MINIMAL RESIDUAL TUMOR IN SMALL CELL LUNG CANCER

描述：(申请人摘要)大约15-25%的肺癌是小细胞肺癌(SCLC)。许多化疗药物对小细胞肺癌具有重要的抗肿瘤活性。对于三分之一的局限期疾病患者，化疗缓解率为80%-100%，其中至少50%是完全的。然而，到两年后，只有20%-40%的人还活着。大多数小细胞肺癌患者死于播散性疾病。利用检测数百万个细胞的新技术，可以检测到血液中循环或驻留在骨髓中的少量肿瘤细胞。申请人的假设是，治疗结束时的BM污染水平将与应答持续时间相关。在造血组织中检测微小残留肿瘤(MRT)不仅可以提供预后信息，还可以指示治疗反应的程度，并识别存活的耐药残留肿瘤细胞的表型。从许多已建立的药物发展而来的方案对小细胞肺癌产生相似的短期和长期结果，这一观察结果强烈表明，我们的许多全身药物根除了相同的肿瘤亚群，但未能消除肿瘤干细胞的中心核心，据推测，该中心核心是为体内异质耐药机制而丰富的。这些存活细胞很可能在生物学上不同于原始的未经治疗和未选择的肿瘤细胞群。对这些残留癌细胞(MRT)的鉴定和对其生物学特性的系统评估可能会指导针对这些细胞的特定策略，如给予非交叉耐药化疗、肿瘤疫苗接种或过继干预自分泌或旁分泌生长循环，这在MRT的设置中将是最有效的。为此，异质性的检测和各种标记共表达模式的分析形成了该程序在MRT检测中的主旨。申请人将重点放在SCLC中存在的特定细胞表面抗原，这些抗原可能是在其他主持下开发的免疫学或基因替换策略的靶点：神经节苷脂GD2和GD3，avb5整合素(涉及腺病毒的跨膜内化)，CD56(NCAM)，以及SM1，一种异常岩藻糖化的糖脂表位。

DESCRIPTION: (Applicant's Abstract) Approximately 15-25% of all bronchogenic carcinomas are small cell lung cancer (SCLC). Numerous chemotherapeutic agents have major activity against SCLC. For the third of patients with limited stage disease, response to chemotherapy is 80-100%, of which at least 50% are complete. However by two years only 20-40% remain alive. Most patients with SCLC die of disseminated disease. With new techniques for examination of millions of cells, small numbers of tumor cells circulating in blood or residing in marrow can be detected. The applicant's hypothesis is that the level of BM contamination at completion of therapy will correlate with duration of response. Detection of "minimal residual tumor" (MRT) in hematopoietic tissues may not only provide prognostic information, but also indicate degree of response to therapy and identify the phenotypes of surviving residual tumor cells resistant to treatment. Regimens developed from the many established agents produce similar short and long term outcomes for SCLC, an observation that strongly suggests that many of our systemic agents eradicate the same tumor subpopulation, but fail to abolish a central core of tumor stem cells, presumably enriched for heterogeneous in vivo resistance mechanisms. It is likely that these survivor cells will be biologically different from the original untreated and unselected tumor cell population. The identification of these residual cancer cells (MRT) and systematic evaluation of their biologic characteristics may guide strategies to specifically target these cells, such as administration of non-crossresistant chemotherapy, tumor vaccination, or adoptive interference with autocrine or paracrine growth loops, which would be most effective in the setting of MRT. To this end, the detection of heterogeneity and analysis of patterns of coexpression of various markers form the thrust of this program in the detection of MRT. The applicant is focusing on specific cell surface antigens present in SCLC which might be targeted by immunologic or gene replacement strategies being developed under other auspices: the gangliosides GD2 and GD3, avb5 integrin (involved in transmembrane internalization of adenovirus), CD56 (NCAM), and SM1, an abnormally fucosylated glycolipid epitope.