Dual anti-leukemic and cardio protective role for ROCK

项目总结/摘要 靶向酪氨酸激酶抑制剂（TKI），如批准用于治疗费城阳性（Ph+） 慢性骨髓性白血病（CML）和Ph+急性淋巴细胞白血病（ALL）（即伊马替尼，达沙替尼， 尼洛替尼（Nilotinib）和泊那替尼（Ponatinib）彻底改变了治疗方法。不幸的是，长期使用伊马替尼治疗（第一次 第二代TKI）和达沙替尼（第二代）用于CML和ALL患者， 耐药性，主要是由于获得新的突变。为了避免第一次和第二次耐药性， 第二代，开发了第三代TKI Ponatinib。虽然它是非常有效的 已报告难治性CML和ALL、重度心脏毒性（CTX）和血管不良事件（VAE） 类似于蒽环类（ANT）在癌症治疗中的报道。因此，两种非特异性疗法， 多柔比星（DOX），ANT原型，以及靶向治疗，如第二代和第三代TKI， 在急性髓细胞性白血病（AML）、CML和ALL治疗期间的CTX中。长期目标是 一项提案是开发新的方法来减轻正在接受AML治疗的患者中TKI诱导的CTX， CML和所有。为了实现这些目标，我们提出了一个多PI应用程序，涉及Kapur博士 和Shi，他们在研究血液恶性肿瘤和心脏功能方面具有互补的专业知识， 压力，分别。他们的专业知识将被用来评估在这种情况下心脏保护的新策略。 白血病和CTX的研究，重点是了解白血病和CTX的分子和/或细胞机制， 癌症治疗引起的严重不良后遗症的发展。重要的是，两个PI有一个 建立了合作的历史，如八篇合著的出版物所指出的，包括“癌症细胞”， “细胞”和其他期刊。Shi和Kapur博士一直在研究Rho激酶（ROCK）在 多年来，他一直致力于白血病的发生和调节心脏功能; Shi博士已经确定了ROCK的关键作用， 在各种压力下保护心脏结构和功能的失活，Kapur博士已经确定了一种 ROCK失活的抗白血病作用。该提案的一个主要目的是研究ROCK抑制是否 在用TKI治疗CML和ALL期间的活性可以减轻CTX，但保留有效的抗白血病作用。 特性.初步证据表明，小鼠中ROCK 1的整体抑制可保护心肌细胞 (CMs)化疗诱导的细胞凋亡和受损的自噬。有趣的是，ROCK活性的抑制 在白血病细胞（AML和CML两者）中的作用导致生长抑制和细胞凋亡。我们假设抑制 CML和ALL治疗期间的ROCK活性，使用累积剂量的强效第二代和第三代 TKI将具有心脏保护作用，并保留高抗白血病活性。

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.