MINIMAL RESIDUAL TUMOR IN SMALL CELL LUNG CANCER

（申请人摘要）大约15-25%的支气管源性癌是小细胞肺癌（SCLC）。许多化疗药物对SCLC具有主要活性。对于三分之一的有限期疾病患者，化疗反应为80-100%，其中至少50%是完全的。然而，两年后只有20-40%存活。大多数SCLC患者死于播散性疾病。有了检测数百万细胞的新技术，可以检测到血液中循环或居住在骨髓中的少量肿瘤细胞。申请人的假设是治疗结束时脑脊膜炎污染水平与反应持续时间相关。在造血组织中检测“最小残留肿瘤”（MRT）不仅可以提供预后信息，还可以表明对治疗的反应程度，并确定对治疗有抗性的存活残余肿瘤细胞的表型。从许多已建立的药物中开发的方案对SCLC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相同的肿瘤亚群，但未能消除肿瘤干细胞的中心核心，可能富集了异质体内耐药机制。很可能这些存活细胞将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。这些残留癌细胞（MRT）的识别和对其生物学特性的系统评估可以指导特异性靶向这些细胞的策略，例如给予非交叉耐药化疗，肿瘤疫苗接种，或过继性干扰自分泌或旁分泌生长环，这些在MRT的设置中是最有效的。为此，检测异质性和分析各种标记物的共表达模式构成了该项目在MRT检测中的主旨。申请人专注于SCLC中存在的特异性细胞表面抗原，这些抗原可能是在其他赞助下开发的免疫或基因替代策略的靶标：神经节苷脂GD2和GD3， avb5整合素（参与腺病毒的跨膜内化），CD56 （NCAM）和SM1，异常集中的糖脂表位。

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.