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.
Public Health Relevance Statement: PROJECT NARRATIVE The application's broad, long-term objectives are to develop cardioprotective agents that enhance breast cancer cell killing by DNA damaging agents. Related to the mission of the National Heart Lung and Blood Institute (NHLBI) goals to: i) develop therapeutics for heart-related disease and to ii) test therapeutics for heart-related diseases and disorders in small animals, we will screen a "super" library of FDA approved compounds for protection from doxorubicin induced cardiac toxicity using patient derived iPSC cardiac myocytes and determine functional synergy between the novel FDA approved compounds and DNA damage inducing chemotherapy in a novel immune competent mouse model of breast cancer in which the immune system and the breast cancer cells are fluorescently tagged with distinct fluorophores.
Project Terms: Animals; Anthracycline; Biological Assay; Assay; Bioassay; Biologic Assays; Biotechnology; Biotech; Breast; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cardiotonic Agents; Cardiac Stimulants; Cardioprotective Agents; Cardiotonic Drugs; Cardiotonics; Myocardial Stimulants; Positive Cardiac Inotropic Agents; Cardiovascular system; Cardiovascular; Cardiovascular Body System; Cardiovascular Organ System; Heart Vascular; circulatory system; Cell Death; necrocytosis; cell growth; Cellular Expansion; Cellular Growth; Cells; Cell Body; Communities; Disease; Disorder; DNA Damage; DNA Injury; Doxorubicin; 14-Hydroxydaunomycin; Adriamycine; Doxorubicina; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Epidemic; Experimental Designs; Genes; Goals; Head; Heart; Heart Transplantation; Cardiac Transplantation; Heart Grafting; cardiac graft; heart transplant; Human; Modern Man; Immune system; allergic/immunologic body system; allergic/immunologic organ system; Kidney; Kidney Urinary System; renal; Lead; Pb element; heavy metal Pb; heavy metal lead; leukemia; Libraries; Literature; Liver; hepatic body system; hepatic organ system; Mission; Morbidity - disease rate; Morbidity; mortality; Multiple Myeloma; Plasma-Cell Myeloma; myeloma; myelomatosis; Mus; Mice; Mice Mammals; Murine; Myocardium; cardiac muscle; heart muscle; Metastasis; Metastasize; Metastatic Lesion; Metastatic Mass; Metastatic Neoplasm; Metastatic Tumor; Secondary Neoplasm; Secondary Tumor; cancer metastasis; tumor cell metastasis; Neoplasm Metastasis; Bone Sarcoma; Osseous Sarcoma; Osteogenic Sarcoma; Skeletal Sarcoma; osteochondrosarcoma; osteoid sarcoma; osteosarcoma; Patients; Scientific Publication; Publications; Publishing; Investigators; Researchers; Research Personnel; Risk; Kaposi's Sarcoma; Multiple Hemorrhagic Sarcoma; Kaposi Sarcoma; gastric; Stomach; Technology; Testing; tissue culture; Tissues; Body Tissues; Woman; Dexrazoxane; Mediating; Ovarian; Acute; Chronic; Clinical; Reporter Genes; Cardiac Muscle Cells; Cardiocyte; Heart Muscle Cells; Heart myocyte; cardiomyocyte; Cardiac Myocytes; Endometrial; pediatric; Childhood; Recovery; European; Oncologist; Oncology Cancer; Oncology; Immunological response; host response; immune system response; immunoresponse; Immune response; Therapeutic; Malignant Cell; cancer cell; Reporter; Immunes; Immune; System; experience; fluorophore; tumor growth; cell killing; synergism; Toxicities; Toxic effect; novel; Reporting; Iatrogenic Cancer; Therapy Related Malignant Neoplasm; Therapy Related Malignant Tumor; Therapy-Associated Cancers; Therapy-Related Cancer; Treatment-Associated Cancer; Treatment-Related Cancer; High Throughput Assay; high throughput screening; Cardiac Toxicity; Cardiotoxic; Cardiotoxicity; Myocardial Diseases; Myocardial Disorder; Myocardiopathies; myocardium disease; myocardium disorder; Cardiomyopathies; therapeutic testing; therapeutic evaluation; Address; Dose; Breast tumor model; mammary cancer model; mammary tumor model; Breast Cancer Model; Detection; breast tumor cell; Breast Cancer Cell; immune competent; Immunocompetent; in vivo; Cancer Survivor; survive cancer; Validation; Cardiac; Development; developmental; National Heart, Lung, and Blood Institute; NHLBI; predictive modeling; computer based prediction; prediction model; novel strategies; new approaches; novel approaches; novel strategy; Population; innovation; innovate; innovative; chemotherapy; mouse model; murine model; induced pluripotent stem cell; iPS; iPSC; iPSCs; inducible pluripotent stem cell; tumor; MDA MB 231; MDA-231; MDA-MB231; FDA approved; effective therapy; effective treatment; screening; Breast Cancer cell line; Breast tumor cell line; Metastatic breast cancer; Knock-in; knockin; improved outcome; cardioprotection; cardioprotectant; cardioprotective; off-label use; off-label application; off-label prescribing; induced pluripotent stem cell derived cardiomyocytes; iPS cell derived cardiomyocytes; iPSC derived cardiomyocytes
