R G Pestell
Pennsylvania Cancer and Regenerative Medicine Center, USA
Title: Immune oncology therapy for breast cancer: CCR5 inhibitors enhance breast cancer cell killing and reduce doxorubicin-induced cardio-toxicity
Biography
Biography: R G Pestell
Abstract
We previously showed that the G-protein coupled receptor CCR5 is expressed on both immune and epithelial cells of ~50% of human Breast Cancers (BCa), thereby inducing cancer “stemness”, cell survival and DNA repair and a pro-metastatic phenotype. CCR5 inhibition by small molecules (Maraviroc) or a humanized monoclonal antibody (Leronlimab) reduced the breast cancer metastatic burden in murine models, with distinct impact on secretomes and promising results in a Phase 1B/2 study. With cancer survivors estimated at 19 million in the USA by 2025, DOX-induced cardio-toxicity is considered part of the “cardio-oncology epidemic”.
Herein, we show that:
- CCR5 inhibitors (CCR5i) enhanced DOX-induced cell death of breast cancer cells.
- CCR5 and its ligand CCl5 were induced by DOX in cardiac myocytes in both the hearts of patients undergoing cardiac transplantation for DOX-induced cardiomyopathy and in a murine model of DOX-cardiac toxicity.
- CCR5i protected human iPSC-derived cardiomyocytes and isolated canine cardiomyocytes from DOX- induced cell death.
- CCR5i substantially reduced (>90%) DOX-induced cardiac dysfunction in mice.
We conclude that CCR5 inhibitors (CCR5i) are “dual function” compounds that provide both cardiac protection and enhanced breast cancer cell killing in the presence of DNA damaging chemotherapy agents. Our studies may have a broad impact by identifying a novel approach to both enhancing therapeutic efficacy and providing cardio-protection from DNA damaging agents that are widely used in cancer treatment.