Multifactorial Targeting of the Prostate Cancer Treatment Landscape

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In 2023, prostate cancer had the highest rate of incidence and second highest rate of mortality in men in the United States. Currently approved therapies, such as hormone therapies and chemotherapies, serve to slow down cancer progression but are unable to cure it permanently. Therefore, it is important to understand this disease to formulate effective therapeutic strategies. In this dissertation, I take a multipronged approach in addressing the prostate cancer diagnostic and treatment landscape. In Chapter 2 of my dissertation, I examined the biomarker potential of a cancer testis antigen called TDRD1. Using an in-house TDRD1 monoclonal antibody, I developed an immunohistochemistry protocol that can successfully detect TDRD1 expression in prostate cancer patient samples. This method can be employed to detect TDRD1 as a clinical biomarker. In Chapter 3 of my dissertation, I investigated the role of TDRD1 in prostate cancer development by examining its role in inflammation. Through TDRD1 knockout and overexpression studies, I discovered that TDRD1 increases the expression of various inflammatory cytokines. Since inflammation of the prostate drives cancer development, modulating the expression of TDRD1 might be a potential way to reduce inflammation and thereby prevent tumorigenesis. Finally, in Chapter 4 of my dissertation, I explored the immunotherapeutic targeting of prostate cancer using CAR T cells. I enhanced a PSMA-based CAR T therapy by co-expression of a mutant version of EZH2. Using T cell killing and interferon gamma release assays, I demonstrated that EZH2 can be used to augment the efficacy of anti-PSMA CAR T therapy.

prostate cancer, TDRD1, PSMA, CAR T
Portions of this document appear in: Kim, Hong, Amrita Barua, Luping Huang, Tianyi Zhou, Modupeola Bolaji, Sharon Zachariah, Aroshi Mitra, Sung Yun Jung, Bin He, and Qin Feng. "The cancer testis antigen TDRD1 regulates prostate cancer proliferation by associating with the snRNP biogenesis machinery." Oncogene (2023): 1-11; and in: Mitra, Aroshi, Amrita Barua, Luping Huang, Siddhartha Ganguly, Qin Feng, and Bin He. "From bench to bedside: the history and progress of CAR T cell therapy." Frontiers in Immunology 14 (2023): 1188049.