Molecularly targeted cancer therapies, such as Abl-targeted tyrosine kinase inhibitors (TKIs), have converting many terminal cancers, including chronic myeloid leukemia (CML), into chronic diseases. Despite the targeted approach, vascular toxicities have emerged. Specifically, the first-generation CML TKI imatinib is safe, yet newer generation TKIs frequently used for resistant CML (nilotinib, dasatinib, ponatinib) confer a 2-5 fold increased risk of arterial thrombosis causing MI, stroke, or limb ischemia. With no validated models to test for vascular toxicity prior to drug approval, this side effect was identified only when adverse events accrued and once recognized, there are no data to guide clinicians as to how to prevent this or to treat these cancer survivors. This proposal addresses these gaps in knowledge by leveraging the CML TKIs, a drug class with both safe and toxic members. We and others showed that toxic CML TKIs damage ECs in some in vitro models and enhance atherosclerosis in mice. As CML patients with underlying CV risk factors are predisposed to toxicity, we hypothesize that the toxic CML drugs impair specific endothelial cell (EC) functions that lead to plaque development, inflammation, rupture, thrombosis and ischemia. As these drugs are kinase inhibitors, we further posit that the toxicity is caused by modulation of the phosphorylation state of signaling proteins in a manner that is deleterious to EC function and have shown this using proteomic approaches. Thus, we now propose to test the hypothesis that toxic CML TKIs act on ECs to impair barrier integrity, enhance leukocyte trafficking, slow wound healing, and increase interaction with platelets, thereby promoting an atherosclerosis phenotype prone to rupture and thrombosis, and that the drug-induced EC proteomic profile can predict vascular toxicity and identify mitigating treatments. We test this with 2 aims using multiple innovative approaches: SA1 interrogates the impact of each CML TKI using human engineered microvessels (hEMVs) to examine the impact on vascular permeability and platelet aggregation and in mice using intravital microscopy to quantify leukocyte-EC interaction, carotid wire injury to measure vascular re- endothelialization, and Apo-E-KO mice with FACS to quantify vascular inflammation in atherosclerosis. SA2 uses a targeted mass spectrometry based phosphoproteomic assay to profile the effects of emerging CML TKIs and a broad range of drugs approved for CV disease in human ECs to determine if this can predict toxicity of new TKIs and identify mitigating therapies. Predicted toxicities and ?antidotes? that oppose the toxic proteomic signature will be tested using the in vitro and in vivo models described in SA1. Completion of the aims will transform cardiooncology by validating preclinical models to predict vascular safety of CML TKIs and identify potential treatments for vascular toxicity that can be rapidly translated to cardiooncology care.

Public Health Relevance

New targeted drugs have dramatically improved cancer survival however, many such cancer treatments have cardiovascular side effects. Specifically, new drugs for leukemia have improved life expectancy to match people without cancer but a higher than normal risk of heart attack and stroke has emerged in these leukemia survivors. This proposal uses multiple innovative technologies to understand how these new cancer drugs may contribute to heart attack and stroke and to develop ways to predict those side effects before exposing patients to the risk. In addition, we test new methods to identify co-treatments that might alleviate the heart disease risk in these cancer survivors.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Charette, Marc F
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Tufts University
United States
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