PO.EN01.02 · 内分泌肿瘤
靶向胰岛素以改善子宫内膜癌
Targeting insulin to improve endometrial cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胰岛素和胰岛素样生长因子通过结合细胞表面受体来刺激子宫内膜黏膜的生长，这些受体可激活磷脂酰肌醇-3激酶（PI3K）信号通路。PI3K的过度活化足以在子宫上皮中启动癌变，在此过程中，该信号通路通过激活包括AKT和mTOR在内的多个胞内靶点来促进增殖。PI3K信号通路的增强主导着人类子宫内膜癌的遗传学特征。编码PI3K的p110a亚基的PIK3CA突变，以及作为PI3K活性分子性关闭开关的PTEN的功能缺失突变，是子宫内膜癌中突变最频繁的基因之一。尽管如此高的突变负荷提示了可成药靶点，但对PI3K通路的药理学抑制在临床上的疗效有限。我们团队此前已证明，作为子宫内膜癌临床生物标志物的高胰岛素血症限制了PI3K抑制剂在小鼠体内的疗效，并且通过给小鼠喂食极低碳水化合物（生酮）饮食（VLCD）可以降低全身胰岛素水平。VLCD与PI3K抑制的联合应用可在癌症小鼠模型中消除肿瘤生长，但在子宫内膜癌中，PI3K抑制与全身葡萄糖稳态失调之间的关系尚未得到阐明。为评估全身胰岛素对子宫内膜癌生长以及PI3K抑制疗效的影响，我们通过患者来源的类器官建立了具有临床相关性的子宫内膜癌异种移植模型。在本研究中，我们证明高胰岛素血症是一个可调控的因素，它限制了PI3K抑制在子宫内膜癌中的疗效。通过使用diazoxide和canagliflozin这两种可对抗高胰岛素血症的药理学制剂，我们能够降低肿瘤内的胰岛素水平，同时增强对PI3K抑制剂copanlisib和alpelisib的凋亡反应。此外，我们还表明生酮饮食可降低全身胰岛素水平，并改善PI3K抑制在子宫内膜癌异种移植模型中的疗效。这些发现对正在进行的PI3K通路抑制剂临床试验具有重要意义，并提示了一种提高癌症患者治疗疗效的方法。
查看英文原文 English abstract
Insulin and insulin-like growth factor stimulate the growth of the endometrial mucosa by binding cell surface receptors that activate the phosphatidylinositol-3 kinase (PI3K) signaling pathway. PI3K hyperactivity is sufficient to initiate carcinoma in the uterine epithelia, where this signaling pathway promotes proliferation by activating several intracellular targets, including AKT and mTOR. Enhancement of the PI3K signaling pathway dominates the genetics of human endometrial cancer. Mutations in PIK3CA , encoding the p110a subunit of PI3K, and loss of function mutations in PTEN , a molecular off switch for the PI3K activity, are among the most frequently mutated genes in endometrial cancer. Although this high mutational burden suggests druggable targets, pharmacological inhibition of the PI3K pathway has had limited clinical outcomes. Our group has previously demonstrated that hyperinsulinemia, a clinical biomarker of endometrial cancer, limits the efficacy of PI3K inhibitors in mice and that systemic insulin can be reduced by feeding mice a very low carbohydrate (ketogenic) diet (VLCD). The combination of VLCD and PI3K inhibition can abolish tumor growth in mouse models of cancer, but the relationship between PI3K inhibition and the dysregulation of systemic glucose homeostasis has yet to be resolved in endometrial cancer. To evaluate the effects of systemic insulin on endometrial cancer growth and the efficacy of PI3K inhibition we established clinically relevant endometrial cancer xenografts via patient-derived organoids. In this study, we demonstrate that hyperinsulinemia is a modifiable factor that limits the efficacy of PI3K inhibition in endometrial cancer. By employing diazoxide and canagliflozin, pharmacological agents that counteract hyperinsulinemia, we can decrease insulin levels in the tumor while enhancing the apoptotic response to the PI3K inhibitors copanlisib and alpelisib. Additionally, we show that ketogenic diet reduces systemic insulin and improves efficacy of PI3K inhibition in xenograft models of endometrial cancer. These findings have significant implications for ongoing clinical trials of PI3K pathway inhibitors and suggest a method for increased treatment efficacy in cancer patients.
利益披露 Disclosure
A. Emmanuelli, None.