# Project 1: Co-Targeting ER and Kinome Deregulation in Breast Cancers with Neurofibromin Deficiency

> **NIH NIH P50** · BAYLOR COLLEGE OF MEDICINE · 2021 · $337,971

## Abstract

PROJECT SUMMARY
 Over 250,000 cases of breast cancer are diagnosed annually in the US alone, and about 80% of these
will be estrogen receptor-α positive (ER+). Despite great progress in treating this ER+ disease by endocrine
therapy, resistanceto this treatment remains a major problem, causing the majority of deaths from breast cancer.
Our clinical studies on resistance have found that inactivation of the NF1 (for neurofibromatosis type 1) gene,
which may occur in as much as 20% of primary ER+ breast cancer patients, correlates with a poor outcome in
tamoxifen-treated patients. NF1 encodes neurofibromin, best known as a Ras repressor (a GTPase Activating
Protein, or GAP), but the scie ntific premise of this project stems from our discovery that besides activating Ras,
loss of NF1 also globally enhances estradiol (E2)-dependent gene expression, thus permitting the cells to grow
in lower levels of E2 or even in tamoxifen, because NF1 also directly interacts with ER as a transcriptional co-
repressor. In contrast to their lack of response to E2-deprivation or tamoxifen treatment, NF1-depleted cells still
respond to fulvestrant, a SERD (Selective ER Degrader), and although the reduced repression of Ras-Raf
signaling in NF1-depleted cells still allows promotion of cell survival/growth, this in turn could be blocked
pharmacologically by FDA-approved kinase inhibitors. This project will therefore investigate the hypothesis that
NF1-deficient ER+ breast tumors should be treated by a SERD together with inhibitors bloc king the Ras-Raf
pathway. To assess whether NF1-status in patient tumors can differentiate treatment responses to various
endocrine agents, Aim 1 will first establish an effective diagnosis for NF1-deficiency and then analyze how NF1-
status impacts long-term treatment responses in two large randomized neoadjuvant clinical trials, ALTERNATE
and P024. The former compares fulvestrant vs. AI (anastrozole), while the latter compares tamoxifen vs. another
AI (letrozole). In addition, we propose that NF1-deficient ER+ breast cancer should be treated by a SERD
combined with kinase inhibitors targeting the Ras-Raf pathway, so that Aim 2 will conduct preclinical modeling
to examine new generation oral SERDs and Ras effector kinase inhibitors to find the best combination to drive
clinical trial design and encourage pharma interest in trial support. A Phase -2 clinical trial to further this treatment
concept has been planned, for which we already have pharma interest and commitment. We will support this
trial here by developing technologies to assess how NF1-heterogeneity impacts treatment response. Finally,
Aim 3 will analyze kinome reprograming after SERD treatment in primary NF1-deficient patients (Aim 1) and in
preclinical models (Aim 2) by a mass spectrometry-based micro-scaled platform called KiP (Kinome Profiling).
While our primary objective is to assess whether the use of a SERD in NF1 -depleted tumors can lead to
compensatory Ras-Raf activati...

## Key facts

- **NIH application ID:** 10219969
- **Project number:** 5P50CA186784-07
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Bora Lim
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $337,971
- **Award type:** 5
- **Project period:** 2014-09-19 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219969

## Citation

> US National Institutes of Health, RePORTER application 10219969, Project 1: Co-Targeting ER and Kinome Deregulation in Breast Cancers with Neurofibromin Deficiency (5P50CA186784-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10219969. Licensed CC0.

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