# Development of Small Molecule Inhibitor of PELP1 for Treating Advanced Breast Cancer

> **NIH NIH F31** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $35,256

## Abstract

PROJECT SUMMARY/ABSTRACT: Breast cancer (BC) is the most prevalent and second most lethal
malignancy in females. Development of novel effective therapies for patients with therapy-resistant BCa (TR-
BC) and triple negative BCa (TNBC) remains the highest unmet need in improving survival outcomes. Proline-,
glutamic acid, and leucine-rich protein 1 (PELP1), is a proto-oncogene that plays a critical role in multiple nuclear
receptor (NR) functions leading to BC progression. PELP1 expression is upregulated in BCa, promotes
epigenetic changes through histone modification, is a prognostic indicator of poor BCa survival, and contributes
to drug therapy-resistance and metastases. The focus of my F31 dissertation research is to develop a First-in-
Class small molecule inhibitor targeting oncogenic PELP1 (SMIPs) and elucidate the efficacy as an advanced
BC therapy. I hypothesize that PELP1 couples NRs with epigenetic modifiers and targeting this axis with SMIPs
will have therapeutic utility in treating both TR-BC and TNBC. My preliminary data indicates lead compound,
SMIP34, inhibits proliferation in an established panel of BCa cell lines with an IC50 between 3-10μM. Results
indicate that SMIP34 has ability to block PELP1 oncogenic functions including reduction of cell viability and
invasiveness and promotion of apoptosis. Aim 1 will define the mechanisms by which SMIP34 functions as a
PELP1 inhibitor. I will use multiple biophysical methods to confirm the direct interaction of SMIP34 with PELP1.
I will further confirm specificity using conditional CRISPR knockout of PELP1. I will evaluate the ability of
SMIP34 to inhibit the PELP1 oncogenic interactome and assess modulation of downstream signaling pathways
using genome wide approaches including ChIP-Seq and Mass Spec analyses. The effects of SMIP34 treatment
on gene expression will be determined by RNA-Seq and further analyzed in order to identify potential correlative
biomarkers. Aim 2 will evaluate the utility of SMIP 34 in treating advanced breast cancer using preclinical and
PDX models. Immuno-competent CD1 mouse models will be used to study toxicity and to determine the
maximum tolerated dose of SMIP34. Patient derived explant (PDEX) models will be utilized to characterize the
ex vivo effects of SMIP34 on growth of human BC tumor explants. Both TR-BC and TNBC syngenic models, in
addition to PDX orthotopic xenograft models, will be utilized to test the effects of treatment on tumor volume,
disease progression, maximum tolerated dose, and observable toxicity. I will use IHC analyses of tumor tissues
to confirm mechanism of action and efficacy. My long-term career objective is elucidating the mechanistic
contributions oncogenic signaling in breast and gynecological cancers for the purpose of developing targeted
therapies. Ultimately, the F31 Fellowship will provide multiple opportunities to develop my career as an
independent extramurally funded investigator focused on novel translational advances in wo...

## Key facts

- **NIH application ID:** 10141137
- **Project number:** 1F31CA257298-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Kristin Ann Altwegg
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $35,256
- **Award type:** 1
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141137

## Citation

> US National Institutes of Health, RePORTER application 10141137, Development of Small Molecule Inhibitor of PELP1 for Treating Advanced Breast Cancer (1F31CA257298-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10141137. Licensed CC0.

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