Dual anti-leukemic and cardio protective role for ROCK

项目摘要/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+)的那些 慢性粒细胞白血病(CML)和Ph+急性淋巴细胞白血病(ALL)(即伊马替尼，达沙替尼， 尼洛替尼和波纳替尼)使治疗方法发生了革命性的变化。不幸的是，伊马替尼的长期治疗(第1名 治疗慢性粒细胞白血病和所有患者的TKI和Dasatinib(第二代)药物的开发 耐药性，主要是由于获得了新的突变。规避First和First遇到的耐药性 第二代，第三代TKI波纳替尼被开发出来。尽管它对以下方面非常有效 难治性CML和ALL、严重心脏毒性(CTX)和血管不良事件(VAEs)已有报道 与在癌症治疗中使用蒽环类药物(ANT)的报道相似。因此，两种非特异性疗法，如 阿霉素(DOX)，一种蚂蚁原型，以及靶向治疗，如第二代和第三代TKIs结果 CTX在急性髓系白血病(AML)、慢性粒细胞白血病(CML)及ALL治疗中的作用。这样做的长期目标是 建议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， 慢性粒细胞白血病和其他疾病。为了实现这些目标，我们提出了一个涉及Kapur博士的多PI应用程序 和史，他们在研究恶性血液病和心脏功能方面有互补的专长 分别强调。他们的专长将被用来评估新的心脏保护战略。 白血病和环磷酰胺，重点是了解其背后的分子和/或细胞机制 癌症治疗的发展引发了严重的不良后遗症。重要的是，这两个PI有一个 如包括《癌细胞》在内的八份合著出版物所指出的那样，建立了合作的历史， 《细胞》和其他期刊。史博士和卡普尔博士一直在研究Rho激酶(ROCK)在 多年来在白血病发生和调节心脏功能中的作用(S)；史博士已经确定了ROCK的关键作用 在各种压力下保护心脏结构和功能的失活，卡普尔博士已经发现 岩石灭活的抗白血病作用。这项提议的一个主要目标是研究对岩石的抑制 CML和ALL在TKI治疗过程中的活动可以减轻CTX，但保留了强大的抗白血病作用 属性。初步证据表明，在小鼠体内全面抑制ROCK1可以保护心肌细胞 (CMS)来自化疗诱导的细胞凋亡和受损的自噬。有趣的是，对岩石活动的抑制 对白血病细胞(包括急性髓系白血病和慢性粒细胞白血病)的作用会导致生长抑制和细胞凋亡。我们假设这种抑制作用 慢性粒细胞白血病期间的岩石活动及第二代和第三代强效累积剂量的所有治疗 TKI将具有心脏保护作用并保持较高的抗白血病活性。

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.