Thursday, April 25, 2024
4/25/2024
PROJECT SUMMARY / ABSTRACT Targeted tyrosine kinase inhibitor (TKI) such as those approved for the treatment of Philadelphia positive (Ph+) chronic myelogenous leukemia (CML) and Ph+ acute lymphocytic leukemia (ALL) (i.e. Imatinib, Dasatinib, Nilotinib and Ponatinib) have revolutionized the treatment. Unfortunately, long-term treatment with Imatinib (1st generation TKI) and Dasatinib (2nd generation) for CML and ALL patients has led to the development of drug resistance, mostly due to acquisition of new mutations. To circumvent drug resistance encountered with first and second generations, the third generation TKI Ponatinib was developed. Although it is highly effective for refractory CML and ALL, severe cardiotoxicity (CTX) and vascular adverse events (VAEs) have been reported similar to that reported with Anthracyclines (ANT) in cancer therapy. Thus, both non-specific therapies such as doxorubicin (DOX), an ANT prototype, and targeted therapies such as second and third generation TKIs result in CTX during acute myelogenous leukemia (AML), CML and ALL treatment. The long-term objective of this proposal is to develop novel approaches to mitigate TKI-induced CTX in patients undergoing treatment for AML, CML and ALL. In an effort to achieve these objectives, we propose a multi-PI application involving Drs. Kapur and Shi, who have complementary expertise in studying hematologic malignancies and cardiac functions under stresses, respectively. Their expertise will be utilized to assess new strategies for cardioprotection in the context of both leukemia and CTX with a focus on understanding the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae. Importantly, the two PIs have an established history of working together as noted by eight co-authored publications including in “CANCER CELL”, “CELL” and additional journals. Drs. Shi and Kapur have been studying the role of Rho kinases (ROCK) in leukemogenesis and in regulating cardiac function(s) for years; Dr. Shi has identified a critical role for ROCK inactivation in protecting cardiac structure and functions under various stresses and Dr. Kapur has identified an anti-leukemic role for ROCK inactivation. A major objective of this proposal is to study if inhibition of ROCK activity during the treatment of CML and ALL with TKIs can mitigate CTX but retain potent anti-leukemic properties. Preliminary evidence suggests that global inhibition of ROCK1 in mice protects cardiomyocytes (CMs) from chemotherapy-induced apoptosis and impaired autophagy. Interestingly, inhibition of ROCK activity in leukemic cells (both AML and CML) results in growth inhibition and apoptosis. We hypothesize that inhibiting ROCK activity during CML and ALL treatment with accumulating dose of potent second and third generation TKIs will be cardioprotective and retain high anti-leukemic activity.
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