Improving Outcomes in Cancer Treatment-Related Cardiotoxicity

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Project Summary/Abstract Anthracyclines, such as Doxorubicin (DOX), are effective for the treatment of many cancers (Ovarian, Multiple Myeloma, Kaposi Sarcoma, Leukemia, Bone Sarcoma, Breast, Endometrial, Gastric, Liver, Kidney, and other Cancers). The global DOX market is increasing annually and expected to reach $1.3B by 2026. DOX toxicity is therefore relevant to a broad number of cancers. However, chemotherapy induced cardiac toxicity has substantial morbidity and mortality. Cardiotoxicity and recovery from DNA damaging chemotherapy is dose-dependent. With cancer survivors estimated at 19 million in the USA by 2025, Dox-induced cardiotoxicity is considered to be part of the “cardio-oncology epidemic”. The development of new approaches to reduce chemotherapy-induced cardiotoxicity is essential. Dexrazoxane (Dex), is FDA approved for the specific indication of “doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain tumor control”. Dex has the risk of myelotoxicity(5). In off label use of Dex in other cancer populations, cardiac protection was incomplete. In the pediatric population Dex provided “'incomplete acute cardioprotection and “no impact on chronic cardioprotection or overall survival”. LightSeed has assembled a highly experienced team (oncologist-cancer biologist (with prior biotechnology company expertise), cardio-oncologist, high throughput lead discovery expert, immune cancer biologist- mouse geneticist) in order to identify and repurpose FDA-approved compounds with “dual function” (enhance cancer cell killing by DOX but protection from DOX cardiotoxicity). Three compounds from the FDA- approved compound library have been validated. We are seeking additional “dual function” compounds from the libraries. We have deployed an innovative genetically modified murine testing system which: (i). allows comparison with the incumbent technology (Dex), (ii). provides a normal immune system for the tumor immune response. (iii). allows analysis of the host immune response using double knockin fluoresecent reporter genes. (iv). allows detection of the tumor growth using a third fluorescent report gene for in vivo progression analysis. LightSeed will identify additional “dual function” compounds by high throughput screening under the direction of a core director who is highly experienced with HTS screening (previously head of Lead Discovery at Janssen for 15 yrs). LightSeed will use cardiomyocyte cells derived from pooled iPSC-CM (iPSC-derived cardiomyocytes) and cancer cells. This proposal will: (SA1). Screen a library that consists of FDA and EU approved compounds, using an assay that protects human cardiac myocytes from DOX-induced cardiac toxicity and enhances cancer cell killing. (SA2). Validate these compounds in tissue culture and (SA3) in a novel “dual function” reporter mouse system.