Elucidation of the mechanisms of cardiac dysfunction caused by cancer cachexia and establishment of novel therapeutic strategies

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16497
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Jikei University School of Medicine (2020-2021); National Cancer Center Japan (2019)
• Principal Investigator: Nonaka Miki 東京慈恵会医科大学, 医学部, 特任講師 (60758077)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: がん悪液質 / 腫瘍循環器学 / Onco-Cardiology

Outline of Final Research Achievements

We have established a novel murine model of cancer cachexia, which represents impaired myocardial function in addition to anorexia and loss of weight and fat-free mass, which are similar to those observed in cancer cachexia patients. By using this model, we evaluated the effects of cachexia on cardiac function and investigated the therapeutic effects of angiotensin converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Microarray analysis revealed that the expression of gene “X”, which is an enzyme belonging to E3 ubiquitin ligase family, wich has not been reported to be related to skeletal muscular atrophy, increased in the myocardium of cachexia mice. Our study demostrated that ACEI and ARB didn't improve cachexia. The gene“X”may be one of key factors, which are associated with myocardial atrophy and cardiac dysfunction on cancer cachexia. The pathway mediated by the gene“X”is currently being further analyzed.

Free Research Field

腫瘍循環器学

Academic Significance and Societal Importance of the Research Achievements

ヒトに奏効する抗がん剤やがん悪液質改善薬の開発の困難さは、非臨床試験での薬効評価にあたり、単一のがん細胞に由来するがん細胞株およびがん株細胞移植動物を用いてきたことにある。これらのモデルは臨床予測が極めて低いことが指摘されており、臨床で認められるような副作用の評価は困難であり、腫瘍循環器学分野の問題解決の糸口もモデルの開発が大きく関与していると考えられる。本研究課題ではヒトと類似したがん悪液質モデルを使用し、心機能低下に遺伝子Xが関与していることを明らかにした。今後は遺伝子Xの経路をより詳細に検討し、遺伝子Xをターゲットとした治療薬の開発を目指し、がん悪液質患者のQOL向上を目指したい。