Combination Therapies Targeting Insulin Signaling in Endometrial Cancer

项目摘要/摘要 子宫内膜癌是发达国家最常见的妇科恶性肿瘤，其发病率和 死亡率正在上升，部分原因是肥胖症的流行。肥胖会显著增加死亡风险 在肥胖状态下发生的各种系统性变化会产生一种 有利于肿瘤发生和发展的环境。其中一个因素，高胰岛素血症，直接导致了 与子宫内膜癌的发病机制有关，可能是肥胖与子宫内膜癌密切相关的基础 这种癌症类型的肿瘤进展。胰岛素刺激PI3K促进细胞生长、增殖和抗凋亡 小路。不幸的是，PI3K抑制剂在子宫内膜癌的临床试验中并不有效。vbl.使用 临床前模型中，我们发现高胰岛素血症是一种急性的、全身性的、药物诱导的适应，它限制了 这些药物的疗效。在动物模型中，使用饮食和药物可以减轻这种不良反应。 以内分泌系统为目标的方法。在这份提案中，我们将测试这些策略是否可以被翻译成 使用患者来源的肿瘤组织、小鼠异种移植模型和来自临床干预的组织进行临床护理 审判。我们假设降低胰岛素会减少PI3K信号的肿瘤标记物，增加 凋亡，并增强PI3K抑制剂对子宫内膜癌患者的疗效。在目标1中，我们将 研究极低碳水化合物饮食(VLCD)对子宫内膜癌信号转导和生长的影响 来自两项正在进行的临床研究的患者来源的血液和肿瘤组织，其中患者正在使用VLCD 使用和不使用PI3K抑制剂。我们将评估胰岛素/PI3K的遗传、组织学和生化标记 途径、增殖和凋亡。在目标2中，我们将使用患者来源的异种移植模型来识别新的 降低全身性胰岛素水平和增强对PI3K的细胞凋亡反应的药物策略 抑制力。具体地说，我们将评估全身胰岛素反应和肿瘤生长速度。 PI3K抑制剂和两种内分泌疗法：Canagliflzin，一种钠-葡萄糖共转运体-2抑制剂，可防止 高血糖和二氮嗪，一种防止高胰岛素血症的钾通道激活剂。我们的数据将 提供强有力的临床前证据支持以胰岛素为靶点的联合策略以限制进展 子宫内膜癌。如果成功，这些饮食和药物干预措施可以迅速实施 进入临床实践。

PROJECT SUMMARY/ABSTRACT Endometrial cancer is the most common gynecologic malignancy in the developed world, and its incidence and mortality rate are increasing due, in part, to the obesity epidemic. Obesity dramatically increases the risk of death from endometrial cancer, and there are a variety of systemic changes that occur in the obese state that create a milieu that favors tumor initiation and progression. One of these factors, hyperinsulinemia, has been directly implicated in the pathogenesis of endometrial cancer, and may underlie the strong association of obesity with tumor progression in this cancer type. Insulin stimulates PI3K to drive cell growth, proliferation, and anti-apoptotic pathways. Unfortunately, PI3K inhibitors have not been effective in clinical trials for endometrial cancer. Using pre-clinical models, we identified hyperinsulinemia as an acute, systemic, drug-induced adaptation that limits the efficacy of these drugs. This adverse effect can be mitigated in animal models using dietary and pharmacologic approaches that target the endocrine system. In this proposal, we will test if these strategies can be translated to clinical care using patient-derived tumor tissue, mouse xenograft models, and tissues from clinical intervention trials. We hypothesize that lowering insulin will reduce tumor markers of PI3K signaling, increase markers of apoptosis, and enhance the efficacy of PI3K inhibitors in patients with endometrial cancer. In Aim 1, we will examine the effects of a very low carbohydrate diet (VLCD) on endometrial cancer signaling and growth using patient-derived blood and tumor tissue from two ongoing clinical studies where patients are consuming a VLCD with and without a PI3K inhibitor. We will assess genetic, histologic, and biochemical markers of the Insulin/PI3K pathway, proliferation, and apoptosis. In Aim 2, we will use patient-derived xenograft models to identify novel pharmacologic strategies that lower systemic insulin levels and enhance the apoptotic response to PI3K inhibition. Specifically, we will assess the systemic insulin response and tumor growth rates in mice treated with PI3K inhibitors and 2 endocrine therapies: canagliflozin, a sodium-glucose cotransporter-2 inhibitor that prevents hyperglycemia, and diazoxide, a potassium channel activator that prevents hyperinsulinemia. Our data will provide robust pre-clinical evidence to support combination strategies that target insulin to limit the progression of endometrial cancer. If successful, these dietary and pharmacologic interventions can be rapidly implemented into clinical practice.