# Project 3: Single Cell Measures of Intratumor Diversity for Optimal Breast Cancer Therapy

> **NIH NIH U54** · DANA-FARBER CANCER INST · 2020 · $126,492

## Abstract

Project 3: Single cell measures of intratumor diversity for optimal breast cancer therapy 
Project Summary / Abstract 
Despite improved treatment, metastatic breast cancer is still inevitably fatal and is a major cause of cancer- 
related deaths. Triple negative and inflammatory breast cancer are breast tumor subtypes that lack targeted 
therapy, which, in combination with the high propensity to distant metastatic spread, leads to poor outcome; 
70-80% of patients diagnosed with TNBC or IBC die within 5 years of diagnosis. Thus, new treatment 
strategies are urgently needed. 
We have previously analyzed the clinical and functional relevance of intratumor heterogeneity in breast cancer. 
We analyzed breast tumor samples before and after pre-operative chemotherapy and at different stages of 
disease progression for intratumor cellular heterogeneity for genetic and phenotypic features. We found that 
lower pretreatment genetic heterogeneity predicts better response and that distant metastases have the 
highest diversity index. We have also developed a xenograft model of intratumor clonal heterogeneity in breast 
cancer and utilized this model to assess the functional relevance of clonal interactions in metastatic 
progression. We found that polyclonal tumors are more likely to metastasize and identified underlying clonal 
cooperative mechanisms driving this process. Lastly, we have developed mathematical models based on these 
experimental data that can infer the evolution of tumors during treatment and disease progression both in 
clinical samples and in xenografts. Based on our preliminary data, we hypothesize that (1) intratumor 
heterogeneity is a driver of disease progression, (2) single cell measures of intratumor heterogeneity and their 
topologic distribution can be used to build mathematical models of tumor evolution and treatment response, (3) 
the use of these models will aid the design of individualized treatment strategies that more effectively eliminate 
breast tumors. We propose three specific aims to test these hypotheses: Aim 1. Single cell analyses of breast 
tumor samples. Aim 2. Characterization of therapeutic responses in xenograft models of breast cancer. Aim 3. 
Predict optimal therapeutic strategies to prevent metastatic outgrowth and treatment resistance and validate 
these strategies in xenograft models. Our goal is to translate our findings into future clinical trials.

## Key facts

- **NIH application ID:** 10134501
- **Project number:** 3U54CA193461-05S1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** KORNELIA POLYAK
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $126,492
- **Award type:** 3
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134501

## Citation

> US National Institutes of Health, RePORTER application 10134501, Project 3: Single Cell Measures of Intratumor Diversity for Optimal Breast Cancer Therapy (3U54CA193461-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134501. Licensed CC0.

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