Dissecting Prostate Cancer Chemoresistance at the Single Cell Transcriptional Level
Abstract
Although the majority of prostate cancers (PCa) initially respond to chemotherapy resulting in decreasing tumor size, the tumors eventually develop resistance to the drug and the tumors progress leading to the patient s death. In many cases, it is not clear why tumors become resistant; however, one possibility is due to the observation that tumors contain a mixture of many tumors cells that are very different from each other. This is termed tumor heterogeneity. Specifically, this suggests that some tumors, even before therapy is initiated, contain a few cells that are resistant to the therapy. Thus, when the tumor is treated, the majority of cells are killed, but the few resistant cells left behind start to grow and eventually grow large enough to form a tumor that is resistant to the therapy. This possibility leads to the hypothesis that heterogeneity within tumors at the single cell level promotes development of resistance to chemotherapy. Although single cell heterogeneity has marked potential in contributing to development of resistance, there are currently no well-documented robust and high-throughput methods to quantify heterogeneity at the single cell level so that it could serve as biomarker for either (1) predicting risk of developing chemoresistance (and its associated prognosis) or (2) facilitating selection of optimal therapeutic regimen based on the clonal populations. Thus, the overall goals of this proposal are to provide preclinical proof of principle of the ability to (1) quantify tumor heterogeneity at the single cell level as a biomarker of risk for development of chemoresistance and (2) predict the optimal therapeutic regimen based on clonal populations that exist prior to therapy. To achieve these goals, the following specific aims will be performed using a novel method that allows us to measure the activity of genes in single cells: Aim 1: Determine if the degree of heterogeneity at the single cell level in patient-derived xenografts (PDX) predicts their response rate to docetaxel and cabazitaxel in mouse models. Aim 2: Identify populations in PDX at the single cell level that predict the response and duration of response to taxane-based chemotherapy in murine models. The project uses a highly innovative concept; i.e., measuring heterogeneity itself as a biomarker of resistance and uses innovative technology; i.e., measuring a large number of genes activity in single cells of a tumor. Successful completion of these preclinical studies will provide the rationale to extend these studies to clinical evaluation of tumor heterogeneity as a biomarker of chemoresistance and therapeutic selection. Furthermore, it will lead to exploration of the role of heterogeneity in development of resistance to other therapeutics in addition to the chemotherapeutics. This will lead to decreasing use of ineffective therapeutics resulting in more efficient therapies and enhancing the duration and quality of life of men experiencing the impact of PCa. This proposal directly addresses the Prostate Cancer Research Program Overarching Challenge "Develop effective treatments and address mechanisms of resistance for men with high-risk prostate cancer." Furthermore, it addresses the PCRP Focus Areas of (1) Biomarker Development in the context of prediction of response to therapies and (2) Mechanisms of Resistance through developing an understanding of how heterogeneity at the single cell level may contribute to resistance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510208
Entities
People
- Evan T Keller
Organizations
- United States Army
- University of Michigan