Sharma, Katyayani (2024). Identification and Targeting of Novel Mechanisms for Treatment of Castration Resistant Prostate Cancer (CRPC). (Thesis). Universität Bern, Bern

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Abstract

Prostate cancer (PCa) is a significant contributor to cancer-related deaths among men globally, with varying prevalence across regions, particularly higher rates in North America, Europe, and Australia. The disease's incidence escalates with age, emphasizing its relevance in aging populations. PCa cells are fueled by androgens through the Androgen Receptor (AR), which activates genes crucial for tumor growth and survival. Thus, reducing circulating androgen levels or blocking AR remains primary in PCa treatment. However, in advanced stages like Castration-Resistant Prostate Cancer (CRPC), tumor cells develop mechanisms to thrive independently of androgens. These mechanisms involve the production of androgens within the tumor itself, highlighting androgen biosynthesis as a key target for CRPC treatment. Androgens, primarily produced in the testes, ovaries, and adrenal glands, regulate male sexual traits and behaviors. The adrenal cortex's Zona Reticularis (ZR) produces precursor hormones like dehydroepiandrosterone (DHEA) and its sulfate, which serve as substrates for androgen production. Cytochrome P450c17 (CYP17A1) plays a pivotal role in adrenal androgen production, catalyzing essential reactions in steroidogenesis. Given its significance, inhibiting CYP17A1 has garnered interest in PCa treatment. Abiraterone, a CYP17A1 inhibitor, albeit effective, lacks specificity and affects other CYP enzymes. Recent discoveries, like mutations abolishing CYP17A1's specific lyase activity, offer hope for developing selective inhibitors. Efforts focus on designing molecules targeting CYP17A1 without resembling androgens to avoid inadvertently stimulating androgen receptor signaling. Small molecule inhibitors are being screened, including those computationally designed to mimic native substrates. Additionally, exploration into endocrine disruptors' role in inhibiting CYP17A1 activity provides insights into environmental factors influencing cancer risk. Understanding the regulation of CYP17A1 activity through phosphorylation pathways offers another avenue. Kinases such as p38α and ROCK1, along with phosphatases like PP2A, play roles in modulating CYP17A1 activity. PLK1 inhibition demonstrated decreased CYP17A1 lyase activity, suggesting its potential as a target. Transcriptomic analysis identified differentially expressed kinases and phosphatases in PCa and polycystic ovary syndrome (PCOS), shedding light on potential therapeutic targets. Insights into CYP17A1 regulation also have implications beyond PCa, extending to hyperandrogenic disorders like PCOS and premature adrenarche. Developing drugs to lower androgen levels without affecting cortisol can mitigate side effects seen with current therapies, offering broader applications in reproductive health. In conclusion, targeting CYP17A1 holds promise in PCa treatment, especially in CRPC. Advances in understanding its regulation and identifying specific inhibitors offer hope for more effective therapies. Moreover, insights into CYP17A1's role in hyperandrogenic disorders present opportunities for broader therapeutic interventions in reproductive health.

Item Type:	Thesis
Granting Institution:	Faculty of Medicine, University of Bern
Dissertation Type:	Cumulative
Date of Defense:	9 February 2024
Subjects:	600 Technology > 610 Medicine & health
Institute / Center:	04 Faculty of Medicine
Depositing User:	Katyayani Sharma
Date Deposited:	25 Mar 2024 08:33
Last Modified:	30 Mar 2024 20:12
URI:	https://boristheses.unibe.ch/id/eprint/1746

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