Novel myeloma stem cell markers for therapy

描述(申请人提供)：癌症干细胞致癌模型最近引起了极大的关注。癌症干细胞已经在急性髓细胞白血病以及乳腺、结肠和脑等实体恶性肿瘤中被发现。尽管有证据表明多发性骨髓瘤(MM)中存在肿瘤始发群体，但到目前为止，确定这类细胞的标志物尚不清楚。造血系统的分级组织和观察到大多数MM细胞无法高频形成肿瘤，支持干细胞在疾病的维持和发展中发挥作用。鉴于多发性骨髓瘤是美国第二常见的血癌，而且100%的患者会复发，肿瘤干细胞在多发性骨髓瘤中的潜在作用值得关注。可视化癌症干细胞的能力来自于识别细胞标记物，这些标记物将罕见的启动肿瘤的细胞与大部分恶性细胞区分开来。虽然有一些数据表明CD138表达阴性的细胞是MM肿瘤干细胞，但基于缺乏抗原表达的鉴定对于治疗靶向、诊断或活体成像目的并不理想。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)来丰富假定的癌症干细胞。阳性标记物将在活体条件下与多发性骨髓瘤细胞系以及多发性骨髓瘤患者样本进行验证。肿瘤干细胞标记物的鉴定可能会促进肿瘤干细胞靶向治疗的发展，从而促进与标准化疗相结合的疾病预测和改变标准治疗策略。如果癌症干细胞模型得到验证，多发性骨髓瘤患者复发的预防和治愈的潜力将触手可及。 与公共卫生相关：美国每年约有16,500例多发性骨髓瘤新发病例，约11,300人死亡。这是一种侵袭性疾病，迫切需要新的治疗方法。最近的进展表明，某些骨髓瘤细胞在物理识别和新疗法的靶向方面可能非常重要。这些所谓的骨髓瘤干细胞可能是抵抗标准化疗的患者复发的原因。我们已经开发了新的技术来识别工具，以可视化和靶向这些骨髓瘤肿瘤形成细胞。我们希望进行实验，从而导致这些新疗法的临床开发。

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.