# Combination Therapies Targeting Insulin Signaling in Endometrial Cancer

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $507,696

## Abstract

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.

## Key facts

- **NIH application ID:** 11138080
- **Project number:** 7R01CA279561-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Marcus DaSilva Goncalves
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $507,696
- **Award type:** 7
- **Project period:** 2024-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11138080

## Citation

> US National Institutes of Health, RePORTER application 11138080, Combination Therapies Targeting Insulin Signaling in Endometrial Cancer (7R01CA279561-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11138080. Licensed CC0.

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