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.

项目摘要 /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的抑制剂（pH+）慢性骨髓性白血病（CML）和pH+急性淋巴细胞性白血病（所有）（即伊马替尼，达萨替尼， Nilotinib和Ponatinib）彻底改变了治疗方法。不幸的是，伊马替尼长期治疗（第一 TKI代）和达沙替尼（第二代）CML和所有患者都导致了药物的发展抵抗，主要是由于获得了新突变。首先遇到的耐药性第二代，开发了第三代tki ponatinib。虽然这对曾报道了难治性的CML和所有，严重的心脏毒性（CTX）和血管不良事件（VAE）类似于癌症治疗中蒽环类药物（ANT）的报道。那两种非特异性疗法，例如阿霉素（DOX），蚂蚁原型和靶向疗法，例如第二代和第三代TKIS结果在急性粒细胞性白血病（AML），CML和所有治疗过程中，在CTX中。这个长期目标建议是开发新的方法来减轻接受AML治疗的患者的TKI诱导的CTX， CML等。为了实现这些目标，我们提出了涉及DRS的多PI申请。卡普尔和Shi，他们在研究血液学恶性肿瘤和心脏功能方面具有完整的专业知识分别是压力。他们的专业知识将用于评估背景下心脏保护的新策略白血病和CTX的侧重于理解构成基础的分子和/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pis有一个正如八个共同作品的出版物所指出的，包括在“癌细胞”中的共同作品中，建立了合作的历史 “牢房”和其他期刊。博士。 Shi和Kapur一直在研究Rho激酶（岩石）在多年来，白血病发生和调节心脏功能多年； Shi博士确定了岩石的关键作用在各种应力下保护心脏结构和功能方面的灭活，卡普尔博士已经确定了抗岩石灭活的抗白血病作用。该提案的主要目的是研究抑制岩石 CML治疗期间的活性和全部使用TKI可以减轻CTX，但保留潜在的抗白血病学特性。初步证据表明，全球对小鼠岩石1的抑制可保护心肌细胞（CMS）来自化学疗法诱导的凋亡和自噬受损。有趣的是，抑制岩石活动在白血病细胞（AML和CML）中，会导致生长抑制和凋亡。我们假设抑制 CML期间的岩石活性以及所有潜在的第二代和第三代剂量的治疗 TKI将是心脏保护区并保留高抗白血病活性。