Characterization of CD99 as a Therapeutic Target in the Myelodysplastic Syndromes and Acute Myeloid Leukemia

CD99 作为骨髓增生异常综合征和急性髓系白血病治疗靶点的表征

• 批准号: 10004582
• 负责人: Stephen Shiu-Wah Chung
• 金额: $ 16.27万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004582
• 关键词: Acute Myelocytic Leukemia; Advisory Committees; Award; Azacitidine; Biological; Biological Assay; Biological Markers; Bone Marrow Diseases; Cell Surface Proteins; Cell physiology; Cell surface; Cells; Clinic; Clinical; Credentialing; Cytogenetics; Data; Data Set; Development; Development Plans; Developmental Therapeutics Program; Diagnosis; Disease; Disease Reservoirs; Disease model; Disease remission; Doctor of Philosophy; Dysmyelopoietic Syndromes; Elderly; Engraftment; Evaluation; Experimental Models; Funding; Gene Expression; Gene Expression Profiling; Goals; Grant; Hematologic Neoplasms; Hematopoietic stem cells; Impairment; In Vitro; Laboratories; Laboratory Research; Lead; Leukemic Cell; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical Oncologist; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Myeloid Leukemia; Myeloproliferative disease; Pathway interactions; Patients; Postdoctoral Fellow; Principal Investigator; Prognostic Marker; Property; Proteins; Proteomics; RUNX1 gene; Rare Diseases; Reagent; Recurrent disease; Regulation; Relapse; Research; Resistance; Resources; Role; Signal Pathway; Specimen; Stem cells; Testing; Therapeutic; Therapeutic Agents; Translating; Validation; Work; Xenograft procedure; cancer stem cell; career development; cell type; chemotherapy; clinical development; clinically actionable; clinically relevant; curative treatments; cytotoxic; cytotoxicity; experience; genetic signature; in vivo; instructor; lenalidomide; leukemic stem cell; mortality; mouse model; new therapeutic target; novel; novel therapeutics; outcome forecast; pre-clinical; prognostic significance; programs; response; self-renewal; src-Family Kinases; stem cell biology; targeted biomarker; therapeutic development; therapeutic target; therapy resistant

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS) are initiated and sustained by self-renewing stem cells. These cells often persist in the face of current standard therapies, and they likely represent the reservoir of disease that promotes therapeutic resistance and disease relapse. Cell surface proteins uniquely expressed on these stem cells may allow for therapies that specifically target diseased cells and not normal hematopoietic stem cells. Through transcriptional profiling followed by flow cytometric validation, CD99 was identified as a cell surface marker highly expressed on MDS hematopoietic stem cells (MDS HSCs) and AML leukemic stem cells (LSCs). Monoclonal antibodies (mAbs) targeting CD99 are directly toxic to disease cells in vitro and in vivo, and this cytotoxicity is associated with rapid activation of Src-family kinases (SFKs). CD99 also has significant clinical potential as a biomarker of chemosensitivity. Leveraging our expertise in hematopoietic stem cell biology and developmental therapeutics, we aim to: Aim 1: Determine the clinical potential of CD99 as a therapeutic target and prognostic biomarker. We will test the ability of anti-CD99 mAbs to deplete AML LSCs and MDS HSCs in robust pre-clinical disease models, and we will identify the spectrum of AML and MDS subtypes most likely to respond to these therapies. We will analyze clinically annotated gene expression data sets to determine if CD99 expression can be used as a biomarker of chemosensitivity. Aim 2: Identify molecular mechanisms of anti-CD99 mAb induced cytotoxicity. We will characterize signaling pathways regulated by CD99 that contribute to CD99-mediated cytotoxicity. We will use proteomic platforms to identify CD99 interacting partners that are functionally required for the cytotoxic effects of anti-CD99 mAbs. These studies promise to contribute towards the development of clinical therapeutics directed against CD99 or its associated biologic pathways, as well as the use of CD99 as a clinically relevant biomarker. Stephen S. Chung, MD is the principal investigator on this proposal and is a practicing medical oncologist with a clinical focus in the myelodysplastic syndromes. He is an Instructor at Memorial Sloan Kettering Cancer Center (MSKCC) and was a postdoctoral fellow from 2010-2016 in the laboratory of Christopher Y. Park, MD PhD, an expert in normal and malignant hematopoietic stem cell biology. He is currently working to translate his findings to the clinic under the mentorship of Ross L. Levine, MD, a world leader in developing novel therapies for myeloid malignancies. In this proposal Dr. Chung outlines a five-year career development plan composed of research, coursework, seminars, and an expert advisory committee. This plan will leverage the rich institutional resources and mentorship at MSKCC to enable him to transition to his own independent laboratory research program and be competitive for R01 funding by the second year of this award.

项目摘要/摘要 急性髓系白血病(AML)和骨髓增生异常综合征(MDS)由 自我更新的干细胞。面对当前的标准疗法，这些细胞通常会持续存在，而且它们很可能 代表促进治疗耐药和疾病复发的疾病的储备库。细胞表面 这些干细胞上独特表达的蛋白质可能会允许专门针对患病细胞的治疗 而不是正常的造血干细胞。通过转录图谱和流式细胞术 验证表明，CD99是MDS造血干细胞高表达的细胞表面标志 (MDS HSCs)和AML白血病干细胞(LSCs)。针对CD99的单抗(MAbs)直接 在体外和体内对疾病细胞的毒性，这种细胞毒性与Src家族的快速激活有关 激酶(SFK)。CD99作为化疗药物敏感性的生物标志物也具有重要的临床应用潜力。利用我们的 在造血干细胞生物学和发育疗法方面的专业知识，我们的目标是： 目的1：确定CD99作为治疗靶点和预后生物标志物的临床潜力。我们将测试 在强大的临床前疾病模型中，抗CD99单抗耗尽AML LSCs和MDS HSCs的能力，以及 我们将确定对这些疗法最有可能反应的AML和MDS亚型的谱系。我们会 分析临床注释的基因表达数据集，以确定CD99表达是否可用作 化疗敏感性的生物标记物。 目的2：探讨抗CD99单抗诱导细胞毒作用的分子机制。我们将描述信号的特征 CD99调节的有助于CD99介导的细胞毒作用的途径。我们将利用蛋白质组学平台 确定抗CD99单抗的细胞毒作用在功能上所必需的CD99相互作用伙伴。 这些研究有望为临床治疗的发展做出贡献。 CD99或其相关的生物途径，以及CD99作为临床相关生物标记物的应用。 钟庭耀医学博士是这项提议的首席研究员，也是一名执业的内科肿瘤学家。 以骨髓增生异常综合征为临床重点。他是斯隆·凯特琳癌症纪念中心的讲师 2010年至2016年，他是马里兰州克里斯托弗·Y·帕克实验室的博士后研究员 他是正常和恶性造血干细胞生物学方面的专家。他目前正在致力于翻译 他的发现在罗斯·L·莱文医学博士的指导下提交给临床，罗斯·L·莱文是开发小说的世界领先者 髓系恶性肿瘤的治疗方法。在这份建议书中，钟博士概述了一个五年的职业发展计划 由研究、课程、研讨会和专家咨询委员会组成。这项计划将利用 丰富的机构资源和在MSKCC的指导使他能够过渡到自己的独立公司 实验室研究计划，并在该奖项的第二年之前具有R01资金的竞争力。