi、Miyawaki Kohta、Mizuno Shinichi、Tsuruta Nobuhiro、Hanamura Fumiyasu、Yamaguchi Kyoko、Yamauchi Takuji、Ariyama Hiroshi、Kusaba Hitoshi、Nakamura Masafumi、Maeda Takahiro、Kuo Calvin J.、Baba Eishi、Akashi Koichi
  • Journal Title: Cancer Science Volume: - Issue: 7 Pages: 15795-12
  • DOI: 10.1111/cas.15795
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions (2022)
  • Author(s): Ito Mamoru、Nakano Michitaka、Ariyama Hiroshi、Yamaguchi Kyoko、Tanaka Risa、Semba Yuichiro、Sugio Takeshi、Miyawaki Kohta、Kikushige Yoshikane、Mizuno Shinichi、Isobe Taichi、Tanoue Kenro、Taguchi Ryosuke、Ueno Shohei、Kawano Takahito、Murata Masaharu、Baba Eishi、Akashi Koichi
  • Journal Title: Cancer Letters Volume: 532 Pages: 215597-215597
  • DOI: 10.1016/j.canlet.2022.215597
  • Peer Reviewed / Open Access
• [Presentation] Classification of BRAF V600E mutated colorectal cancer based on microsatellite stability (2023)
  • Author(s): Michitaka Nakano, Kosuke Sagara, Sakuya Koreishi, Tomomi Aikawa,Tomohiro Nishijima, Kotoe Takayoshi, Masato Komoda, Eishi Baba, Taito Esaki
  • Organizer: ASCO-GI 2019, Annual Conference 2019
• [Presentation] Classification of BRAF V600E mutated colorectal cancer based on microsatellite stability (2019)
  • Author(s): Michitaka Nakano, Kosuke Sagara, Sakuya Koreishi, Tomomi Aikawa,Tomohiro Nishijima, Kotoe Takayoshi, Masato Komoda, Eishi Baba, Taito Esaki
  • Organizer: ASCO-GI
  • Int'l Joint Research