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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

基本信息

批准号：
9533506
负责人：
Stephen Shiu-Wah Chung
金额：
$ 1.46万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9533506
关键词：
Acute Myelocytic Leukemia Advisory Committees Award Azacitidine Biological Assay Biological Markers Blast Cell 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 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 leukemia 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

项目摘要

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.

项目概要/摘要急性髓系白血病 (AML) 和骨髓增生异常综合征 (MDS) 的引发和维持是自我更新的干细胞。面对当前的标准疗法，这些细胞通常会持续存在，并且它们可能代表促进治疗抵抗和疾病复发的疾病库。细胞表面这些干细胞上独特表达的蛋白质可能允许专门针对患病细胞的治疗而不是正常的造血干细胞。通过转录分析，然后进行流式细胞术验证，CD99被鉴定为MDS造血干细胞上高表达的细胞表面标志物 (MDS HSC) 和 AML 白血病干细胞 (LSC)。靶向 CD99 的单克隆抗体 (mAb) 直接在体外和体内对疾病细胞具有毒性，这种细胞毒性与 Src 家族的快速激活有关激酶（SFK）。 CD99 作为化学敏感性生物标志物也具有显着的临床潜力。利用我们的凭借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：目标 1：确定 CD99 作为治疗靶点和预后生物标志物的临床潜力。我们将测试抗 CD99 mAb 在稳健的临床前疾病模型中消除 AML LSC 和 MDS HSC 的能力，以及我们将确定最有可能对这些疗法产生反应的 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 CD99 表达是否可以用作化学敏感性的生物标志物。目标 2：确定抗 CD99 mAb 诱导细胞毒性的分子机制。我们将表征信号 CD99 调节的途径有助于 CD99 介导的细胞毒性。我们将使用蛋白质组平台确定抗 CD99 mAb 的细胞毒性作用在功能上所需的 CD99 相互作用伙伴。这些研究有望有助于开发针对该疾病的临床疗法 CD99 或其相关生物途径，以及 CD99 作为临床相关生物标志物的用途。 Stephen S. Chung 医学博士是该提案的主要研究者，也是一名执业肿瘤科医生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），2010-2016年在医学博士Christopher Y. Park实验室担任博士后研究员博士，正常和恶性造血干细胞生物学专家。他目前正在从事翻译工作在世界小说开发领域的领导者罗斯·L·莱文医学博士的指导下，他将研究结果带到了诊所骨髓恶性肿瘤的治疗。在这份提案中，钟博士概述了五年职业发展计划由研究、课程作业、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获得 R01 资助的竞争力。