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Winter 2001/2002 Volume 4, Issue 8:
IMF Grant Program Celebrates 8 Years of Research Funding
By Robert A. Kyle, M.D.

The IMF has played an important role in research support for multiple myeloma since the first Brian D. Novis Award was given in 1995. The number of awards has gradually increased and now currently funds nine new investigators annually. These awards are given to junior faculty members who we hope will develop an on-going research interest in multiple myeloma. The size of the grants is rather modest at $40,000 per year, but this provides seed money for the investigator to obtain preliminary data which will lead to success in extramural funding.

During the past three years the IMF has awarded senior grants in the amount of $80,000 to $100,000 annually. These are given to senior investigators who are already established in the field of multiple myeloma.

2002 Brian D. Novis Junior Grants

The Brian D. Novis Junior awardees for 2002 include Jaime O. Claudio, Ph.D. from the Toronto General Research Institute, Toronto, Ontario, Canada. The development of microarray platforms for gene expression analysis is important in multiple myeloma. New gene discovery will be useful for the future. Dr. Claudio and his group have developed a first generation myeloma chip containing 4,300 myeloma-enriched genes. There is a genetic heterogeneity in the genesis of multiple myeloma and in the gene expression profile. This heterogeneity may account for varied responses of patients to current treatment regimens. He is developing a more gene-focused myeloma chip that may lead to the development of a molecular diagnostic test for myeloma therapy. Thus, this study aims to design a second generation myeloma chip with a smaller but a well-defined subset of gene markers from their first generation myeloma enriched cDNA microarray. The results of these cDNA microarrays will be used for patient stratification, assessment of validation of therapeutic interventions, and molecular profiling of myeloma patients.

Amit C. Nathwani, MBChB, Ph.D., University College, London Medical School, London, England, will attempt to deliver the relevant genes for anti-angiogenesis rather than utilizing anti-angiogeneic drugs for the treatment of multiple myeloma. He plans to use the lenti-viral system to deliver the genes. He has already transferred sFIK-1 and TiMP-3 genes in Raji cells which resulted in a marked reduction of tumor growth in SCID mice. He has developed a murine xenograft model that replicates many of the key features of multiple myeloma. He has constructed three lenti-viral vectors that encode different anti-angiogenic genes. He will eventually test the combined efficacy of cytotoxic drugs and anti-angiogenic agents.

The next project will define the novel signal pathways of c-KIT in myeloma cells by Atanasio Pandiella, M.D., Ph.D. at the Spanish National Research Council, Salamanca, Spain. He will infect c-KIT in multiple myeloma cell lines that have previously been shown to be unresponsive to c-KIT ligand. He will then utilize Gleevec? since it specifically inhibits c-KIT. A novel MAPK pathway, Erk5 has been implicated recently in proliferative responses. He proposes to study the role of the Erk5 pathway in the regulation of myeloma cell proliferation. He will also study the Erk1-2 and the p38 pathways to determine the relative contribution of each to the growth of myeloma cells. He plans to use both established cell lines and myeloma cells isolated from patients. Erk5 activation will be correlated with the activation status of other classical MAPK pathways.

Klaus Podar, M.D., Dana-Farber Cancer Institute, Boston, Massachusetts, will continue his work on the pathophysiological relevance of VEGF (vascular endothelial growth factor) in multiple myeloma. During his 2001 Brian D. Novis Award he has demonstrated that VEGF triggers proliferation and migration by myeloma cells, proliferation by a protein kinase-C-independent pathway, and migration by a PKC-dependent pathway. He has also shown that these effects are mediated by binding of VEGF to the Flt-1 receptor which is expressed in plasma cells. He has proven that VEGF induced Erk phosphorylation is blocked by antibody to Flt-1. He has shown that stimulation by VEGF leads to Raf-1 activation in myeloma cells which may have an anti-apoptotic effect. He plans to extend his work to look at the effect of Flt-1 antibody and Raf-1 antisense on VEGF-induced proliferation and migration. He will use biological and chemical assays in a mouse model of myeloma. He will also use both myeloma cell lines and myeloma cells from patients. The actions of VEGF will be explored by looking to see if, like IL-6, it can protect against dexamethasone-induced apoptosis. VEGF is one of the most important biological mediators in the interaction of myeloma cells with the marrow stroma, and the proposed work will further advance our understanding of the biology of myeloma. It may also result in therapeutic targeting of the pathways that are involved.

