# Timing is everything: applications in precision oncology for ER+ breast cancer

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2021 · $74,539

## Abstract

Precision oncology requires delivering the right drug to the right patient at the right time, but “time” is rarely
studied preclinically before a new drug enters the clinic. As a result, drugs shown to prevent progression of
advanced/metastatic solid tumors are sometimes found to be ineffective at preventing recurrence when
administered in the adjuvant or neoadjuvant settings. The long-term clinical benefit realized from adjuvant and
neoadjuvant therapies lies in anti-cancer effects on residual/disseminated/micrometastatic, clinically dormant
cancer cells that are undetectable by routine clinical methods; the biology underlying such anti-cancer effects
is practically unknown, creating a gap for evaluating new drugs. Clinically dormant cancer cells that survive
(neo)adjuvant therapy can ultimately give rise to recurrent/advanced tumors that frequently develop resistance
to all approved therapies. Thus, understanding how clinically dormant cancer cells vs. established tumors
respond to a novel therapy will guide clinical testing in the appropriate disease setting(s), and reveal targets for
combination therapies to enhance efficacy. More thorough characterization of drug efficacy in relevant
preclinical models will increase the drug success rate in clinical trials, thus decreasing the cost of drug
development. Estrogen receptor α (ER)-positive breast cancer is a disease for which improved drug
development could ultimately impact treatment options for hundreds of thousands of patients. Patients with
early-stage ER+ breast cancer are treated with adjuvant anti-estrogen therapies that neutralize ER and
suppress, but do not eliminate, tumor-initiating cells. We and others have implicated activation of the
phosphatidylinositol 3-kinase (PI3K) pathway in anti-estrogen resistance, and PI3K inhibitors (PI3Ki) are in
clinical development in combination with anti-estrogens. Based on our preliminary findings, we hypothesize
that short-term treatment with anti-estrogen/PI3Ki combination therapy kills clinically dormant ER+ breast
cancer cells and prevents recurrence (Aim 2), while established tumors develop resistance to anti-
estrogen/PI3Ki therapy via suppression of apoptosis (Aim 1) due in part to microenvironmental cytokine
signaling (Aim 3). We will test this hypothesis through the following Specific Aims: 1) To determine why anti-
estrogen/PI3Ki combination therapy is acutely but not sustainably cytotoxic in established ER+ breast tumors;
2) To determine how clinically dormant ER+ breast tumor cells respond to short-term anti-estrogen/PI3Ki
combination therapy; 3) To identify cytokines in stroma-derived secretomes that drive resistance to anti-
estrogen and anti-estrogen/PI3Ki therapies in ER+ breast cancer. These studies are aligned with the NCI
Precision Medicine Initiative of Overcoming Drug Resistance, the Cancer Moonshot Panel recommendation to
develop ways to overcome cancer's resistance to therapy, and the NCI Provocative Question `What cancer
mode...

## Key facts

- **NIH application ID:** 10411360
- **Project number:** 3R01CA211869-05S1
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Todd W. Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $74,539
- **Award type:** 3
- **Project period:** 2017-09-04 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10411360

## Citation

> US National Institutes of Health, RePORTER application 10411360, Timing is everything: applications in precision oncology for ER+ breast cancer (3R01CA211869-05S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10411360. Licensed CC0.

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