# Circumventing acquired carboplatin resistance in triple-negative breast cancers

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $350,917

## Abstract

The uncontrolled growth of breast cancer cells in vital organs is attributable to nearly all the ~40,000 deaths that
happen each year in the United States. The long-term goal of this project is to identify new therapeutic strategies
to overcome chemotherapy resistance in triple-negative breast cancers (TNBC). The objective of this proposal
is to identify biological pathways that can be targeted in addition to the epidermal growth factor receptor (EGFR)
to promote apoptosis of disseminated cancer cells. The central hypothesis is that EGFR inhibition leads to
activation of cellular stress responses that can be targeted with pro-apoptotic agents. The goal at the completion
of this project is for the results to immediately translate to the clinical setting and provide options for current
patients with metastatic disease. The proposed work will also develop a unique dataset that can be used for
further research towards identifying and developing targeted inhibitors that bypass carboplatin-resistance. The
central hypothesis will be tested by pursuing two specific aims: 1) Delineate targetable pathways that are
synergistic with Afatinib for cytotoxicity of carboplatin-resistant TNBCs; 2) Determine the efficacy of Afatinib-
synergsitic combinations in multiple diverse in vivo models of TNBC. These aims will be pursued using an
innovative set of patient-derived xenograft models (PDX) which consist of isogenic pairs that are carboplatin-
sensitive or those that have been generated to be carboplatin-resistant. This research proposal is
significant because it will identify new therapeutic targets that can be used to treat patients with advanced
disease, and then compare the effectiveness of various targeted combinations on surgically unresectable
metastases. The expected outcome of these efforts is that we will identify subsets of TNBC PDXs that will
favorably respond to Afatinib-based combination therapies, and subsequently that we will identify genomic and/
or proteomic predictors of anti-EGFR response that will make a positive impact on disease management by
identifying patients that may benefit from this treatment approach.

## Key facts

- **NIH application ID:** 10048434
- **Project number:** 1R01CA246182-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Joshua (Chuck) Harrell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $350,917
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048434

## Citation

> US National Institutes of Health, RePORTER application 10048434, Circumventing acquired carboplatin resistance in triple-negative breast cancers (1R01CA246182-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10048434. Licensed CC0.

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