Ornadel, Dan; (1998) An investigation of the biological role of the neural cell adhesion molecule in lung cancer and its clinical potential as a target for antibody-directed therapy. Doctoral thesis (M.D), UCL (University College London).

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Abstract

The neural cell adhesion molecule (NCAM) is strongly expressed by small cell lung cancers (SCLCs). NCAM functions as a homophilic and heterophilic adhesion molecule in many biological systems and its binding function can be modified by a unique post translational modification with polysialic acid. Previous studies have suggested an association between NCAM and morpholgy of SCLC in culture and it has been proposed that polysialylated NCAM contributes to the highly metastatic nature of SCLC. Using an aggregation assay, the biological function of NCAM in SCLC was investigated by attempting to inhibit its function with antibodies, peptides and antisense molecules. No differences in the rate of aggregation were observed except in clonal cell lines with high expression of PSA which aggregated at a slower rate than lines with low PSA expression. Approximately 20% of non-SCLCs express NCAM and they appear to have a worse prognosis, higher metastatic rate and greater chemosensitivity. To investigate the role of NCAM, the NSCLC cell line L23 was transfected with NCAM and its biological characteristics were compared with the parent cell line. No differences were seen in growth rate, invasiveness, chemo- or radiosensitivity in vitro, and growth rate in vivo after transfection with NCAM. However the tranfectants expressed PSA which suggested that polysialylation was activated by transfection with NCAM. Anti-NCAM monoclonal antibodies (MAbs) localise well in SCLC xenografts in mice and produce regression of tumours when conjugated to a radioactive label. To investigate whether NCAM was a suitable target for antibody directed therapy in man, an anti-NCAM MAb NY3D11 and its F(ab')2 fragment were radiolabelled and injected into patients with SCLC. No evidence of localisation in tumours was seen but antibody localised preferentially to bone marrow and liver. The most likely explanation for this distribution was binding to circulating natural killer cells.

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