Alteration of cellular phenotype by therapeutic modulation of epigenetic gene regulation to induce synthetic lethality in prostate cancer
Final Report Abstract
Aims of this proposal were to test combinations of epigenetic drugs at low doses and existing targeted drugs for cytotoxicity of prostate cancer cells and to perform genome-wide RNAi screens to identify functional vulnerabilities or synthetic lethal interactions with epigenetic drugs. Furthermore, these synergistic combinations were planned to be evaluated in human prostate cancer xenograft models. In the first screening strategy, a chemical compound screen of a library of ~3,500 clinically used drugs was carried out to identify those drugs that would synergize with the epigenetic drug decitabine in inhibiting prostate cancer cell growth. This screen has yielded 121 hits, many of which were enriched in various drug classes including antineoplastic drugs (n=38), antibiotics (n=12), cardiotonic drugs (n=17), antiseptic drugs (n=9), and immunosuppressants and antirheumatics (n=5). Among the most provocative hits were anthracenediones like mitoxantrone, used already for prostate cancer treatment, and novel compounds, such as an XPB and dCTP pyrophorylase (DCTPP1) inhibitor. Further characterization of these hits in preclinical cell line and animal models is currently underway. In the second screening strategy, a novel functional screening approach using pooled shRNA libraries was carried out to identify those shRNAs that produced synthetic lethality with the epigenetic drug decitabine in prostate cancer cells. Among the lead candidates emerging from this innovative screening approach were seven hits for which targeted inhibitors are currently in clinical or preclinical development. Of these, Aurora kinase A (AURKA) inhibitors and phosphodiesterase 1 (PDE1) inhibitors have emerged as leading targets through efficacy testing in multiple prostate cancer cell models. Subsequent work in vivo using xenograft models showed strong synergistic effects on tumor growth and survival for a combination of a novel Aurora kinase A inhibitor and low dose decitabine. Preparations for translation of this combination treatment to a human clinical trial are currently underway.
