# Repurposing RET Inhibitors for Endocrine Resistant Breast Cancer

> **NIH NIH K08** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $203,026

## Abstract

PROJECT SUMMARY/ABSTRACT
Breast cancer is the most common cancer and the second most common cause of cancer death in
women. Most breast cancers are estrogen receptor (ER) positive. The primary cause of treatment failure
and death in patients with ER+ breast cancer is resistance to endocrine therapy (ET). Novel therapeutics
are needed to improve outcomes for patients with resistant tumors. Several findings demonstrate that the
RET receptor tyrosine kinase alters sensitivity to ET. RET expression in ER+ breast cancer is associated
with worse outcome and recurrent tumors that are resistant to ET express RET at higher levels than
primary tumors. Preliminary data show that RET is overexpressed over time in breast cancer cells treated
with ET and that inhibiting RET reduces ERK/MAPK activity and sensitizes ER+ cell lines and xenografts
to ET. We have established and validated ER+ breast cancer organoids which we will use to dissect
precise mechanisms of increased RET expression, how RET impacts sensitivity to ET, and how RET
directs kinase signaling with ET treatment. We hypothesize that high expression of RET in ET resistant
ER+ breast cancers drives tamoxifen resistance and is a therapeutic target to overcome resistance. To
test this hypothesis, in Aim1 we will define reprogramming of regulatory elements at the RET promoter
over time with tamoxifen leading to increased expression of RET. In Aim2, we will determine the efficacy
of targeting RET to enhance response to ET in cell lines, organoids, and patient derived xenografts.
Finally, in Aim3 we will determine how RET alters kinase signaling adaptation in response to tamoxifen
using a functional inhibitor bead capture assay coupled with mass spectroscopy. Cumulatively, these
studies will form a scientific basis to develop clinical strategies and select patients for RET inhibitor
therapy. In addition to advancing scientific knowledge, this proposal provides training to a physician-scientist.
Dr Spanheimer is a practicing surgical oncologist specializing in breast cancer with a background in molecular
biology. His long-term goal is to combine his research and clinical expertise to develop an independently
funded research program focused on therapeutic vulnerabilities of altered gene regulation in response to
therapy. He benefits from established mentors with a strong track record of training independent scientists and
an extremely supportive research environment. This proposal includes a structured career development plan
and training in: 1) molecular biology of transcriptional regulation, 2) targeted therapeutics and translationally
relevant breast cancer models, and 3) functional proteomics. Training will also include development of
expertise in increasingly complex hypothesis driven experimental design, execution, and analysis. The
proposal includes mentored experiential learning, course work and conference participation, frequent mentor
meetings and a graded increase in research independence. Cumul...

## Key facts

- **NIH application ID:** 10867348
- **Project number:** 5K08CA280388-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Philip M. Spanheimer
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $203,026
- **Award type:** 5
- **Project period:** 2023-06-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867348

## Citation

> US National Institutes of Health, RePORTER application 10867348, Repurposing RET Inhibitors for Endocrine Resistant Breast Cancer (5K08CA280388-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10867348. Licensed CC0.

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