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Mitochondrial Dysfunction Underlies the Integrated Stress Response Activation in Ponatinib-Induced Cardiotoxicity

Award Number: R01HL164729
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/18/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Mitochondrial Dysfunction Underlies the Integrated Stress Response Activation in Ponatinib-Induced Cardiotoxicity - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $526,507 )
2026	2026	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	4	6/26/2026	NON-COMPETING CONTINUATION	$526,507
														Subtotal = $526,507

Issue Date FY: 2025 ( Subtotal = $537,250 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	3	7/10/2025	NON-COMPETING CONTINUATION	$537,250
														Subtotal = $537,250

Issue Date FY: 2024 ( Subtotal = $529,969 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	2	6/14/2024	NON-COMPETING CONTINUATION	$529,969
														Subtotal = $529,969

Issue Date FY: 2023 ( Subtotal = $547,212 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	1	7/18/2023	NEW	$547,212
														Subtotal = $547,212

Grand Total All Awards = $2,140,938

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Mitochondrial Dysfunction Underlies the Integrated Stress Response Activation in Ponatinib-Induced Cardiotoxicity

Award Number: R01HL164729

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/18/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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