There is currently no effective treatment for recurrent small-cell lung cancer (rSCLC). The objective of this project is to utilize a monoclonal antibody, MAG-1, to develop new, rational, and successful treatment of rSCLC. The hypothesis being tested is that a cancer -specific provasopressin antigen, called GRSA, present at the surface of these tumors will provide a sensitive, tumor-specific, and reliable target for the effective treatment by MAG-1 antibodies in combination with cyclophosphamide. Our preliminary data clearly show that treatment of variant SCLC tumor xenografts, with native and 90Yttrium-labelled mouse MAG-1 significantly slows growth, but this growth is almost completely impaired when antibody treatment follows cyclophosphamide. GRSA expression is a feature common to all, or most, SCLC and is absent from normal tissues. Phase 1 of this study is directed at advancing treatment of rSCLC using both mouse MAG-1 and already generated human chimeric MAG-1 antibodies in combination with different pretreatments with second tier therapeutics such as cyclophosphamide, and elucidating the synergistic mechanisms of this combination therapy. Phase 1 goals are directed towards (i) characterizing and evaluating the mechanism through which MAG-1 antibodies (both m and cMAG-1) add to the killing power of cyclophosphamide. determining the dose combinations of cyclophosphamide, or other therapeutics, with mouse MAG-1 that are most effective in preventing growth of subcutaneous and orthotopic rSCLC xenografts in nu/nu mice;(ii) determining the dose combination of cyclophosphamide with human chimeric MAG-1 that is most effective in preventing growth of rSCLC xenografts in nu/nu mice;and (iii) determining the dose combinations of cyclophosphamide, or other therapeutics, with human chimeric MAG-1 that are most effective in preventing growth of rSCLC xenografts in nu/nu mice;These investigations will employ, RT-PCR, and cloning, DNA recombinance, DNA sequencing, immunohistochemistry, antibody modification, Northern and Western analysis with densiometric quantitation, ELISA, RIA, tumor-directed targeting, cytofluorographic and radiometric quantitation, confocal microscopy, radioligand binding, flow cytometry, and cell and tumor growth assessments with mechanism analysis in vitro and for nu/nu mice. Tumor size will be evaluated by direct micometric and xenogenic measurement. A successful end-point of our Phase 1 studies would be the demonstration that both mMAG-1 and cMAG-1 forms of our antibody in combination with cyclophosphamide, or another therapeutic, can prevent the growth and/or reduce the size of rSCLC tumors in vivo. The proposed research is expected to rapidly lead to new and successful therapeutic approaches for managing recurrent small-cell lung cancer.
This project will introduce a new targeted therapeutic approach for the treatment of recurrent small-cell lung cancer, a disease that is refractory to all current treatments. This refractoriness means <10% expected 5 year survival rate for patients representing >40,000 new cases of SCLC that arise in the USA each year. Our targeted approach is directed at a provasopressin protein called GRSA that seems to be a tumor-specific surface marker of recurrent small-cell lung cancer. Targeting will employ an available monoclonal antibody, MAG-1, acting in synergy with cyclophosphamide, (or other therapeutic), to treat this deadly disease. MAG-1 antibody recognizes a unique extracellular portion of the marker. Currently patients with recurrent SCLC usually succumb to the disease in 3 to 6 months. The proposed research is expected to lead to new successful therapies for managing recurrent SCLC, thereby leading to a higher long-term survival rate for these patients.
