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SPORE in Prostate Cancer

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PROJECT 3: Toward Understanding Prostate Cancer Heterogeneity

Co-Leaders Dr. Mark Rubin, Dr. Ronglai Shen, and Dr. Saravana Mohan Dhanasekaran

No study has systematically explored molecular relationships of primary PCa and the eventual CRPC clone, which requires paired specimen assessment. Multiple studies have assessed the molecular landscape of lethal CRPC. However, it is unclear whether alterations found in CRPC were present prior to ADT or mediated progression to CRPC or they represent lesions acquired after CRPC progression. The multi-institution SU2C/PCF-funded clinical trial has prospectively performed comprehensive transcriptome sequencing (RNAseq) and WES on 500 patients with CRPC prior to clinical trial enrollment. Hence, the CRPC500 trial provides a unique cohort with comprehensively profiled CRPC from genomically consented patients with robust clinical annotation. At RP, about 80% of patients harbor multi-clonal (also referred to as multi-focal) PCa, where spatially distinct tumor foci, which may show similar morphology and/or grade (Gleason score), are present in the same prostate. Hence, there is a critical need to accurately identify the true “index” or dominant focus at RP that will drive progression to CRPC. 

Although high-risk localized PCa is often cured by multi-modal therapy–including radical prostatectomy [RP], radiation therapy [RT] and androgen deprivation therapy [ADT]-the development of CRPC after metastatic progression is lethal. Studies from several groups have profiled untreated localized PCa and CRPC; however, these studies represent static snapshots from convenient samples or rapid autopsies from earlier treatment eras. Lacking are molecular studies addressing PCa progression during current treatments or clinical trials. Recently, a multi-institutional “Dream Team” was assembled to perform whole exome sequencing (WES) and RNA sequencing (RNAseq) on metastatic tumor biopsies and germline DNA from 500 CRPC patients (the “CRPC500” study) prior to enrollment on trials involving enzalutamide, abiraterone, and a PARP inhibitor (olaparib). We recently published the first 150 cases (Robinson et al, Cell. 2015) and over 500 men have now been enrolled with clinical follow-up expected through the next 3 years. We now have the extraordinary opportunity to examine the original untreated diagnostic material from the prostates of the CRPC500 patients and compare these data with the treated metastatic samples to explore key critical questions relevant to progression to CRPC and treatment response. Our over-arching goal is to determine the extent to which early mutations/other alterations inform disease progression and response to AR- or PARP-directed therapy. 

Specific Aims:

Aim 1: Collect, characterize, and immunohistochemically profile primary ADT-naïve specimens from CRPC500-trial patients. 

Aim 2: Determine the molecular landscape of multiple tumor foci from the primary ADT-naïve CRPC500 specimens. 

Aim 3: Identify molecular mediators of PCa progression and track the progressing clone through an integrative molecular profiling analysis