"Expression Profiling following Androgen Deprivation Therapy Suggests New Combination Therapies for Aggressive Prostate Cancers"

Carlos Moreno, Ph.D.
Associate Professor
Department of Pathology & Laboratory Medicine
Department of Biomedical Informatics
Winship Cancer Institute of Emory University
Director, Cancer Biology PhD Program
Emory University School of Medicine

Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived, and responses are variable. ADT failure results in castration-resistant prostate cancer (CRPC), that inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis. We performed whole transcriptome analysis of 20 patient-matched Pre-ADT biopsies and 20 Post-ADT prostatectomy specimens, and identified transcription factor coordinated groups (TFCGs) using the PANDA algorithm.  We identified two subgroups of patients (high impact and low impact groups) that exhibited distinct transcriptional changes in response to ADT. We found that all patients lost AR-dependent subtype (PCS2) transcriptional signatures. The high impact group maintained the more aggressive subtype (PCS1) signal, while the low impact group more resembled an AR-suppressed (PCS3) subtype. Computational analyses identified transcription factor coordinated groups (TFCGs) enriched in the high impact group network. Leveraging a large public dataset of over 800 metastatic and primary samples, we identified 33 TFCGs in common between high impact group and metastatic lesions, including a TFCG containing JUN, JUNB, JUND, FOS, FOSB, and FOSL1. These studies led us to hypothesize that combination therapies targeting AR and the MAPK and/or JNK pathways may synergistically kill prostate cancer cells and prevent recurrence and progression to CRPC.  Our preliminary analyses of several compounds suggest that they may be highly effective for treatment of aggressive prostate cancers in combination with ADT.