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.

R21CA081324

1999-04-05

2003-03-31