Session 2C: Inaugural Lectures by Fellows / Associates

Mechanistic underpinnings and therapeutic interventions for major prostate cancer subtypes

Abstract: Prostate cancer (PCa) represents a heterogeneous collection of malignancies with diverse molecular frameworks. Earlier, we showed that ~50% of PCa patients from India, harbor TMPRSS2-ERG gene fusion, while ~14% with the advanced-stage disease showed higher SPINK1 levels. We also elucidated the underlying mechanism involved in SPINK1 upregulation, wherein microRNA-338-5p/-421 negatively regulates its expression, and EZH2, an epigenetic regulator, silences the expression of these miRNAs. Regardless of molecular subtype, androgen-deprivation therapy (ADT) remains the mainstay treatment for locally advanced and metastatic PCa patients, but a majority of these individuals eventually progress to castration-resistant disease. We found that anti-androgen drugs commonly used for treating advanced-stage patients are counterproductive in the long-term. For instance, ADT in mice xenograft models and patients results in elevated SPINK1 levels accompanied by neuroendocrine-like features. Furthermore, we established the utility of DLX1 as a prognostic marker and a drug target, which is highly expressed in ~60% of the organ-confined or metastatic CRPC patients. We showed that bromodomain and extra-terminal inhibitors disrupt AR and ERG-mediated DLX1 transcriptional circuitry, thereby mitigating tumorigenesis and metastases. Taken together, we have been working at the forefront of translational molecular oncology, which would have an impact on clinical decision-making, diagnosis, and therapeutic interventions