Combination Therapies Targeting Insulin Signaling in Endometrial Cancer

子宫内膜癌中针对胰岛素信号传导的联合疗法

基本信息

批准号：
10637167
负责人：
Marcus DaSilva Goncalves
金额：
$ 55.14万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10637167
关键词：
Acute Address Adult Adverse effects Animal Model Apoptosis Apoptotic Biochemical Biochemical Markers Blood Carbohydrates Carcinoma Cessation of life Clinical Clinical Data Clinical Research Clinical Trials Combined Modality Therapy Consumption Data Development Diazoxide Diet Dietary Intervention Endocrine system Endocrinologist Endometrial Carcinoma Epithelium Genetic Glucose Goals Growth Histologic Human Human Genetics Hyperglycemia Hyperinsulinism Implant Incidence Insulin Intervention Intervention Trial Knowledge Link Malignant Female Reproductive System Neoplasm Medical Oncologist Memorial Sloan-Kettering Cancer Center Metabolism Mus Nature Obesity Obesity Epidemic Organoids PIK3CG gene Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Phosphotransferases Potassium Channel Pre-Clinical Model Proliferating Publishing Qualifying Randomized Recurrence Research Risk Role Signal Pathway Signal Transduction Sodium Testing Tissues Translating Tumor Markers Tumor Tissue Urine Uterus Woman Xenograft Model Xenograft procedure cancer cell cancer therapy cancer type cell growth clinical care clinical practice combat detection of nutrient dietary drug efficacy effectiveness validation feasibility trial feeding glycemic control hormone therapy inhibitor insulin signaling kinase inhibitor mortality mortality risk mouse model novel novel strategies novel therapeutic intervention open label patient derived xenograft model pharmacologic phase 2 study pre-clinical prevent response safety testing small molecule inhibitor symporter targeted treatment translational approach translational scientist treatment response tumor tumor growth tumor initiation tumor progression

项目摘要

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.

项目概要/摘要子宫内膜癌是发达国家最常见的妇科恶性肿瘤，其发病率和发病率死亡率不断上升，部分原因是肥胖流行。肥胖显着增加死亡风险子宫内膜癌，并且在肥胖状态下会发生各种全身变化，从而产生有利于肿瘤发生和进展的环境。这些因素之一，高胰岛素血症，已直接与子宫内膜癌的发病机制有关，并且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 驱动细胞生长、增殖和抗凋亡途径。不幸的是，PI3K抑制剂在子宫内膜癌的临床试验中尚未有效。使用在临床前模型中，我们将高胰岛素血症确定为一种急性、全身性、药物诱导的适应，限制了这些药物的功效。在动物模型中，可以通过饮食和药物来减轻这种副作用针对内分泌系统的方法。在这个提案中，我们将测试这些策略是否可以转化使用患者来源的肿瘤组织、小鼠异种移植模型和临床干预组织进行临床护理试验。我们假设降低胰岛素会减少 PI3K 信号传导的肿瘤标志物，增加细胞凋亡，增强 PI3K 抑制剂对子宫内膜癌患者的疗效。在目标 1 中，我们将使用以下方法检查极低碳水化合物饮食 (VLCD) 对子宫内膜癌信号传导和生长的影响来自患者的血液和肿瘤组织来自两项正在进行的临床研究，患者正在服用 VLCD 有或没有 PI3K 抑制剂。我们将评估胰岛素/PI3K 的遗传、组织学和生化标志物途径、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胰岛素水平并增强对 PI3K 的细胞凋亡反应的药理学策略抑制。具体来说，我们将评估接受治疗的小鼠的全身胰岛素反应和肿瘤生长率 PI3K 抑制剂和 2 种内分泌疗法：卡格列净，一种钠-葡萄糖协同转运蛋白 2 抑制剂，可预防高血糖和二氮嗪（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来支持针对胰岛素限制进展的联合策略子宫内膜癌。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。