# Characterizing and targeting intra-tumor heterogeneity in triple negative breast cancer chemoresistance and multi-organ metastasis

> **NIH NIH K22** · BAYLOR COLLEGE OF MEDICINE · 2020 · $157,680

## Abstract

PROJECT SUMMARY / ABSTRACT
Half of all triple negative breast cancer (TNBC) patients harbor significant residual cancer burden following
standard neoadjuvant chemotherapy treatment, resulting in distant metastasis and death for most of these
patients. Clinically overt metastases are incurable, so there is an urgent need to develop targeting strategies to
eradicate metastatic cells growing in secondary organs. Intra-tumor heterogeneity (ITH) is pervasive in TNBC
as is a barrier to development of effective therapeutic strategies. Dr. Echeverria’s proposal aims to unravel this
complexity, with the long-term goal of distilling evolutionary patterns that can be leveraged therapeutically to halt
local and distant disease progression. Dr. Echeverria’s postdoctoral studies elucidated patterns of clonal
dynamics in TNBC chemoresistance and metastasis using patient-derived xenograft (PDX) models and found
that multi-organ metastases are seeded and predominated by the same subclone populations. Furthermore, she
identified mitochondrial oxidative phosphorylation (OXPHOS) as a functional vulnerability in PDX models and
demonstrated efficacy of a novel OXPHOS inhibitor (OXPHOSi) in chemoresistant TNBCs. This proposal aims
to address the following hypotheses: that transcriptomic ITH is present in chemoresistant TNBCs and multi-
organ metastases, that subclones in multi-organ metastases share transcriptomic features, that TNBC subclones
modulate metabolic programs as they resist chemotherapy and metastasize, and that OXPHOS is a functional
vulnerability of multi-organ metastases in TNBC. These hypotheses will be tested in three specific aims. In Aim
1, the subclonal dynamics of transcriptomic programs as cells resist NACT and OXPHOSi treatment will be
elucidated by single-cell RNA sequencing (SCRS) and functional metabolic assays. Aim 2 will delineate
transcriptomic ITH in the most common sites of human TNBC metastasis by conducting SCRS on lung, liver,
and brain metastases isolated from PDXs. These studies will be complemented by functional metabolic
experiments and analyses of tumor biopsies obtained from TNBC patients. In Aim 3, the functional role of
OXPHOS in driving multi-organ metastasis will be determined by genetic and pharmacologic disruption of
OXPHOS activity in PDX models and TNBC cell lines. These studies will elucidate functions of candidate
metastasis driver genes discovered in Dr. Echeverria’s postdoctoral studies and will proceed with additional
candidate drivers discovered by SCRS in this proposal. Dr. Echeverria has assembled an outstanding team of
collaborators and mentors that will enable her to apply novel technologies to understand TNBC chemoresistance
and metastasis and will facilitate her development as an independent investigator. The immersive research
environment at MD Anderson has provided Dr. Echeverria with rigorous inter-disciplinary training in cancer
research and she will establish her independent research program at a research...

## Key facts

- **NIH application ID:** 9805151
- **Project number:** 1K22CA241113-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Gloria Vittone Echeverria
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $157,680
- **Award type:** 1
- **Project period:** 2020-02-06 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9805151

## Citation

> US National Institutes of Health, RePORTER application 9805151, Characterizing and targeting intra-tumor heterogeneity in triple negative breast cancer chemoresistance and multi-organ metastasis (1K22CA241113-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9805151. Licensed CC0.

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