Activity of Galeterone in Hepatocellular Carcinoma and Description of Androgen Receptor Expression in Mouse Liver
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. College of Pharmacy Undergraduate Research Theses; 2019
Globally, liver cancer is the sixth most commonly diagnosed cancer, fourth leading cause of cancer deaths, and has increasing incidence and mortality rates. Hepatocellular carcinoma (HCC) is the dominant form of liver cancer. Although HCC treatments are improving, the 5-year survival rate in the United States remains low at 18%. A 3-fold higher prevalence of HCC in men than women suggests androgens, such as testosterone, promote the disease. Androgens bind and activate the androgen receptor (AR), a transcription factor that regulates a diverse set of genes. Despite evidence that AR contributes to HCC, traditional antiandrogen therapies, which are steroid-competitive at the ligand binding domain of AR, are ineffective in treating advanced HCC. In primary HCC patient samples and HCC cell lines, we identified alternatively-spliced forms of AR (ARsvs) that lack the ligand binding domain, are constitutively active, and are unaffected by traditional antiandrogens. We hypothesize that full-length AR and ARsvs contribute to liver disease progression, and novel selective AR degraders (SARDs) will have anti-HCC activity by inhibiting all forms of AR. The data support that pharmacologic activation or inhibition of full-length AR does not affect HCC cell line proliferation. However, a novel SARD, galeterone, decreases proliferation potentially by inhibiting full-length AR, ARsvs, and mTOR signaling. Future work aims to identify and investigate signaling through AR in immune and non-immune cells of the liver that is relevant to disease.
Academic Major: Pharmaceutical Sciences
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