Angiogenesis is increased in multiple myeloma (MM) and has prognostic value. The anti-angiogenic agent, thalidomide, is effective in refractory MM and has shown marked synergy with dexamethasone. A randomized multi-institutional ECOG study will compare thalidomide plus dexamethasone versus dexamethasone alone in newly diagnosed MM. This proposal will utilize blood and bone marrow (BM) samples from this important study to test the central hypothesis that angiogenesis is important in MM and that anti-angiogenic therapy will be an effective way to treat MM. Preliminary data indicate that thalidomide can lead to decreased BM angiogenesis and VEGF expression. We hypothesize that thalidomide decreases the expression of VEGF and its receptors and inhibits BM angiogenesis, resulting in increased plasma cell apoptosis, decreased proliferation and tumor response. We also have data that support our hypothesis that thalidomide plus dexamethasone can inhibit mesenchymal progenitor cell (MPC) cytokine expression and differentiation. The proposal is organized into 3 specific aims: 1) To compare changes in BM angiogenesis and the level of expression of VEGF and its receptors before and after therapy and to correlate these measurements with response to therapy. 2) To determine the relationship between BM angiogenesis and MM cell VEGF expression with rates of myeloma cell apoptosis and proliferation and 3) To determine if thalidomide therapy inhibits expression of angiogenic cytokines/growth factors by BM MPC's and restores normal BM MPC function. For all 3 aims, our hypothesis is that the effects will be more pronounced with thalidomide plus dexamethasone than with dexamethasone alone. BM angiogenesis will be studied using immunohistochemical staining for CD34 and the rat aortic ring assay. Immunohistochemistry, in-situ hybridization, ELISA and RT-PCR assays will be used for the study of VEGF and its receptors and MPC cytokine expression. MPC growth and differentiation will be studied and compared to normal controls. Apoptosis will be measured using flow cytometric assays that gate on tumor cells; plasma cells in S-phase and circulating plasma cells will be estimated using slide based immunofluorescent assays. This study offers a unique opportunity to serially study tumor cells and the tumor microenvironment following potential anti-angiogenic therapy.
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