Project 3: Induction of synthetic lethality with combined DNMT and PARP inhibition

PROJECT SUMMARY Recent data have shown that PARP inhibitors are an effective therapeutic strategy for DNA repair-deficient metastatic castration-resistant prostate cancer (mCRPC). The response rates to PARP inhibition have been most pronounced in patients with a homologous recombination deficiency (HRD) alteration, specifically BRCA1 or BRCA2 mutations. Since only 10-20% of mCRPC patients harbor sensitizing HRD mutations, the group of men that may potentially benefit from this therapy is limited. Novel strategies to unlock the utility of PARP inhibitors for treatment of patients that lack HRD defects would therefore have tremendous impact in the treatment of advanced prostate cancer. Based on our strong preliminary data, here we will test the innovative hypothesis that the combination of DNA methyltransferase inhibitors (DNMTi) and poly-ADP ribose polymerase inhibitors (PARPi) will produce a “triple-threat” to cancer cells by inducing synthetic lethality even in HR- proficient mCRPC patients via any of three complementary mechanisms: i) DNMTi-mediated downregulation of homologous recombination coupled with synergistic generation of DNA damage with both drugs, each trapping their target enzyme on DNA; ii) epigenetic and DNA damage mediated activation of immunogenic interferon pathways to promote anti-tumor immune responses; and iii) inhibition of AR signaling, which remains vital to support growth and survival of mCRPC. We will determine the utility and safety of this combination in different subtypes of prostate cancer using multiple prostate cancer pre-clinical models in vitro and in vivo (Aim 1), determine the mechanisms by which the combination induces synthetic lethality in mCRPC (Aim 2), and carry out a pharmacodynamic biomarker-driven phase 1/1b clinical trial of the combination in men with advanced mCRPC (Aim 3). If successful, these studies will yield a powerful new therapeutic strategy for mCRPC and expand the utility of PARPi to men without underlying HRD mutations.