# DELINEATING THE EVOLUTION AND ECOLOGY OF CHEMORESISTANCE IN BREAST CANCER WITH SINGLE CELL GENOMICS

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $352,047

## Abstract

PROJECT SUMMARY
Triple-negative breast cancer (TNBC) is an aggressive subtype in which patients display extensive intratumor
genomic heterogeneity and frequently (50%) develop resistance to neoadjuvant chemotherapy (NAC) which
leads to metastatic disease and death. Due to the absence of hormonal receptors and targeted therapies,
TNBC patients with refractory disease are often left with limited treatment options. Currently, our understanding
of the genomic evolution of tumor cells and the role of the tumor microenvironment in chemoresistant disease
at primary and metastatic organ sites represents a major gap in knowledge that this proposal aims to address.
Our group has developed cutting-edge single cell DNA and RNA sequencing technologies that can overcome
previous technical barriers and limitations with `bulk' genomic methods for studying the genomic and
phenotypic evolution of tumor cells in response to chemotherapy. Our preliminary data in a small number of
TNBC patients suggests that genomic evolution of chemoresistance occurs through the adaptive selection of
pre-existing mutations and copy number alterations, which is followed by transcriptional reprogramming, to
achieve a chemoresistant phenotype (Kim et al. 2018, Cell). We further hypothesize that transcriptional
reprogramming of cell types in the tumor microenvironment occurs in chemoresistant disease and that
resistance programs are clonally inherited at distant metastatic organ sites. To comprehensively investigate
these questions in matched longitudinal samples from TNBC patients in a large neoadjuvant chemotherapy
trial (ARTEMIS), we propose three synergistic aims: Aim 1 will determine if copy number aberrations (CNAs)
and subclonal mutations associated with chemoresistance are pre-existing and adaptively selected in response
to therapy. Aim 2 will investigate if tumor cells and cell types in the microenvironment undergo transcriptional
reprogramming in refractory disease. Aim 3 will determine if subpopulations of resistant cells in the primary
tumor seed the metastatic lesions and confer resistance programs at distant organ sites. Completion of these
aims will define the genomic and evolutionary basis of chemoresistance in TNBC patients and will provide new
diagnostic biomarkers and therapeutic targets for overcoming chemoresistant disease, which is a critical unmet
clinical need. Our long-term goal is to translate single cell sequencing technologies into the clinic, where they
are poised to have a major impact on the diagnosis and treatment of breast cancer patients. The proposed
aims are directly aligned with the mission of NIH to reduce morbidity and improve the quality of life for breast
cancer patients.

## Key facts

- **NIH application ID:** 10741817
- **Project number:** 5R01CA236864-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Nicholas Navin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $352,047
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10741817

## Citation

> US National Institutes of Health, RePORTER application 10741817, DELINEATING THE EVOLUTION AND ECOLOGY OF CHEMORESISTANCE IN BREAST CANCER WITH SINGLE CELL GENOMICS (5R01CA236864-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10741817. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*