Germline Variation in HSD3B1 as a Novel Biomarker in Prostate Cancer
Abstract
Nearly all prostate cancers express the androgen receptor (AR), the importance of which is underscored by androgen deprivation therapy (ADT), which has been the most effective and widely used systemic therapy for prostate cancer for the past 70 years. ADT improves survival in multiple clinical contexts and represents the cornerstone of treatment among men with metastatic prostate cancer or in whom local therapy has failed. Although the vast majority of men will demonstrate an initial response to ADT, most will eventually develop castration-resistant prostate cancer (CRPC). There is marked heterogeneity in this regard, however, as the time frame ranges from much less than a year to well beyond 5 years. We currently are unable to reliably predict where on this spectrum a man s cancer is likely to fall and therefore are unable to tailor therapy accordingly. Recently, our group identified a mutation in HSD3B1, the gene encoding an enzyme required for a critical step in the synthesis of dihydrotestosterone (DHT), the most potent androgen. This mutation renders the enzyme resistant to degradation, which results in a dramatic increase in the synthesis of DHT within tumor cells, thereby furnishing a molecular mechanism of resistance to ADT. Importantly, while this mutation can develop de novo in a prostate cancer cell, it is also commonly inherited as a germline variant. Taken together, (1) variation in HSD3B1 provides a molecular mechanism for ADT resistance and (2) many men are born with this sequence, so we recognized the possibility for a novel biomarker with potential to predict resistance to ADT. Accordingly, we developed an efficient assay to determine HSD3B1 genotype and correlated long-term clinical outcomes in a cohort of men treated with ADT at Cleveland Clinic. We hypothesized that inheritance of the variant sequence would engender intrinsic resistance to ADT and that men with two copies of the variant allele would have worse clinical outcomes than men with no copies, while men with one copy would potentially have intermediate outcomes. Our preliminary work strongly suggests this hypothesis is correct, with profound differences (years) in time to progression, distant-metastasis-free survival, and overall survival. The consistency of our preliminary findings with what would be predicted from the underlying molecular mechanism, together with evidence of a gene-dosage effect (stepwise decrements in clinical outcomes correlating with the number of variant alleles a man has inherited), lend credibility to our preliminary results. Nonetheless, validation in an independent cohort is necessary and represents the impetus for this proposal. We have already formed a collaboration with the Mayo Clinic for this purpose. We additionally propose to measure serum steroid profiles and correlate these with genotype to ascertain whether they may provide an alternative biomarker, and possibly even add further predictive value. Finally, given that ADT is used in many contexts across the landscape of prostate cancer, including in combination with radiotherapy, we propose to specifically evaluate whether HSD3B1 genotype also has predictive value in this setting. In summary, our preliminary work suggests germline variation in HSD3B1 has a profound effect on resistance to ADT and can identify patients more likely to progress, develop distant metastases, and die of their disease on traditional ADT. If validated, this would represent a unique genetic biomarker that could be used to select patients -- prior to therapy -- who may benefit from escalated treatment. This could provide the foundation for a logical algorithm to aid decision making with regard to selective early incorporation of highly potent inhibitors of the AR pathway, such as enzalutamide or abiraterone acetate. This would have major implications for clinical trial design and could be incorporated immediately. Additionally, the proposed research will provide i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510503
Entities
People
- Jason Hearn
Organizations
- United States Army
- University of Michigan