Research Design And Methods For Patients With Castration Resistant Disease
Our proposal will develop and employ systematic computational approaches to understand complex regulatory relationships that lead to the emergence of castration-resistance, uncover mechanisms of treatment failure, and predict novel therapeutic options for patients with castration-resistant disease. Aim 1 will computationally identify regulatory drivers of CRPC. Aim 2 will develop a systematic approach to predict therapeutic strategies to inhibit activity of the identified drivers. Aim 3 will validate identified drivers and drug combinations (Aim 3.1) and will conclude with computational analysis of predicted drug response (Aim 3.2)
Aim 1. Identification of drivers that transcriptionally control signatures of castration-resistance.
Rationale and strategy: The discovery of novel therapeutic strategies for patients with CR prostate cancer has been impaired by our limited understanding of the molecular mechanisms that distinguish treatment failure from treatment success. To investigate molecular mechanisms leading to the emergence of treatment failure in CRPC, we will use publically available gene expression profiles of hormonally-intact, androgen-sensitive, and castration-resistant prostate cancer (from cell lines, xenografts, animal models, and human patients) to define molecular signatures of response to androgen deprivation in these distinct conditions. These molecular signatures will be used to interrogate transcriptional regulatory networks…