Targeting sphingosine kinase 2 for the treatment of multiple myeloma

靶向鞘氨醇激酶 2 治疗多发性骨髓瘤

• 批准号: 9527057
• 负责人: Yubin Kang
• 金额: $ 36.37万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-03 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9527057
• 关键词: Apoptosis; Cell Death; Cell Proliferation; Cell Survival; Cells; Ceramides; Cessation of life; Clinical; Clinical Data; Clinical Research; Clinical Treatment; Clinical Trials; Correlative Study; Data; Development; Dexamethasone; Disease; Dominant-Negative Mutation; Down-Regulation; Drug Kinetics; Elements; Equilibrium; Exposure to; FDA approved; Goals; Growth; Hematologic Neoplasms; Human; Immunomodulators; In Vitro; Knowledge; Maximum Tolerated Dose; Mediating; Medical; Metabolism; Mission; Molecular; Multiple Myeloma; Outcome; Pathogenesis; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physicians; Proteasome Inhibitor; Protein phosphatase; Public Health; Publishing; RNA Interference; Radiation; Refractory; Relapse; Research; Resistance development; Role; Safety; Site; Sphingolipids; Testing; Therapeutic; Therapeutic Agents; Tumor Biology; United States; United States National Institutes of Health; Work; Xenograft Model; Xenograft procedure; c-myc Genes; disability; exhaust; genetic approach; imaging approach; immunomodulatory drugs; improved; in vivo; inhibitor/antagonist; innovation; intravital imaging; mouse model; multicatalytic endopeptidase complex; mutant; neoplastic cell; novel; novel therapeutics; overexpression; public health relevance; safety testing; sphingosine 1-phosphate; sphingosine kinase; therapeutic target; trafficking; tumor; tumor growth

 DESCRIPTION (provided by applicant): Multiple myeloma (MM) is the second most common hematological malignancy in the United States where it accounts for about 11,000 deaths annually. MM remains an incurable disease, and nearly all MM patients will eventually relapse and develop resistance to currently available agents including newer proteasome inhibitors (carfilzomib) and immunomodulatory agents (pomalidomide). There is an unmet medical need for the development of novel therapeutic agents that do not share similar mechanism of action with these agents. Sphingolipid metabolism is increasingly recognized as a key pathway in tumor biology. In particular, sphingosine kinase 2 (SK2) provide a potential site for manipulation of the ceramide/sphingosine 1-phosphate (S1P) rheostat that regulates the balance between tumor cell proliferation and apoptosis, as well as tumor sensitivity to drugs and radiation. The research in the applicant's lab has demonstrated that SK2 is overexpressed in MM and that SK2 inhibitor (ABC294640) down-regulated c-Myc expression and inhibited myeloma growth in vitro and in vivo in myeloma xenograft mouse model. The long-term goal is to target SK2 for the treatment of MM. The overall objective in this application is to determine the mechanisms through which SK2 inhibition down-regulates c-Myc expression and to further define the roles of SK2 in MM development and progression. The central hypothesis is that SK2 provides an important therapeutic target for the treatment of MM. The rationale for the proposed research is that these studies will contribute a missing, fundamental element of knowledge to the roles of SK2 in MM pathogenesis and establish critical safety profile, maximal tolerated dose, pharmacokinetics and pharmacodynamics data of ABC294640 in myeloma patients. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) determine the mechanisms and the role of c-Myc down-regulation in ABC294640-mediated myeloma cell death); 2) define the roles of SK2 in myeloma disease pathogenesis and progression; and 3) perform a phase Ib clinical trial testing the safety of ABC294640 combined with dexamethasone in relapsed and/or refractory MM patients. Under the first aim, the role of c-Myc down regulation in ABC294640-mediated killing and the mechanism through which ABC294640 down-regulates c-Myc will be determined. Under the second aim, the role of SK2 in myeloma development will be investigated using myeloma mouse model and intravital imaging. Under the third aim, a phase Ib clinical trial will be carried out and correlative studies will be performed. The approach is innovative, in the applicant's opinion, because it departs from the status quo by targeting sphingolipid metabolism pathway for the treatment of MM. A new class of therapeutic drugs for MM is expected to attain as a result. The proposed research is significant, because it is expected to vertically advance and expand the knowledge of MM pathogenesis and the treatment of MM. Such knowledge has the potential to improve the care of patients with MM, a disease with a high unmet clinical need.

 描述（由申请人提供）：多发性骨髓瘤（MM）是美国第二常见的血液恶性肿瘤，每年约有11，000例死亡。MM仍然是一种不治之症，几乎所有MM患者最终都会复发，并对目前可用的药物产生耐药性，包括较新的蛋白酶体抑制剂（卡非佐米）和免疫调节剂（泊马度胺）。对于开发与这些药物不具有相似作用机制的新型治疗剂存在未满足的医学需求。鞘脂代谢越来越被认为是肿瘤生物学中的关键途径。特别地，鞘氨醇激酶2（SK 2）提供了用于操纵神经酰胺/鞘氨醇1-磷酸（S1 P）变阻器的潜在位点，所述变阻器调节肿瘤细胞增殖和凋亡之间的平衡，以及肿瘤对药物和辐射的敏感性。申请人实验室的研究表明，在骨髓瘤异种移植小鼠模型中，SK 2在MM中过表达，SK 2抑制剂（ABC 294640）下调c-Myc表达，并在体外和体内抑制骨髓瘤生长。长期目标是靶向SK2治疗MM。本申请的总体目标是确定SK2抑制下调c-Myc表达的机制，并进一步确定SK2在MM发生和进展中的作用。中心假设是SK2为MM的治疗提供了一个重要的治疗靶点。拟议研究的基本原理是，这些研究将为SK2在MM发病机制中的作用提供一个缺失的基本知识要素，并建立ABC 294640在骨髓瘤患者中的关键安全性特征、最大耐受剂量、药代动力学和药效学数据。在强有力的初步数据的指导下，该假设将通过追求三个具体目标来检验：1）确定c-Myc下调在ABC 294640介导的骨髓瘤细胞死亡中的机制和作用; 2）确定SK 2在骨髓瘤疾病发病机制和进展中的作用;和3）进行Ib期临床试验，测试ABC 294640与地塞米松组合在复发性和/或难治性MM患者中的安全性。在第一个目标下，将确定c-Myc下调在ABC 294640介导的杀伤中的作用以及ABC 294640下调c-Myc的机制。在第二个目标下，将使用骨髓瘤小鼠模型和活体成像研究SK 2在骨髓瘤发展中的作用。在第三个目标下，将进行Ib期临床试验，并进行相关研究。在申请人看来，该方法是创新的，因为它通过靶向鞘脂代谢途径来治疗MM而脱离现状。因此，预计将获得一类新的MM治疗药物。拟议的研究是重要的，因为它有望纵向推进和扩大MM发病机制和MM治疗的知识。这些知识有可能改善MM患者的护理，MM是一种临床需求高度未满足的疾病。