# Targeted Therapy for Endometrial Cancer

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $293,550

## Abstract

While outcomes have substantially improved for many types of cancer, endometrial cancer incidence and
deaths are on the rise, with the five year survival rate worse today than three decades ago. Inadequate
sensitivity to chemotherapy is a primary cause of therapeutic failure. To improve patient outcomes, we must
identify the appropriate molecularly targeted agents to combine with chemotherapy, a concept we term
molecularly enhanced chemotherapy. Such combinations must be based upon a mechanistic understanding of
tumor cell vulnerabilities which can be exploited to create synergism and synthetic lethality. Our objective in
this renewal application is to capitalize on the most common mutation in high-risk endometrial cancers, p53, to
design new and more active combinatorial regimens that can improve response in the upfront setting. p53
mutations alter the master regulators of cell cycle checkpoints in predictable yet distinct ways which can be
capitalized upon to overcome resistance to chemotherapy using targeted agents that block compensatory
survival pathways. Therefore, our central hypothesis is that molecular inhibitors of key master regulators,
chosen based upon the knowledge of the p53 mutational status, synergize with chemotherapy and promote
catastrophic tumor cell death. We term this concept molecularly enhanced chemotherapy. In Specific Aim #1,
we will determine the role of p53, other cell cycle checkpoint controllers and angiogenic markers as predictors
of sensitivity when anti-angiogenic molecular inhibitors are combined with chemotherapy. This aim
incorporates clinical specimens from a completed trial, GOG/NRG 86P, the first national study to combine
molecular inhibitors with chemotherapy for advanced/recurrent endometrial cancer. In Specific Aim #2, we will
assess the mechanisms of resistance to therapy as defined by outcomes from NRG/GOG 86P and identify
alternative molecularly enhanced combinations. In Specific Aim #3, we will interrogate the function of p53
mutations that are variants of unknown significance (VUS) to define the best therapy for these tumors. The
major goal of this aim is to bin VUS from NRG/GOG 86P into functional categories and understand the impact
of recurrent VUS on cell transcription and cell cycle regulation. At the completion of these studies, it is our
expectation that we will have designed and tested synergistic drug combinations tailored for specific
endometrial cancer subtypes. These studies will make a significant positive impact on the field by enhancing
the design and choice of therapy for future endometrial cancer clinical trials.

## Key facts

- **NIH application ID:** 9867664
- **Project number:** 5R01CA099908-17
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Kimberly K. Leslie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $293,550
- **Award type:** 5
- **Project period:** 2002-07-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867664

## Citation

> US National Institutes of Health, RePORTER application 9867664, Targeted Therapy for Endometrial Cancer (5R01CA099908-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9867664. Licensed CC0.

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