Our laboratory uses animal models to understand the molecular mechanism of prostate cancer initiation and progression in order to rationally design therapeutic approaches for the prevention and treatment of the disease. The ultimate goal of the laboratory is to use preclinical testing of putative therapeutic agents to rapidly identify promising effective agents and facilitate the rapid movement of these compounds from the benchtop to the bedside.
The current focus of the lab is on understanding the molecular mechanism underlying corruption of vitamin D signaling in prostate cancer (PCa) progression and the impact of the serotonin 2C receptor (5HT2cR)/HBII-52 axis in PCa. Transgenic adenocarcinoma of mouse prostate (TRAMP) is used as a model of progressive PCa. The lab identified vitamin D (calcitriol) as a chemopreventive agent for primary PCa in hormone-intact TRAMP mice. However, long-term treatment of TRAMP mice with calcitriol increased the incidence of metastatic lesions. These studies suggest that early intervention with vitamin D can slow androgen-stimulated tumor progression, but prolonged treatment may result in development of a resistant and more aggressive disease associated with increased distant organ metastasis. LSD1 was identified as both a coregulator and coactivator of the vitamin D receptor. Current studies focus on understanding VDR/LSD1 in complex with other transcriptional regulators as determinants of transcriptional output in the context of the epigenome.
Another project in the lab has identified the small nucleolar RNA (snoRNA), MBII-52 (human homolog: HBII-52) as a potential marker and driver of castration-recurrent (CR) PCa. HBII-52 affects processing (A-to-I RNA editing and RNA splicing) of the serotonin 2c receptor (5HT2cR) pre-messenger RNA, which results in expression of isoforms of the 5HT2cR that are more active, and in some cases constitutively active (i.e. signal independent of ligand binding). These activated isoforms propagate a cascade of downstream signaling events that involves numerous pro-proliferative and pro-invasive target pathways, which include extracellular signal-regulated kinase (Erk) and RhoA. Mouse models of PCa (e.g. TRAMP, Pten-/-), a panel of human PCa cell lines, and clinical samples demonstrated that the putatively brain-specific snoRNA HBII-52 is elevated in PCa and correlates with aggressiveness, clinical outcomes, and development of the neuroendocrine phenotype. Thus, HBII-52 may provide a biomarker for PCa, the HBII-52 -> 5-HT2cR axis may represent a druggable target for aggressive and CR- PCa. We propose a model of PCa progression in which HBII-52 modulates editing and splice-site selection of the 5HT2cR pre-mRNA to produce a constitutively active isoform 5-HT2c-INIR. This isoform aberrantly activates downstream oncogenic signaling pathways (Erk and RhoA) and correlates with poor differentiation or the emergence of a neuroendocrine phenotype, thereby contributing to cancer progression. This pathway could be effectively treated by repositioning currently available selective inhibitors of 5HT2cR.
This work has been supported by National Institute of Health RO1, Department of Defense, American Italian Cancer Foundation, and RPCI Alliance Foundation.