CCR5 inhibitors to enhance therapeutic response of breast cancer to DNA damaging agents

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PROJECT SUMMARY/ABSTRACT The current studies propose a fundamental change in approach to treating cancer in order to reduce cardiac toxicity. Anthracyclines, such as Doxorubicin, are currently used to treat many cancers including leukemia, lymphoma, and cancers of the breast, stomach, uterus, ovary, bladder, and lung. Cardiotoxicity from Anthracyclines limits therapeutic effectiveness and compromises patient’s quality of life. Anthracycline induced cardiotoxicity is cumulative and dose-dependent. In order to reduce cardiac toxicity, the DNA damaging agents have been formulated into liposomes to enhance penetration into leaking microvasculature found in tumors. Despite this, 9% of patients present with diminished ejection fraction within 1 year of anthracycline therapy, increasing to >25% of patients over 5 years. DNA damage and inflammation contribute to cardiac toxicity of Anthracyclines. There is an urgent need to reduce this iatrogenic disease. Our approach is novel. We have found that the G-protein coupled receptor CCR5 is expressed in ~50% of human breast cancers (BCa) and >95% of triple negative BCa, wherein CCR5 activates DNA repair and promotes metastasis. CCR5 inhibitors enhance BCa cell killing by DNA damaging cancer therapies (anthracyclines, γ-radiation and PARP inhibitors). CCR5+ BCa stem cells are less prone to cell death. CCR5 is not normally expressed in the heart. In preliminary studies, we show anthracycline treatment increases CCR5 in the murine and human myocardium. We show CCR5+ cardiac progenitor cells are more prone to cell death than their CCR5- counterparts. We hypothesize that CCR5 antagonists (Maraviroc, Vicriviroc), will enhance BCa cell killing. CCR5 antagonists are cardioprotective in several models of cardiac damage. We hypothesize that CCR5 inhibitors will provide both direct cardiac cytoprotection and indirect cardioprotection, through increasing the efficacy of anthracyclines to kill BCa cells allowing for a reduction in total dose. We will determine the cardioprotective effect of CCR5 inhibitors in preclinical models of anthracycline induced toxicity. Moreover, we will examine the differential effects of CCR5 in doxorubicin-induced tissue injury in vitro. These studies bring together an expert in oncology (Dr. Pestell), cardiac death (Dr. Kitsis), G-protein receptor signaling and vascular biology (Dr. Ashton) in order to define a novel approach to reducing anthracycline cardiotoxicity. Initial studies will be conducted using BCa cells. The approach is paradigmatic of the approach for a broad array of cancers in which DNA damage inducing chemotherapy or radiation is used. These studies are likely to impact BCa treatment by simultaneously enhancing efficacy of currently available therapies and reducing cardiac side effects.