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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.

项目总结/文摘