Novel myeloma stem cell markers for therapy

用于治疗的新型骨髓瘤干细胞标记物

• 批准号: 8302293
• 负责人: WAFIK S. EL-DEIRY
• 金额: $ 16.64万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302293
• 关键词: Acute Myelocytic Leukemia; Animals; Antibodies; Antibody Specificity; Antibody Therapy; Antigen Targeting; Antigens; Attention; B-Lymphocytes; Bacteriophages; Binding; Biological Assay; Bioluminescence; Bone Marrow; Brain; Breast; CD19 gene; Cell Line; Cell Separation; Cell model; Cell surface; Cells; Cessation of life; Clinical; Colon; DNA; Data; Development; Diagnosis; Diagnostic; Differentiation Antigens; Disease; Disease Progression; Etiology; Event; Firefly Luciferases; Fluorescence; Freezing; Frequencies; Goals; Heart Ventricle; Hematopoietic Neoplasms; Hematopoietic System; Human; Image; Immunoprecipitation; In Vitro; Label; Lead; Left; Lesion; Libraries; Life; Ligands; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Methods; Modeling; Multiple Myeloma; Mus; Nude Mice; Patients; Phage Display; Plasma Cells; Population; Population Analysis; Relapse; Reporting; Role; Sampling; Screening procedure; Side; Solid; Specificity; Specimen; Stem cells; Surface Antigens; Techniques; Technology; Testing; Therapeutic; Time; Treatment Efficacy; Tumor Burden; Tumorigenicity; United States; Work; advanced disease; aldehyde dehydrogenase 1; base; cancer cell; cancer stem cell; carcinogenesis; chemotherapy; clinically significant; cytotoxic; design; disorder later incidence prevention; drug development; in vitro Assay; in vivo; killings; mouse model; novel; outcome forecast; plasma cell differentiation; precursor cell; prognostic indicator; research study; self-renewal; stem; stem cell population; therapeutic target; tool; treatment strategy; tumor; tumorigenic

DESCRIPTION (provided by applicant): The Cancer Stem Cell model of carcinogenesis has recently garnered a great deal of attention. Cancer stem cells have been identified in acute myelogenous leukemia, as well as in solid malignancies such as those of the breast, colon and brain. Although there exists evidence of a tumor-initiating population in multiple myeloma (MM), to date the markers positively identifying such cells are unknown. The hierarchical organization of the hematopoietic system and the observation that a majority of MM cells are unable to form tumors at high frequency support a role for stem cells in the maintenance and progression of the disease. Given that MM is the second most common blood cancer in the United States and relapse occurs in 100% of patients, the potential role of cancer stem cells in MM warrants attention. The power in visualizing cancer stem cells stems from the identification of cellular markers that distinguish the rare tumor-initiating cells from the bulk of malignant cells. Although there is some data suggesting that cells negative for CD138 expression are the MM cancer stem cells, identification based on the lack of antigen expression is not ideal for therapeutic targeting, diagnostic, or in vivo imaging purposes. We have proposed to screen for antibodies that identify MM cancer stem cells by positive selection with phage display technology which allows for the screening of 1010 antibody clones. Prior to the screening of phage we will first enrich for putative cancer stem cells based on side population analysis (or lack of CD138 cell surface expression). Positive markers will be validated under in vivo conditions with MM cell lines as well as MM patient specimens. The identification of cancer stem cell markers is likely to advance disease prognostication and alter standard therapeutic strategy by promoting the development of cancer stem cell targeting therapeutics to be used in conjunction with standard chemotherapy. In the event that the cancer stem cell model is validated, the prevention of relapse and the potential for a cure of MM patients will be within reach.

描述（由申请人提供）：癌症发生的癌症干细胞模型最近引起了极大的关注。癌症干细胞已经在急性骨髓性白血病以及实体恶性肿瘤如乳腺癌、结肠癌和脑癌中被鉴定。虽然有证据表明多发性骨髓瘤（MM）中存在肿瘤起始群体，但迄今为止，阳性识别此类细胞的标志物尚不清楚。造血系统的分层组织和观察到大多数MM细胞不能以高频率形成肿瘤支持干细胞在疾病的维持和进展中的作用。鉴于MM是美国第二常见的血液癌症，并且100%的患者会复发，因此癌症干细胞在MM中的潜在作用值得关注。可视化癌症干细胞的能力源于细胞标记物的鉴定，这些细胞标记物将罕见的肿瘤起始细胞与大量恶性细胞区分开来。尽管有一些数据表明CD138表达阴性的细胞是MM癌症干细胞，但基于缺乏抗原表达的鉴定对于治疗靶向、诊断或体内成像目的并不理想。我们已经提出通过噬菌体展示技术的阳性选择来筛选鉴定MM癌症干细胞的抗体，所述噬菌体展示技术允许筛选1010个抗体克隆。在筛选噬菌体之前，我们将首先基于侧群分析（或缺乏CD138细胞表面表达）富集推定的癌症干细胞。阳性标志物将在体内条件下使用MM细胞系以及MM患者标本进行验证。癌症干细胞标志物的鉴定可能通过促进与标准化疗结合使用的癌症干细胞靶向治疗剂的开发来推进疾病诊断并改变标准治疗策略。如果癌症干细胞模型得到验证，那么预防复发和治愈MM患者的可能性将触手可及。