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Potential Therapeutic Targets Identified in Multiple Myeloma

Research investigators have identified molecular changes in multiple myeloma cells that activate an important biological pathway associated with cell growth and survival, thereby revealing potential new targets for drugs to treat this cancer. The researchers, led by a team from the National Cancer Institute (NCI), part of the National Institutes of Health, have shown that malignant cells in multiple myeloma frequently harbor mutations that activate what is called the NF-kappaB signaling pathway, which plays a key role in promoting cell growth and preventing programmed cell death. The results of this research appear in the August, 2007, issue of Cancer Cell.

Multiple myeloma is a cancer of plasma cells, a type of white blood cell that produces antibodies. Multiple myeloma is expected to result in 10,790 deaths and 19,900 newly diagnosed cases this year in the United States.

The research team’s discovery began with the observation that the NF-kappaB pathway was activated in a majority of the multiple myeloma research cells they tested. Using an inhibitor of a key enzyme, named IkappaB kinase beta, needed to activate this pathway, the researchers demonstrated that these myeloma cells either died or stopped dividing when the NF-kappaB pathway was disrupted. The researchers were able to show that the NF-kappaB pathway was activated in most of the tumor samples examined from 451 patients with newly diagnosed multiple myeloma.

To identify the specific genes that might be driving NF-kappaB activation in multiple myeloma, the researchers studied genes known to regulate the NF-kappaB pathway in normal cells, focusing on those with abnormally high or low expression levels in samples from patients with multiple myeloma. The expression level reflects the biological activity of a gene. Molecular analysis revealed that diverse genetic abnormalities in the tumors accounted for the abnormal gene expression levels.

"This work provides compelling genetic evidence for the involvement of the NF-kappaB pathway in multiple myeloma. This signaling pathway prevents cell death and therefore this study suggests inhibitors of the NF-kappaB pathway would provide a rational approach to the treatment of this cancer. This is an important prospect because currently our therapies are not aimed at genetically-defined pathways, and multiple myeloma remains difficult to treat,” said NCI Director John E. Niederhuber, M.D.

According to Louis M. Staudt M.D., Ph.D., chief of the Lymphoid Malignancies Section of the Metabolism Branch in NCI’s Center for Cancer Research (CCR) and lead author of the report, “The development of effective and non-toxic therapies for cancer depends on an understanding of the genetic defects in cancer cells. Our work demonstrates that the genetic basis for multiple myeloma includes activation of the NF-kappaB pathway. Inhibitors of this pathway that target IkappaB kinase beta are being developed by many pharmaceutical companies, and our studies suggest that these agents should be evaluated in clinical trials in patients with multiple myeloma.”

W. Michael Kuehl, M.D., chief of the Molecular Pathogenesis of Myeloma Section of the CCR Genetics Branch and a co-director of the study, stated that “Our studies suggest that activation of the NF-kappaB pathway by signals from normal bone marrow cells is critical not only for survival of normal plasma cells but also for pre-malignant and malignant myeloma tumors. The importance of this pathway is highlighted by essential mutations in some myeloma tumors. Regardless of whether or not there are mutations in this pathway, most myeloma tumors may be sensitive to NF-kappaB inhibitors.”

This research study was a collaborative effort among basic scientists, pharmaceutical partners, and large clinical trial groups. “This is one of the largest collaborative translational cancer research efforts of its kind,” said John Shaughnessy, Jr., Ph.D., director of the Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics and chief of Basic Sciences at the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences, Little Rock, Ark., and another of the report’s authors. “These results attest to the power of patient participation in clinical trials and the collaborative interactions between clinical and basic scientists, which is anticipated to provide a quantum leap in the speed at which we understand how cancer starts, how best to treat it, how to prevent resistance to treatment, and how to prevent the unwanted toxicities associated with many treatment strategies currently in use.”

For more information on NCI's Center for Cancer Research, go to http://ccr.cancer.gov/.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.


References: Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, Lenz G, Hanamura I, Wright G, Xiao W, Dave S, Hurt EM, Tan B, Zhao H, Stephens O, Santra M, Williams DR, Dang L, Barlogie B, Shaughnessy JD, Kuehl WM, and Staudt LM. Frequent engagement of the classical and alternative NF-kappaBeta pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell, August 2007.

Researchers are from the Metabolism Branch and the Genetics Branch of the Center for Cancer Research, and the Biometric Research Branch of the Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Md.; the Computational Bioscience and Engineering Laboratory, NIH, Bethesda, Md.; the University of Arkansas for Medical Sciences, Little Rock, Ark; and Millennium Pharmaceuticals, Cambridge, Mass.
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