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IMF 1995 Research Grant Award
By Atsushi Ogata, Dana Farber Cancer Institute
Multiple myeloma is a neoplastic disease characterized by the growth and accumulation of malignant plasma cells. Since myeloma responds poorly to conventional chemotherapy and radiation therapy, the need exists for new therapeutic approaches. It is well known that interleukin-6 (IL-6) plays an important role in myeloma cell growth by means of an autocrine or paracrine mechanism both in vitro and in vivo. Indeed, recent reports demonstrate that antibodies to IL-6 and IL-6 receptor (IL-6R) inhibit the growth of myeloma cells in vitro and in vivo, suggesting that blocking of IL-6 may be a novel approach for myeloma therapy.

Previous reports have demonstrated several pathways of IL-6 signal transduction: the Ras dependent MAPK cascade, the APRF dependent pathway, and the p91 dependent pathway. However, these studies were carried out in several cell lines and did not include studies in either fresh myeloma cells or myeloma-derived cell lines. Therefore, little is known at present about intracellular IL-6, signal transduction in myeloma cells.

In this study, it is proposed to characterize the myeloma cell lines. Once the IL-6 dependency of the myeloma cells is clarified, the effects of known therapeutic agents, such as prednisolone (PSL), Interferon alpha, interferon gamma, and all-trans retinoic acid (ATRA) on IL-6 signal transduction, since I have previously demonstrated that PSL, IFNa, IFNy and ATRA inhibit the growth of IL-6 dependent myeloma cells. The goals of this project are therefore 1) to clarify the pathway which mediates IL-6 signal transduction in the growth of IL-6 dependent myeloma cells; 2) to define the sites in IL-6 signal transduction pathway where known therapeutic agents may act; and 3) to define intracellular signal transduction pathways in the growth of IL-6 independent myeloma cells compared with IL-6 dependent myeloma cells. Once the signal transduction pathways in myeloma cells have been identified, new therapeutic methods which interfere with signal transduction and growth of myeloma cells may be possible.
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