Ivan Van Riet, Ph.D. was the recipient of a Brian D. Novis grant in 1999. He is a post-doctoral fellow and Director of the Stem Cell Laboratory at the Free University Brussels in Brussels, Belgium. He has utilized a mouse model, 5T2, for his work which indicated that the homing of myeloma cells comes from a combination of selective entry/adhesion of the 5T2 myeloma cells and the selective survival and growth of these tumor cells in the bone marrow and spleen. He proved that homing to the bone marrow involves the CD44v10 molecule. He has shown that laminin-1, which is a component of the basement membrane, acts as an important chemo-attractant for myeloma cells. He has also reported that the chemokine receptor CCR2 can be demonstrated in several human myeloma cell lines. The monocyte chemotactic proteins MCP-1, 2, and 3 which are ligands for CCR-2, are produced by bone marrow stromal cells. This suggests a potential contribution of CCR-2 and MCP's to the bone marrow homing of myeloma cells. He plans to determine the function of the chemokine receptors, CCR-4, CXRC-4, and CCR-8 in the bone marrow homing of myeloma cells. He also will study the adhesion molecules VLA-4, CD44, and CD38 which are expressed by myeloma cells and their involvement in binding and migration through the bone marrow endothelium. He also plans to investigate the functional role of the metalloproteinases (MMP-2 and MMP-9) in the transendothelial migration of myeloma cells.

Michael A. Morgan, Ph.D. from Hannover Medical School, Hannover, Germany, will study the inhibition of ras signaling in multiple myeloma. Ras activation may potentiate myeloma cell growth, increase the expression of adhesion molecules, and increase the production of VEGF, MMP's, and cyclin D1. He plans to study the activation of ras and the MAP-K pathway and cell lines as well as in myeloma cells. He will compare myeloma cells with ras mutations with cells containing no ras mutations. He will also look at the therapeutic potential of the inhibition of ras signaling by looking at the effects of inhibitors on cells lines and primary myeloma cells. The expression of adhesion molecules and MMP's will be addressed. Cell viability and proliferation as well as migration and cell-cycle dependent expression will also be studied.

The IMF (Japan) awarded its first research grant to Masahiro Abe, M.D. of the University of Tokushima School of Medicine, Tokushima, Japan. This award was presented in memory of IMF (Japan) founder Akira Horinouchi. Dr. Abe will study the mechanism of skeletal destruction in patients with multiple myeloma. He has found that the macrophage inflammatory proteins (MIP-1a and b) are secreted by most myeloma cells. They induce osteoclast activity which leads to bone destruction. The osteoclasts also support myeloma cell growth and survival. Dr. Abe plans to investigate the possibility of the use of inhibitors of MIP-1 production or its activity. There are several MIP-1 receptor antagonists that are currently available for study.

2002 Brian D. Novis Senior Grants

Senior research awards have been made available since 2000 when two awards were made. Two awards were also granted in 2001. The recipients of the 2002 awards are Hervé Avet-Loiseau, M.D., Ph.D. of the University of Nantes, Nantes, France. The other award was granted to Elliot Epner, M.D., Ph.D. of the University of Arizona, Tucson, Arizona.

Dr. Avet-Loiseau plans to analyze a large number of plasma cell specimens including normal, premalignant, and malignant plasma cells using DNA microarray technologies. He will attempt to define genes specifically associated with different types of normal plasma cells as well as genes associated with MGUS, and genes responsible for disease progression. He also hopes to identify genes involved in response to therapy or genes predicting patients' outcome. His ultimate goal is to develop an optimized "myeloma chip" enabling one to determine prognosis and to propose an individual patient-adapted therapeutic approach.

Dr. Epner points out that the majority of B-cell malignancies including multiple myeloma contain translocations involving the immunoglobulin heavy chain (IgH) locus. These translocations result in deregulated expression of target genes such as cyclin D1, c-maf, and FGFR3 by regulatory elements from the IgH locus located up to several hundred kilobases away. He has developed homologous recombination approaches to study the mechanisms involved in long-distance, deregulated gene expression in B-cell malignancies. He also plans to determine the functional requirement for the expression of these deregulated genes in malignant B-cells. The identification of the sequences and proteins involved in long-range deregulation will be used to develop and test new therapies for multiple myeloma.

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