A therapeutic strategy for malignant mesothelioma with reconstituting tumor suppressor pathways which were defective due to the characteristic genetic deletion

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09598
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: Shingyoji Masato 千葉県がんセンター(研究所), 呼吸器内科, 部長 (60450433)
• Co-Investigator(Kenkyū-buntansha): 田川 雅敏 千葉県がんセンター(研究所), がん治療開発グループ, 部長 (20171572)
• Research Collaborator: TAGAWA masatoshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 悪性中皮腫 / p53経路 / Hippo経路 / 細胞障害活性 / アデノウイルス / MDM2阻害剤

Outline of Final Research Achievements

Clinical specimens from malignant mesothelioma patients showed two characteristic genetic abnormalities, a defect in the INK4A/ARF region and several types of gene mutations mapped in the Hippo pathway, which consequently induced a functional loss of the p53 pathway, and up-regulation of pRb and Hippo pathways. These genetic changes can be therapeutic targets for mesothelioma treatments. We then took an approach to reconstitute the p53 pathway, which suppressed pRb functions accordingly, and to inhibit effectors of the augmented Hippo pathway. Enhanced expression of endogenous or exogenous p53 and inhibition of down-stream signaling of the Hippo pathways achieved growth suppressive effects in mesothelioma and a combination of activated p53 and inhibited Hippo pathway produced synergistic cytotoxic effects to mesothelioma.

Free Research Field

呼吸器内科

Academic Significance and Societal Importance of the Research Achievements

悪性中皮腫は今後とも本邦で増加する疾患であり、その治療は難しく、また多くの場合早期診断も容易ではなく、極めて予後不良の疾患である。さらにアスベスト（石綿）の消費は新興国を中心に継続しており、今後とも世界的レベルで患者数が増加する。そこで本研究では同疾患の特徴的な遺伝子変異に着目し、
それに起因する細胞増殖機構に基づいて、幾つかの薬剤による細胞傷害効果を検討した。その結果複数の経路を薬物で制御することによって、当該疾患の治療法が開発できる可能性を示した。