Novel myeloma stem cell markers for therapy

描述（由申请人提供）：癌症干细胞模型的癌变最近引起了极大的关注。癌症干细胞已经在急性髓性白血病以及实体恶性肿瘤（如乳腺癌、结肠癌和脑癌）中被发现。虽然有证据表明多发性骨髓瘤（MM）中存在肿瘤启动细胞群，但迄今为止尚无确定此类细胞的标记物。造血系统的分层组织和大多数MM细胞不能高频形成肿瘤的观察支持了干细胞在疾病维持和进展中的作用。鉴于MM是美国第二大最常见的血癌，并且100%的患者会复发，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力量源于细胞标记的识别，这些细胞标记将罕见的肿瘤起始细胞与大量恶性细胞区分开来。虽然有一些数据表明CD138表达阴性的细胞是MM癌干细胞，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。我们建议通过噬菌体展示技术的阳性选择来筛选识别MM癌症干细胞的抗体，该技术允许筛选1010个抗体克隆。在筛选噬菌体之前，我们将首先根据侧群分析（或缺乏CD138细胞表面表达）富集推定的癌症干细胞。阳性标记将在MM细胞系和MM患者标本的体内条件下进行验证。癌症干细胞标记物的鉴定可能会促进癌症干细胞靶向治疗的发展，并与标准化疗结合使用，从而促进疾病预后和改变标准治疗策略。如果癌症干细胞模型得到验证，预防复发和治愈MM患者的潜力将是触手可及的。

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. PUBLIC HEALTH RELEVANCE: There are ~16,500 new cases of Multiple Myeloma each year in the U.S. and ~11,300 deaths. This is an aggressive disease for which new therapies are urgently needed. Recent advances have suggested that certain Myeloma cells may be very important to physically identify and target with new therapies. These so- called Myeloma stem cells may be responsible for relapses in patients that resist standard chemotherapy. We have developed new techniques for identification of tools to visualize and target these Myeloma tumor- forming cells. We hope to carry out experiments that will lead to the clinical development of these new therapies.