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

项目总结/摘要 急性髓性白血病（AML）和骨髓增生异常综合征（MDS）是由以下疾病引发和持续的： 自我更新的干细胞这些细胞在目前的标准疗法面前通常会持续存在， 代表疾病的储存库，促进治疗抗性和疾病复发。细胞表面 在这些干细胞上独特表达的蛋白质可能允许特异性靶向病变细胞的治疗 而不是正常的造血干细胞。通过转录谱分析，随后进行流式细胞术 验证，CD 99被鉴定为在MDS造血干细胞上高度表达的细胞表面标志物 (MDS HSC）和AML白血病干细胞（LSC）。直接靶向CD 99的单克隆抗体（mAb） 在体外和体内对疾病细胞具有毒性，并且这种细胞毒性与Src家族的快速激活有关 激酶（SFK）。CD 99作为化疗敏感性的生物标志物也具有显著的临床潜力。利用我们 在造血干细胞生物学和发育治疗学方面的专业知识，我们的目标是： 目的1：确定CD 99作为治疗靶点和预后生物标志物的临床潜力。我们将测试 抗CD 99 mAb在稳健的临床前疾病模型中耗尽AML LSC和MDS HSC的能力，以及 我们将确定最有可能对这些治疗产生反应的AML和MDS亚型谱。我们将 分析临床注释的基因表达数据集，以确定CD 99表达是否可用作 化学敏感性的生物标志物。 目的2：探讨抗CD 99单克隆抗体诱导细胞毒作用的分子机制。我们将描述信号 由CD 99调节的途径，有助于CD 99介导的细胞毒性。我们将使用蛋白质组学平台， 鉴定抗CD 99 mAb的细胞毒性作用在功能上所需的CD 99相互作用配偶体。 这些研究有望有助于开发针对以下疾病的临床治疗方法： CD 99或其相关生物学途径，以及CD 99作为临床相关生物标志物的用途。 Stephen S. Chung，MD是该提案的主要研究者，是一名执业医学肿瘤学家 临床重点是骨髓增生异常综合征。他是纪念斯隆-凯特琳癌症中心的讲师 中心（MSKCC），并于2010-2016年在Christopher Y.马里兰州帕克 博士，正常和恶性造血干细胞生物学专家。他目前正在努力翻译 在Ross L.的指导下，他将自己的发现提交给了诊所。莱文，医学博士，开发小说的世界领导者 骨髓恶性肿瘤的治疗。在这份建议书中，钟博士概述了一个五年职业发展计划 由研究、课程、研讨会和专家咨询委员会组成。该计划将利用 MSKCC丰富的机构资源和指导，使他能够过渡到自己的独立 实验室研究计划，并在该奖项的第二年竞争R 01资金。

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.