| Project/Area Number |
18K07957
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 53010:Gastroenterology-related
|
|---|
| Research Institution | Shizuoka Cancer Center Research Institute |
|---|
Principal Investigator |
Ohnami Shumpei 静岡県立静岡がんセンター(研究所), その他部局等, 主任研究員 (60291142)
|
|---|
| 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
|
|---|
| Keywords | KRAS / BMP4 / PHLDA1 / Colon cancer / Colorectal cancer / KRAS G12 mutation / Therapeutic targets / colon cancer / whole exsome sequencing / Whole exome sequencing / Gene expression profile |
|---|
| Outline of Final Research Achievements |
In this study, we identified potential effector molecules, based on differences in gene expression between CRC patients carrying wild-type KRAS (n=390) and those carrying KRAS mutations in codon 12 (n=240). CRC patients with wild-type KRAS harboring mutations in HRAS, NRAS, PIK3CA, PIK3CD, PIK3CG, RALGDS, BRAF, or ARAF were excluded from the analysis.
At least 11 promising candidate molecules showed greater than two-fold change between the KRAS G12 mutant and wild-type and had a Benjamini-Hochberg-adjusted P value of less than 1E-08, evidence of significantly differential expression between these two groups. Among these 11 genes examined in cell lines transfected with KRAS G12 mutants, BMP4, PHLDA1, and GJB5 showed significantly higher expression level in KRAS G12A, G12D, and G12V transfected cells than in the wild-type transfected cells. We expect that this study will lead to the development of novel treatments that target signaling molecules functioning with KRAS G12-driven CRC.
|
| Academic Significance and Societal Importance of the Research Achievements |
大腸癌では軽度異型粘膜の段階からKRASドライバー変異が認められる。従って、RAS経路はKRAS変異型大腸癌に対して魅力的な分子標的であるが、大腸癌に対するKRASシグナル伝達経路を標的とする明確な臨床治療薬は未だ存在しない。もし、大腸癌の約半数を占めるKRAS変異を阻害する分子標的薬が開発されれば、その恩恵を受ける患者さんは膨大な数に上る。報告者は遺伝的背景の異なる癌患者の新鮮凍結組織を用いた解析から、「KRAS変異によって制御されている遺伝子が癌形質獲得や悪性度の高い癌の鍵を握っている」という信念で、真の創薬ターゲットを同定し、革新的な治療薬開発の基盤を構築し、国際誌に発表した。
|
