PG545 synergizes with PARP inhibitors in ovarian cancer to disrupt DNA repair through modulation of DEK-RAD51 axis

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Recent studies have highlighted the importance of DNA repair pathway alterations and the significance of PARP inhibitors (PARPi) in ovarian cancer (OC). The use of PARPi therapy has resulted in extending the median progression-free survival, mainly for patients whose OCs are homologous recombination (HR) repair deficient. Likewise, inhibiting specific growth factor (GF)-mediated signaling has also led to increased PARPi sensitivity in HR proficient OC cells. Despite these observations, resistance to PARPis and tyrosine kinase inhibitors against individual growth factors (GFs) continues to be a major problem due to altered expression of GF ligands produced in the tumor microenvironment that may worsen responsiveness to kinase inhibitors by upregulating redundant survival pathways. Consequently, if multiple GF-mediated signaling pathways could be targeted simultaneously, the acquired resistance could potentially be minimized and treatment is more effective in cancer eradication than targeted therapy for which OCs eventually develop resistance. To this end, we have identified PG545, a highly sulfated small molecule (Pixatimod, Zucero Therapeutics, Brisbane, Australia) with reported safety in advanced cancer patients (NCT02042781) and significant effect in multiple tumor models, including ovarian, endometrial and pancreatic cancers, as demonstrated by our group and in colon, breast, and lung cancers by other groups. Importantly, PG545 inhibits heparanase and disrupts signaling mediated by heparin-binding growth factors (HBGFs) such as HB-EGF, FGF, VEGF and HGF. Our preliminary data have shown that PG545 has the potential to overcome PARP resistance in PARP resistant OC cell lines by inducing DNA damage and “BRCAness” by downregulating RAD51 and diminished the nuclear accumulation of the secreted DEK that plays a vital role in HR repair by forming complexes with RAD51 raising the possibility that DEK contributes to RAD51 stability, or function. The goal in this application is to determine the efficacy of PG545 to synergize with PARP inhibitors in vivo using PDX models and in patient derived ascites cells and also to confirm whether the underlying mechanism by which PG545 downregulates RAD51 in OC cells mirrors our in vitro preliminary data. Currently, there are no effective treatment options for patients with HR- proficient and PARPi-resistant recurrent ovarian cancer. New effective drug combinations are urgently needed to address this critical clinical challenge. The drug combination proposed here will address this deficiency.