# Restoring Progestin Sensitivity in Endometrial Cancer

> **NIH NIH R37** · UNIVERSITY OF IOWA · 2024 · $331,586

## Abstract

Project Summary/Abstract
While outcomes have substantially improved for many types of cancer, endometrial cancer (EC) 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 EC 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 EC.
The objective of this application is to identify the molecular mechanisms driving the downregulation of the PR
in EC 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 EC. 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 EC 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 EC,
setting the stage for new therapeutic opportunities. In Aim 1, we will determine the impact of epigenetic
modulators on PR expression and activity in EC patients from the clinical trial NRG-GY011 results. In the
extended period we will evaluate the potential new endpoint markers. In Aim 2, we will enhance PR expression
using small molecular drugs and test drug efficacy using in vitro and in vivo EC models. In the extended period,
we will identify and validate novel drug and target sites for PR regulation such as Topoisomerase II inhibitor. In
Aim 3, we will identify novel PR downregulation mechanisms using genome-wide gene silencing. In the
extended period, we will focus on novel PR repressor PHB2 and SETDB1. At the completion of these studies,
we will have better understanding of mechanisms of hormonal resistance and integrate innovative molecular
therapies into enhanced progestin therapeutic regimens in preclinical and clinical studies, and as well as
design future EC clinical trials. Therefore, these studies will have a strong impact on the treatment of EC.

## Key facts

- **NIH application ID:** 10732994
- **Project number:** 4R37CA238274-06
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Shujie Yang
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $331,586
- **Award type:** 4N
- **Project period:** 2019-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10732994

## Citation

> US National Institutes of Health, RePORTER application 10732994, Restoring Progestin Sensitivity in Endometrial Cancer (4R37CA238274-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10732994. Licensed CC0.

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