Manipulating Sex Hormone Signaling for Therapeutic Benefit in Liver Cancer

Project Summary/Abstract Hepatocellular carcinoma (HCC) is on track to surpass breast, prostate, and colorectal cancer to become the third-leading cause of cancer death in the United States by 2040. HCC-related deaths in men outnumber those in women by more than 3:1 and this is thought to be due to male hormone signaling mediated by the transcription factor androgen receptor (AR). AR is commonly expressed in HCC and increased AR activity corresponds with worse HCC outcomes. AR inhibition is highly effective for the treatment of prostate cancer, but clinical trials to inhibit AR signaling in advanced HCC have been unsuccessful to date. Here, we study a new genetically engi- neered mouse model of HCC (Alb-Cre;Trp53fl/fl;Tsc1fl/fl) that recapitulates the sex differences observed in human HCC. Resultant liver tumors are AR positive and tumor growth is responsive to hormonal manipulations, making the model an ideal platform to functionally assess the role of AR in HCC. We hypothesize that AR is a required mediator of mTOR-driven growth in HCC and propose combinatorial AR and mTOR inhibition may be an effective therapeutic strategy to treat advanced HCC. Our preliminary data demonstrate that AR inhibition via surgical castration prevents the development of liver tumors while treatment with AR agonist dihydrotestosterone pro- motes liver tumors in this mTOR-driven model. To test our central hypothesis, we propose the following aims: 1) measure the effect of AR signaling on the oncogenic traits of HCC models, 2) define the transcriptional profile of the AR in HCC, and 3) determine the therapeutic potential of AR inhibition in patient-derived HCC xenografts and a genetically defined autochthonous mouse model of HCC. The accompanying training plan incorporates a broad range of experimental methods to orthogonally assess the role of AR in HCC while cultivating critical problem-solving skills and immersing the trainee in a highly productive multi-disciplinary scientific laboratory environment combined with focused clinical training in clinical oncology.