Abstract 5551: Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment

Abstract

Abstract Several mutations have been identified that are associated with an increased risk of triple-negative breast cancer (TNBC), including those that are deleterious in the BRCA gene. TNBC is associated with the worst prognosis and the highest incidence of brain metastasis (30%) among all subtypes of BC. Despite objective responses to poly (ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-mutated TNBC, benefits are transitory. Furthermore, our understanding of the effect of PARP inhibitors (PARPi) in treating breast cancer brain metastasis (BCBM) and modulating its tumor microenvironment (TME) is still lacking. To this end, we analyzed the brain TME of BRCA-mutated BCBM in the absence or presence of treatment with PARPi. Interestingly, we found that the immune TME of the brain hinder the antitumor activity of PARPi by upregulating multiple immunosuppressive molecules, including PD-L1. Furthermore, we found that BCBM overexpress P-selectin through its interaction with the tumor-associated microglia, bone marrow-derived macrophages and endothelial cells in the TME. Thus, we designed a novel nanoparticle (NP) targeting P-selectin to serve as a brain-penetrant delivery system for the treatment of BCBM. In order to target BRCA-mutated BCBM, we harnessed our novel P-selectin-targeted NPs to entrap PARPi and other immune modulators that we found to exert synergistic activity when combined. To evaluate the antitumor activity of our P-selectin-targeted NPs, we established 3-dimensional (3D) ex vivo and in vivo BRCA-mutated BCBM models. Importantly, we saw favorable effects of the P-selectin-targeted NPs in comparison to the combination of the free drugs, suggesting that out targeted-NPs overcome the TME-mediated resistance to PARPi through the modulation of the immunosuppressive microenvironment of the brain. Citation Format: Rami Khoury, Ron Kleiner, Eilam Yeini, Daniel Rodriguez Ajamil, Sahar Israeli Dangoor, Tamer Sanalla, Iris Barshack, Roni Satchi-Fainaro. Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5551.