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.