Combination of PARP inhibitor olaparib and a vascular disrupting agent reduces tumor growth in a preclinical model of prostate cancer.

PURPOSE: This study aims to characterize the antiproliferative and antitumor activity of NOV202, a novel vascular-disrupting and microtubule-destabilizing compound, alone and in combination withthe PARP inhibitor olaparib, in preclinical prostate cancer models in vitro and in vivo. METHODS: DU145 (carrying a BRCA2 variant of unknown significance) and PC-3 (BRCA2 wildtype) prostate cancer cells were implanted in NMRI nude mice. Mice received oral olaparib, NOV202, or both for 21 days. Tumor growth was monitored via bioluminescence imaging and caliper measurements. By immunohistochemistry we assessed DNA damage (γH2AX), homologous recombination repair (RAD51), hypoxia (HIF-1α), proliferation (Ki-67), vascularization (CD31) and apoptosis (cleaved caspase 3). Cell viability assays and western blot analyses were performed to assess treatment-induced DNA-damage and apoptosis markers and to evaluate synergistic effects in vitro. RESULTS: Olaparib and NOV202 independently reduced tumor growth in both xenograft models. NOV202 was the dominant single agent in vivo, and adding olaparib resulted in a modest increase in tumor growth inhibition over NOV202 alone. Immunohistochemistry showed treatment-associated increases in DNA damage and reduced vascularization in tumors. All treatments were well tolerated with minimal signs of toxicity. In vitro, the combination induced synergistic antiproliferative effects. At the protein level, DNA-damage and apoptosis markers were increased mainly by olaparib and were not further enhanced by the combination. CONCLUSION: NOV202 showed potent single-agent antitumor activity in both prostate cancer xenograft models. The combination with olaparib was synergistic in vitro at low nanomolar NOV202 concentrations but did not provide a clear additional benefit over NOV202 alone in vivo.