Abstract 15594: Decreasing the High Risk of Ponatinib-Induced Cardiovascular Toxicity in Chronic Myeloid Leukemia

Abstract

Introduction: Cardiovascular (CV) toxicity of cancer therapeutics is a growing problem. Ponatinib is one of the most cardiotoxic Tyrosine Kinase Inhibitors (TKIs) and is used as a highly effective TKI against ABL T315I mutation in Chronic Myeloid Leukemia (CML). Long-term exposure to ponatinib increases CV events including myocardial infarction, heart failure, stroke, peripheral vascular disease and venous thrombosis. There is need of novel therapeutics to provide treatment for CML while avoiding CV toxicity. Hypothesis: Using in vitro and in vivo models of CV toxicity can make possible to reengineer ponatinib to minimize its toxicity. Methods: We developed new safer analogues of ponatinib using fragment-based approach. Their anti-tumor efficacy was tested in 2 different CML cell lines and CML patient samples. We assayed for myocardial toxicity by measuring contractile function in human iPSC-cardiomyocytes (hiPSC-CMs) using high-throughput functional imaging, for vascular toxicity by measuring vasculogenesis in human microvascular endothelial cells (HMVECs), and for bone marrow toxicity by colony formation assay in human bone marrow cells (HBMCs). Finally, we confirmed the safer CV profile and adequate anti-tumor efficacy in an in vivo xenograft mouse model of CML. Results: The new analogues inhibited T315I BCR-ABL kinase activity similar to ponatinib and suppressed T315I mutant CML tumor growth in vitro and in vivo . Compared to ponatinib, the new compounds showed markedly decreased adverse effects on contractility of hiPSC-CMs, vasculogenesis in HMVECs and bone marrow toxicity in HBMCs in vitro . The therapeutic window was increased in vivo , leading to regression of human T315I mutant CML xenografts comparable to ponatinib but without increased levels of cardiac troponin. Additionally, we identified multiple kinases, including FGFR1, that were inhibited by ponatinib but not the analogues, suggesting that there is a specific set of kinases responsible for ponatinib toxicity. Conclusions: This study demonstrates that chemical reengineering can generate novel, CV-safe TKIs that retain effective therapeutic properties against CML carrying ABL T315I mutation, but that exhibit minimal CV toxicity compared to ponatinib.