Targeting CD47-SIRPa Axis to Overcome Therapy Resistance in Ovarian Cancer

Project summary

PARP inhibition has shown promising activity and it is widely used in ovarian cancer (OC). However there is a need to identify novel therapies to enhance the benefit and reverse resistance to PARP inhibition. Macrophages are prominent immune cells in OC tumors and has been shown to induce resistance to therapy and cancer progression. Macrophages with a specific “suppressor” phenotype (M2 subtype) play a significant role in mediating treatment resistance. However, another phenotype (M1 subtype) provides a favorable anti-tumor effect Targeting macrophages and switching them from M2 to M1 is potentially promising approach. In this study, we propose to target them with CD47 inhibition. CD47 is utilized by tumor cells to evade phagocytosis by macrophage and thereby impairs the innate immune response. We pursue a novel combination therapy with anti-CD47 inhibition combined with PARP inhibition to target the macrophages and switch their phenotype. We hypothesize that PARP inhibition resistance in OC may be overcome by targeting immunosuppressive myeloid cells, through a targeted inhibition of CD47 pathway. We aim to demonstrate the macrophage “phenotype switch” within ovarian tumors responding to the combined therapy and reveal unique mechanisms of PARP inhibitors resistance related to targeting this pathway in OC. The potential impact is high as the data generated from this project will provide a rationale to advance a novel treatment option in PARP inhibitor resistant OC.