Role of Androgen Receptor Splice Variants in Development, Progression as well as Response to Treatment in Prostate Cancer

• Applicant: Privatdozent Christof Bernemann, Ph.D.
• Subject Area: Reproductive Medicine, Urology ; Hematology, Oncology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 434121518

Androgen receptor splice variants are known to influence the progression of prostate cancer. A correlation between expression of AR splice variant 7 (AR-V7) and poor prognosis has been described recently. However, the exact mechanisms by which AR variants influence the progression of disease is poorly understood.In the metastatic castration resistant state (mCRPC) AR-V7 positive patients show much lower response rates to antihormonal therapeutics compared to AR-V7 negative patients. Nevertheless, a non-negligible subgroup of AR-V7 positive patients still exhibit response to these agents despite expression of AR-V7. Contrary, a large subgroup of AR-V7 negative patients displays a primary resistance.We hypothesize that a more detailed predictive conclusion can be drawn by analysis of combinations of AR variants. Thus, aim of the proposed project is the dissection of AR variants or combinations of AR variants in distinct stages of disease.By performing in vitro experiments, we aim to analyze to what extent AR variants influence the early progression of the prostate cancer disease. This will be performed by in vitro experiments in primary epithelial prostate (cancer) cells as well as correlation analysis between expression of AR variants in primary tumors and clinical follow-up.RNA seq followed by differential gene expression analysis will be performed in order to dissect novel AR variant specific target genes. Identification of novel target genes might allow insights into mechanisms of resistance. Furthermore, this might become a clinical tool for future patient stratification.We also aim to analyze the effect of alternative treatments in case of AR positivity. Currently, the AR degrading agent niclosamide is being analyzed in clinical phase I and phase II trials in combination with abiraterone and enzalutamide. In vitro studies will dissect whether niclosamide is able to inhibit either AR variants or effects tumorigenic potential of AR positive cells.Finally, we want to gain insights of whether single AR or combinations of AR variants might be used as clinical biomarker for response to antihormonal therapies. This is mostly based on preliminary studies demonstrating that AR-V7 as a single biomarker is not sufficient to stratify patients for response to treatment.A more detailed dissection of mechanisms responsible for both primary and secondary resistance might therefore improve the prediction of response to therapy as well as personalized cancer treatment.The clinical relevance of the proposed project is given by its translational basis of analysis of patient materials combined with basic research approaches. This is in line with the current discussion of analysis of liquid biopsy for biomarker determination to finally improve personalized medicine.

• DFG Programme: Research Grants