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Principal Investigator: Won Hee Lee
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2024
Award: $529,969
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
There has been a significant decline in cancer related mortality, partly due to the emergence of molecular
targeted therapies. Unfortunately, the success of these drugs including tyrosine kinase inhibitors (TKIs) has been
tempered by a concomitant rise in the prevalence of cancer therapies-related cardiotoxicity. Ponatinib, a currently
FDA-approved third-generation TKI, is used to treat chronic myeloid leukemia (CML) patients carrying the
gatekeeper mutation breakpoint cluster region-Abelson (BCR-ABL) T315I. Despite its effectiveness, a
considerable number of patients receiving ponatinib suffers from various cardiac complications. Several studies
have linked ponatinib-induced cardiotoxicity to impaired pro-survival signaling pathways leading to cell death.
However, the molecular signaling pathways leading to these events remain obscure and a better understanding
of how cardiomyocytes respond to ponatinib may provide new insights into novel mitigation therapies. The heart
must adapt to stress conditions that occur as a result of intracellular or extracellular factors. The integrated stress
response (ISR) is one of the circuits responding to stress and serving to restore proteostasis by regulating protein
synthesis, although prolonged ISR activation leads to cell death. Whether the ISR is activated and plays a
protective or detrimental role in ponatinib-induced cardiotoxicity are largely unknown and may represent an
amenable therapeutic target which will be the focus of my current proposal. My preliminary data suggests that
ponatinib causes mitochondrial dysfunction in human induced pluripotent stem cell-derived cardiomyocytes
(hiPSC-CMs). Interestingly, mitochondrial damage appears to trigger activation of the ISR and is mediated by a
kinase called general control non-repressed 2 (GCN2). I also found that inhibition of the ISR using a novel small
molecule called ISR inhibitor (ISRIB) successfully blunted the cardiotoxic effects of ponatinib both in vitro and in
vivo. Hence, the central hypothesis of my proposal is that the ISR pathway which is activated upon sensing
mitochondrial damage plays a pivotal role in mediating ponatinib-induced cardiotoxicity. Aim 1 will investigate
whether activation of GCN2 couples mitochondrial damage to ISR activation upon impaired mitochondrial
reactive oxygen species (ROS) and adenosine triphosphate (ATP) level. Aim 2 will assess whether ponatinib
induces apoptosis and cardiac dysfunction through the GCN2/eIF2α/ATF4 axis. Lastly, aim 3 will explore whether
pharmacological suppression of the ISR even after the onset of ponatinib-induced cardiotoxicity remains
cardioprotective without compromising the efficacy of ponatinib against tumor cells. Taken together, at the
conclusion of these studies, we will have significantly expanded our knowledge by which how ponatinib-induced
mitochondrial dysfunction is sensed to trigger the ISR; whether this activation contributes to cardiac pathology;
and if crosstalk between these two pathways can be targeted as a therapeutic avenue to mitigate ponatinib-
induced cardiotoxicity clinically.
Terms: <21+ years old><Active Oxygen><Adenosine Triphosphate><Adenylpyrophosphate><Adult><Adult Human><Affect><Apoptotic><BCR gene><BCR1><Binding><Breakpoint Cluster Region><CRISPR><CRISPR/Cas system><Cancer Burden><Cancer Patient><Cancer Prognosis><Cancer Survivor><Cancers><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac Toxicity><Cardiocyte><Cardiotoxic><Cardiotoxicity><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Death><Cell Line><Cell Signaling><CellLine><Cells><Chronic Granulocytic Leukemia><Chronic Myelocytic Leukemia><Chronic Myelogenous Leukemia><Chronic Myeloid Leukemia><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Complement><Complement Proteins><Complex><Coupled><Couples><Data><Defect><Distress><Drugs><EIF-2 alpha><EIF-2alpha><EIF-2α><Effectiveness><Event><FDA approved><Gatekeeping><Generations><Genes><Genetic Alteration><Genetic Change><Genetic defect><Heart><Heart Injuries><Heart Muscle Cells><Heart Vascular><Heart failure><Heart myocyte><Human><Iatrogenic Cancer><Impairment><In Vitro><Individual><Induction of Apoptosis><Injury><Intervention><Intervention Strategies><Intracellular Communication and Signaling><K-562><K562><K562 blasts><Kinases><Knock-out><Knockout><Knowledge><Link><Maintenance><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Mutation><Myocardial depression><Myocardial dysfunction><Names><National Cancer Burden><Oncology><Oncology Cancer><Outcome><Oxidation-Reduction><Oxidative Stress><Oxygen Radicals><PTK Inhibitors><Pathogenicity><Pathology><Pathway interactions><Patients><Pharmaceutical Preparations><Phosphotransferase Gene><Phosphotransferases><Play><Prevalence><Pro-Oxidants><Protein Biosynthesis><Protein Tyrosine Kinase Inhibitors><Reactive Oxygen Species><Redox><Research Proposals><Resistance><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Risk><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Strains Cell Lines><Stress><Study models><TK Inhibitors><Therapeutic><Therapy Related Malignant Neoplasm><Therapy Related Malignant Tumor><Therapy-Associated Cancers><Therapy-Related Cancer><Time><Toxic effect><Toxicities><Transgenic Organisms><Transphosphorylases><Treatment Efficacy><Treatment-Associated Cancer><Treatment-Related Cancer><Tumor Cell><Tyrosine Kinase Inhibitor><Up-Regulation><Upregulation><adulthood><alpha Subunit Eukaryotic Initiation Factor 2><biological adaptation to stress><biological signal transduction><cancer cell><cancer progression><cardiac dysfunction><cardiac failure><cardiac injury><cardiomyocyte><cardioprotectant><cardioprotection><cardioprotective><cell type><chronic myelogenous leukemia cell><chronic myeloid leukemia cell><circulatory system><clinical relevance><clinically relevant><complementation><cultured cell line><drug/agent><extracellular><gatekeeper><genome mutation><heart dysfunction><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS><iPS cell derived cardiomyocytes><iPSC><iPSC derived cardiomyocytes><iPSCs><improved><in vivo><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cell derived cardiomyocytes><inducible pluripotent stem cell><inhibitor><injuries><innovate><innovation><innovative><insight><intervention efficacy><interventional strategy><knockout gene><malignancy><mitochondrial><mitochondrial dysfunction><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mortality><mouse model><murine model><name><named><naming><necrocytosis><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><novel><overexpress><overexpression><oxidation reduction reaction><pathway><patient prognosis><pharmacologic><protective effect><protein homeostasis><protein synthesis><proteostasis><reaction; crisis><resistant><small molecule><social role><stress response><stress; reaction><success><systemic toxicity><therapeutic efficacy><therapeutic target><therapy efficacy><tool><transgenic><tumor><tumor progression>