Dual anti-leukemic and cardio protective role for ROCK

ROCK的双重抗白血病和心脏保护作用

基本信息

批准号：
10597132
负责人：
Reuben Kapur
金额：
$ 18.15万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10597132
关键词：
ABL1 gene ABL2 gene Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Address Adverse effects Adverse event Anthracycline Apoptosis Area Autophagocytosis BCR/ABL fusion gene Blood Vessels Cardiac Cardiac Myocytes Cardiotoxicity Cardiovascular Physiology Cardiovascular system Cells Cholesterol Chronic Myeloid Leukemia Clinical Cytoprotection Dasatinib Development Disease Dose Doxorubicin Drug resistance Endothelial Cells FDA approved Gene Expression Profiling Generations Goals Growth Hematologic Neoplasms Human Imatinib Impairment Induction of Apoptosis Investigation Journals Knock-in Knockout Mice Leukemic Cell Mediating Modeling Molecular Mus Mutation Outcome Study Patients Philadelphia Phosphorylation Phosphotransferases Principal Investigator Property Prospective Studies Publications ROCK1 gene Recording of previous events Refractory Reporting Retrospective Studies Rho-associated kinase Role Signal Pathway Smooth Muscle Myocytes Stress Structure Testing Therapeutic Index Time Toxic effect Tyrosine Kinase Inhibitor Vascular Smooth Muscle Work antileukemic activity cancer cell cancer therapy cardioprotection cell type chemotherapy design drug resistance development fasudil heart function human model improved innovation insight kinase inhibitor leukemia leukemia treatment leukemogenesis mouse model novel novel strategies prototype side effect targeted treatment

项目摘要

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.

项目概要/摘要靶向酪氨酸激酶抑制剂 (TKI)，例如批准用于治疗费城阳性 (Ph+) 的药物慢性粒细胞白血病 (CML) 和 Ph+ 急性淋巴细胞白血病 (ALL)（即伊马替尼、达沙替尼、尼洛替尼和帕纳替尼）彻底改变了治疗方法，不幸的是，伊马替尼的长期治疗（第一种）。用于 CML 和 ALL 患者的第一代 TKI）和达沙替尼（第二代）导致了药物的开发耐药性，主要是由于获得新的突变，以避免第一次和第二次遇到的耐药性。第二代，第三代 TKI 帕纳替尼 (Ponatinib) 已被开发出来，尽管它对于治疗非常有效。难治性 CML 和 ALL、严重心脏毒性 (CTX) 和血管不良事件 (VAE) 已有报道与报道的蒽环类药物（ANT）在癌症治疗中的情况类似，因此，这两种非特异性疗法，例如阿霉素 (DOX)、ANT 原型以及第二代和第三代 TKI 等靶向治疗的结果急性髓性白血病 (AML)、CML 和 ALL 治疗期间的 CTX 是本次治疗的长期目标。提议是开发新方法来减轻接受 AML 治疗的患者中 TKI 诱导的 CTX，为了实现这些目标，我们提出了 Kapur 博士参与的多 PI 应用程序。和石，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他们的专业知识将被用来评估新的心脏保护策略。白血病和 CTX 的研究重点是了解其背后的分子和/或细胞机制重要的是，这两种 PI 具有预防癌症治疗引起的严重后遗症的作用。正如《癌细胞》等八本合着出版物所指出的那样，双方已建立了合作历史， Shi 博士和 Kapur 博士一直在《CELL》和其他期刊中研究 Rho 激酶 (ROCK) 在细胞中的作用。多年来，石博士已经确定了 ROCK 在白血病发生和调节心脏功能中的关键作用；在各种压力下保护心脏结构和功能的失活，卡普尔博士已经确定了一种 ROCK 失活的抗白血病作用该提案的一个主要目标是研究 ROCK 是否受到抑制。使用 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初步证据表明，小鼠体内 ROCK1 的整体抑制可保护心肌细胞。（CM）来自化疗诱导的细胞凋亡和受损的自噬。在白血病细胞（AML 和 CML）中会导致生长抑制和细胞凋亡。强效第二代和第三代累积剂量治疗 CML 和 ALL 期间的 ROCK 活性 TKI 具有心脏保护作用并保留高抗白血病活性。