# Restoring Progestin Sensitivity in Endometrial Cancer

> **NIH NIH R37** · UNIVERSITY OF IOWA · 2021 · $353,419

## Abstract

Project Summary/Abstract
While outcomes have substantially improved for many types of cancer, endometrial cancer incidences and
deaths are on the rise, with the five year survival rate worse today than three decades ago; owing largely to the
ineffectiveness of current treatments. As a tumor is exquisitely sensitive to the growth promoting effects of
estrogen and the growth limiting effects of progesterone, hormonal therapy for endometrial cancer using
progestins has been a traditional choice for treatment. It is highly effective in the short term; however,
responsiveness wanes over time due to loss of progesterone receptor (PR) expression, and recurrences are
common. There is a critical need to identify strategies to improve or restore responsiveness to progestin
therapy, and we propose that molecularly enhanced progestin therapy will make a major positive impact on
survival of patients with endometrial cancer. The objective of this application is to identify the molecular
mechanisms driving the downregulation of the PR in endometrial cancer patients and identify novel strategies
to further enhance the effectiveness of progestin therapy. We will develop molecular agent combinations with
progestins that will significantly enhance tumor cell differentiation in vitro and improve survival in mouse
xenograft models of human endometrial cancer. Our central hypothesis is that targeting PR repressors will
enhance the expression of PR, the most important tumor suppressor in the endometrium, thereby improving
response to progestin therapy. This hypothesis stems from our strong recently published data in endometrial
cancer cells that PR expression is downregulated through distinct molecular mechanisms, and epigenetic
modulators potently increase PR expression and tumor suppressor activity. We have now identified additional
PR suppressors that have the potential to more clearly define the multiple mechanisms of PR inhibition in
endometrial cancer, setting the stage for new therapeutic opportunities. In Aim 1, we will determine the impact
of epigenetic modulators on PR expression and activity in endometrial cancer patients from our related clinical
trial NRG-GY011 results; in Aim 2, we will enhance PR expression using small molecular drugs and test drug
efficacy using in vitro and in vivo endometrial cancer models. In Aim 3, we will identify novel PR
downregulation mechanisms using genome-wide gene silencing. At the completion of these studies, it is our
expectation that we will have identified mechanisms of hormonal resistance, successfully integrated innovative
molecular therapies into enhanced progestin therapeutic regimens in preclinical and clinical studies, and inform
for the design of future endometrial cancer clinical trials. As such, these studies have a strong potential to
impact the alarming trend towards declining survival in endometrial cancer.

## Key facts

- **NIH application ID:** 10165666
- **Project number:** 5R37CA238274-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Shujie Yang
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $353,419
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165666

## Citation

> US National Institutes of Health, RePORTER application 10165666, Restoring Progestin Sensitivity in Endometrial Cancer (5R37CA238274-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10165666. Licensed CC0.

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