Characterization of the Anti-Cancer Activities of Clinical Candidate Galeterone (VN/124-1) and its Novel Analogs in Human Prostate and Pancreatic Cancer Models In Vitro and In Vivo

Abstract

Cancer is a "moving target" disease, as the condition progresses, critical driving oncogenes evolve. Effective treatment for cancers, such as prostate cancer (PC) and pancreatic ductal adenocarcinoma (PDAC) are based on targeting multiple oncogenes implicated in disease progression and drug resistance. Our group pioneered the development of galeterone (gal, originally designated VN/124-1); a small molecule inhibitor that impedes both AR positive and negative tumor growth, suggesting its ability to modulate multiple oncogenes. The goal of this thesis was to assess the ability of gal and novel analogs to modulate multiple oncogenic targets in a variety of clinically relevant human PC and PDAC models to inhibit cell viability, tumor growth and metastatic potential. Our studies show that gal and VNPT55 induce proteasomal degradation of AR/AR-V7, implicating Mdm2/CHIP E3 ligase. Gal/VNPT55 also degraded ARv567es, with VNPT55 exhibiting additional effects on AR-V7 mRNA. We also observed significant gal/VNPT55-induced increase in Bax/Bcl-2 ratio preceding cytochrome c release with a concomitant cleavage of caspase 3 and PARP, culminating in apoptosis. Gal and analogs also repressed pathways implicated in invasiveness (NF-KB, Twist1 and Mnk1/2-eIF4E axis), depleted expression of epithelial-mesenchymal-transition markers (N-Cadherin, MMP-2/-9 and Snail) and down-regulated putative stem cell factors (CD44, Oct-4 and BMI-1). These effects resulted in inhibition of cellular biological activities (migration and invasion) in vitro. Furthermore, gal/analogs effectively decreased viability of several drug-resistant PC cells. Strong anti-proliferative activity on gal-resistant cells by the novel analogs unraveled the lack of cross resistance. Additionally, anti-tumor activity of gal and VNPT55 on CWR22Rv1 xenograft (CRPC model) recapitulated in vitro activities of the compounds, with no apparent host toxicity. Finally, based on the findings that these agents effectively inhibited pathways associated with PDAC disease progression and drug-resistance, we assessed the potential of the agents as PDAC therapy. Gal/analogs alone or in combination with gemcitabine significantly decreased viability of gemcitabine-naive/resistant PDAC cells. Gal/analogs also inhibited transcription factors, prominent in PDAC disease progression. These agents also caused strong growth inhibition of MiaPaCa-2 xenografts. Together, these data demonstrate that gal and novel analogs possess multiple anti-cancer properties, providing a strong rationale for their development in prostate and pancreatic cancer therapy.