We will construct a broad spectrum of markers for assessment of risk of anthracycline-induced cardiotoxicity (ACT) in cancer survivors, and a discovery tool for analysis of its pathogenesis in individual patients. Anthracyclines (such as doxorubicin) are highly effective in treatment of hematologic malignancies (including Hodgkin and non-Hodgkin lymphoma), and many childhood cancers where they are responsible for a significant part of the spectacular increase in survival rates, as well as in HER2+ breast cancers and other solid tumors in adults. However, in 50% of survivors they cause subclinical heart injury that can progress into incurable congestive heart failure. As ACT contributes significantly to morbidity and mortality of cancer survivors, prediction of ACT risk could strongly improve their long term prognosis by personalizing the therapy and post-treatment follow-up, while a better understanding of ACT's pathogenesis could lead to novel means of its prevention and therapy. We will use a specialized mouse model to develop a large set of new genetic markers of ACT risk and investigate individual heterogeneity of ACT pathogenesis. Genetic influence on ACT pathogenesis is indicated by the large range of tolerated cumulative doxorubicin dose 180 - 800 mg/m2 and by impact of genes CBR3 and SLC28A3 on ACT risk, although they cannot predict individual risk, due to involvement of numerous other genes. We will therefore map novel ACT-susceptibility (ACTS) genes in mice and then analyze their human homologues. We will use mouse recombinant congenic (RC) strains - a powerful mapping tool that allowed us to detect >130 novel disease susceptibility genes and to show that their homologues can affect human disease. It also detected 15 genes affecting risk of irinotecan toxicity, all of them new and different from known irinotecan-processing genes. Preliminary tests of susceptibility to doxorubicin toxicity revealed significant differences among RC strains, indicating that we can detect 30 - 40 novel ACTS genes. As a preliminary test of their role in humans, we will compare the alleles of human homologues of these genes in the worst ACT affected humans who received heart transplant and matched controls. As the pathogenesis of ACT is only partly clear and its individual differences are not known, we will produce mouse lines with different ACTS genes that will serve as a permanent tool for study of ACT pathogenesis and will test the impact of different ACTS genes on global gene expression patterns in hearts of doxorubicin-treated mice and in future additional functional tests. For future similar tests in humans we will collect RNAs from diagnostic myocardial biopsies. This will have strong prospects to uncover novel pathways influencing ACT and open the way for definition of individual ACT pathogenesis in mice and humans.
Many cancer survivors suffer negative consequences of the otherwise successful chemotherapy. The powerful drugs of the anthracycline family, which are responsible for the dramatic increase of survival in childhood cancers and adult leukemia, affect the heat of many patients, which may be lethal. We will apply a novel strategy to identify genes that facilitate this damage to heart. This will help to identify patients that need special follow p, but also to understand and eventually prevent this damage.