# Project 1: High Grade Cancers: Capitalizing on PARPness in Ovarian Carcinoma

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $358,686

## Abstract

Project 1 SUMMARY/ABSTRACT
Unfortunately, there are few “druggable” alterations in high-grade serous ovarian cancer (HGSOC). Thus,
exploration of therapeutic liabilities engendered by defects in homologous recombination (HR), the second
most common aberration in ovarian cancer after TP53 mutation, has taken a dominant role. HR defects caused
by germline and somatic BRCA1/2 aberrations, as well as aberrations in other pathway members, lead to
synthetic lethality in combination with inhibition of poly (ADP-ribose) polymerase–1 (PARP). However, crucial
gaps in knowledge exist that hinder our long-term goal of optimal implementation of PARP inhibitors
(PARPi) including: 1) the identification of patients most likely to benefit from PARPi (i.e., “PARPness”) and 2)
the development of rational combination therapies able to prevent or overcome resistance to PARPi.
In our prior SPORE project, we developed and implemented DNA, RNA and protein assays designed to predict
benefit from PARPi as well as identified new members of the HR pathway, providing approaches to expand the
population of patients likely to benefit from PARPi. In this SPORE proposal, we will complete our ongoing
multi-arm combination trial with PARPi and phosphatidylinositol 3 kinase (PI3K) inhibitors and implement a
resensitization trial in PARP resistant patients of Wee1 inhibition compared to PARP plus Wee1i. Using these
trials, based on strong preliminary data from cell line, PDX and animal models, we will refine the utility of
biomarkers to predict response and resistance to PARPi in HGSOC. We will further develop the preclinical and
clinical data to justify a series of rational combination trials in this SPORE.
Our overarching hypothesis is that the identification of a “PARPness” molecular profile will expand the utility of
PARPi in HGSOC. As a corollary, optimal outcomes will only manifest by rational combination therapy with
PARPi. Thus, we will perform a systematic analysis of cell lines, animal models and patient samples, combined
with our combinatorial adaptive resistance therapy platform and ultra-deep shRNA and CRISPR/CAS screens
to targetable molecules to systematically identify rational combinations with PARPi therapy. To accomplish our
long term goals and to test our overarching hypothesis, we propose two specific aims: Specific Aim 1: To
identify and refine biomarkers of benefit from PARPi in ovarian cancer and Specific Aim 2: To establish
a preclinical framework to identify and prioritize rational combination therapies in ovarian cancer.
The successful implementation of the proposed studies will contribute to: 1) development of personalized
treatment of women with advanced and recurrent ovarian cancer based on molecular profiles, 2) an expanded
definition of patients likely to benefit from PARP inhibitors, 3) identification of resistance mechanisms to PARP
inhibitors, and 4) rational combination therapies that will increase the spectrum of patients likely to benefit and
als...

## Key facts

- **NIH application ID:** 10005294
- **Project number:** 5P50CA217685-04
- **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:** $358,686
- **Award type:** 5
- **Project period:** 2017-09-22 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005294

## Citation

> US National Institutes of Health, RePORTER application 10005294, Project 1: High Grade Cancers: Capitalizing on PARPness in Ovarian Carcinoma (5P50CA217685-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10005294. Licensed CC0.

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