# Development of Potent Inhibitors of proto-oncogene PELP1 for Treating Advanced Breast Cancer

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2022 · —

## Abstract

Project summary
Breast cancer (BCa) is the second leading cause of cancer death in women. Among Servicewomen, BCa is the
most commonly diagnosed cancer, accounting for 30% of female cancers with increased prevalence in older
Veterans. BCa has distinct molecular subtypes; estrogen receptor (ER) positive and triple negative breast
cancer (TNBC). A significant portion of ER-positive BCa initially respond to anti-estrogens or aromatase inhibitors
but eventually exhibit unresponsiveness to therapy, develop therapy-resistant breast cancer (TR-BC), and
ultimately progress to incurable metastasis. Moreover, TNBC has a more aggressive clinical course and overall
lack of targeted therapies. Development of effective therapies for female Veterans with TR-BC or TNBC
represents the highest unmet need in breast cancer treatment. Our ongoing research on PELP1, an oncogenic
coregulator protein originally cloned in this lab, displays an integral role in multiple nuclear receptor (NR)
functions associated with BCa progression. PELP1 expression is commonly dysregulated in BCa eliciting a
conducive environment for epigenetic modifications. Concomitantly, PELP1 is a prognostic indicator for poorer
BCa survival and indicator of therapy resistance and metastases. We have developed a first-in-class small
molecule inhibitor of PELP1 (SMIP) displaying effectivity against TR-BC and TNBC. SMIPs block PELP1’s ability
to promote epigenetic modifications. The objective of this proposal is to further develop a lead SMIP into a novel
drug for the clinical treatment of TR-BC and TNBC. Our overarching hypothesis is that PELP1 couples NRs
with epigenetic modifiers; therefore, targeting the PELP1 axis with SMIPs will have a therapeutic utility in treating
both TR-BC and TNBC. In Aim 1, we will determine lead SMIPs mechanism of action using biochemical,
molecular, unbiased mass spectroscopy, and whole genome sequencing approaches. In Aim 2, we will optimize
SMIP derivatives and conduct studies establishing the maximum tolerated dose and dose efficacy in vivo using
TR-BC and TNBC models. In Aim 3, we will test the translatability of optimized SMIPs using therapy resistant
xenografts, metastatic models, and patient derived xenografts (PDX). This proposal is innovative as SMIPs block
signaling from multiple oncogenic PELP1 activated NRs to uniquely promote repression of epigenetic modifiers.
Successful completion of the proposed work will result in the development of a first-in-class cancer therapy
drug specifically addressing the current lack of TR-BC and TNBC targeted therapies. This research program is
significant as it is expected to aid in identifying therapeutic targets critical to the treatment and prevention of
advanced breast cancer in the population of Servicewomen.

## Key facts

- **NIH application ID:** 10412909
- **Project number:** 5I01BX004545-03
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** Ratna K Vadlamudi
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412909

## Citation

> US National Institutes of Health, RePORTER application 10412909, Development of Potent Inhibitors of proto-oncogene PELP1 for Treating Advanced Breast Cancer (5I01BX004545-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10412909. Licensed CC0.

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