# P4: A Framework for Identification of Novel Targeted Therapy Combinations in Endometrial Cancer

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $302,813

## Abstract

Project 4 – SUMMARY/ABSTRACT
Endometrial cancer (EC) is the most frequent gynecologic malignancy and the fourth most common cancer
among women in the United States. Although cure is possible for early disease, outcomes for patients with
metastatic or recurrent disease have not improved significantly over the last two decades. Based on extensive
characterization by our team and The Cancer Genome Atlas, EC has a high frequency of aberrations in
targetable pathways including the phosphatidylinositol 3 kinase (PI3K, 92%), ARID1A (33%), and homologous
recombination (HR 22% core and 77% extended members) pathways. However, to date, targeted monotherapies
have not had a major impact in EC. Thus, how to leverage the therapeutic opportunities in EC represents
a major gap in knowledge that represents the overarching goal of this application.
Our overall goal is: to design and implement rational combination therapy clinical trials based on high
quality clinical and preclinical data and models to improve outcomes for EC patients.
Aim 1 To identify and refine biomarkers of benefit in a combination trial of PARP and PI3K pathway
targeted therapy in EC: Based on the underlying mutational aberrations present in EC, we are actively enrolling
on the first information-rich, biopsy-embedded investigator-initiated trial targeting two nodes in the PI3K pathway
(mTOR (2 dose schedules) and AKT) in combination with an effective “trapping” PARP inhibitor, olaparib. We
will test the hypothesis that combined targeting of key nodes in the PI3K pathway and PARP inhibition will
demonstrate benefit in EC patients. Extensive characterization of pre- and post-treatment biopsies at the DNA,
RNA and protein levels will facilitate the identification of biomarkers of benefit including our current suite of
biomarkers of responsiveness to PARP and PI3K pathway inhibitors. This is a unique approach and opportunity,
supported by our evidence that PI3K and HR pathways aberrations are extremely common in EC, likely rendering
patients sensitive to combined PI3K and PARP pathway inhibition.
Aim 2 To establish a preclinical framework to identify rational combination targeted therapies for EC to
be evaluated in future EC clinical trials: Emergence of adaptive resistance to targeted therapies contributes
to the lack of efficacy of monotherapy. We have used our Combinatorial Adaptive Resistance (CART) platform
to identify a limited number of potential additional rational combinations for validation, aimed at adaptive
resistance induced by targeting the DNA damage response. This Aim will focus on in vitro and in vivo preclinical
data and biomarkers to prioritize combinations in future trials. To rapidly translate these rational drug
combinations to clinical trials in this SPORE, AstraZeneca has signed a contract to provide funding for EC clinical
trials with their complete therapeutic pipeline.

## Key facts

- **NIH application ID:** 10006206
- **Project number:** 5P50CA098258-15
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** GORDON B. MILLS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $302,813
- **Award type:** 5
- **Project period:** 2003-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006206

## Citation

> US National Institutes of Health, RePORTER application 10006206, P4: A Framework for Identification of Novel Targeted Therapy Combinations in Endometrial Cancer (5P50CA098258-15). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10006206. Licensed CC0.

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