Santiago Quevedo

Introduction Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males, accounting for 14% (903,500) of the total new cancer cases and 6% (258,400) of the total cancer deaths in males in 2008. Diagnosis can be obtained through prostate specific antigen (PSA) level and digital rectal exam, but a biopsy is the only way to confirm the diagnosis. Prostate cancer typical presents with trouble urinating, decreased force in the stream of urine, blood in the urine, blood in the semen, bone pain, losing weight without trying, and erectile dysfunction. Most treatments revolve around androgen deprivation therapy (ADT) and thus castration, usually medical, is an effective treatment. While castration is an effective treatment, approximately 28% of these patients develop castration resistant cancer. Some new treatments have begun to focus on the use of high-testosterone treatment; however, the exact mechanism of action is not known. The study focuses on discovering the mechanism for which high-testosterone treatment functions as well as how to optimize it. It was hypothesized that it functions through the retinoblastoma protein (Rb). By comparing the effects of high-testosterone on both Rb+ and Rb- cells, it was concluded that high-testosterone functions through the Rb protein. Knowing that high-testosterone functions through the Rb protein, it was hypothesized that the use of a CDK4/6 inhibitor along with the high-testosterone could increase the overall effects of the treatment. CDK4/6 inhibitor treatment has been approved in treating estrogen receptor positive and HER2 negative breast cancer. Methods For these tests, LNCaP C4-2 cells were used which are androgen-sensitive human prostate adenocarcinoma cells derived from the left supraclavicular lymph node metastasis. Palbociclib, an FDA-approved CDK4/6 inhibitor, was shown to prevent the hyperphosphorylation of Rb and p130 in CRPC cells. Furthermore, patient xenografts of the LuCaP35CR cell line were passaged into castrated SCID mice to test in vivo function. RNA-seq analysis using tumor samples from the study was conducted and the inhibition of Rb phosphorylation by Palbociclib was confirmed by immunohistochemistry staining. Results While 1,220 genes or 1,403 genes were downregulated by high-T or Palbociclib treatment, respectively, significantly more genes (2,750) were repressed by the combination treatment. Conclusion While most treatments focus on ADT, high-testosterone treatment has shown promise in treating prostate cancer, including castration resistant prostate cancer, and can be further optimized through the combination of high-testosterone and a CDK4/6 inhibitor.

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