Personalized optimization of tumor response to chemotherapy by evaluating Intra-tumor Heterogeneity in Triple Negative Breast Tumors

Background: Triple negative breast cancer (TNBC) is highly resistant to cytotoxic chemotherapy such as Paclitaxel (PTX). One of the reasons for the development of resistance is intra-tumor heterogeneity. We examine protein expression levels of central biomarkers in thousands of individual cells, to gain insight on the changes in different cellular subpopulations within the tumor in response to PTX. We hypothesize that identifying the subpopulations which expand in response to PTX will enable us to predict targeted drugs that will optimize TNBC response to chemotherapy.

Methods: We follow changes in 11 central TNBC biomarkers in response to PTX in single cells (>50000 cells per treatment) using flow cytometry. These changes are analyzed computationally by utilizing an information-theoretic approach. This allows us to accurately characterize cellular subpopulations in each tumor, which expand in response to PTX.

Results: The analysis reveals that after treatment with PTX, there is an expansion of 2 distinct cellular subpopulations within the tumor. The first subpopulation harbors induced expression of C-KIT receptor along with CD44, while the second subpopulation harbors induced expression of PDL-1. Based on the analysis we suggest that PTX treatment should be complemented with inhibitors against PD-L1 and C-KIT or their downstream effectors.

Conclusions: Although this project is in its initial stages, it provides us with the hypothesis that TNBC response to PTX can be optimized by combining it with anti-C-KIT and PDL1 inhibitors. We plan to test our predicted combination in-vivo, in-vitro and to show how these results can be extended to patient derived xenografts.