Preet Chaudhary, M.D., Ph.D.
Research at the Keck School of Medicine, conducted with other scientists, has shown that a cellular-signaling mechanism spurs the advancement of multiple myeloma, a bone-marrow cancer accounting for 10 percent of all blood-borne malignancies, and also makes the disease resistant to drugs.
“We have found that a single signaling pathway not only contributes to disease progression in myeloma, but also contributes to the development of resistance to some of the commonly used drugs for the disease,” said Preet Chaudhary, principal investigator for the study, “NF KappaB Confers IL6 Independence in Myeloma.” The findings were published in the Aug. 12 edition of the Journal of Biological Chemistry.
Chaudhary, a nationally recognized physician-scientist, serves as a professor in the Keck School, and chief of the Nohl Division of Hematology and Center for the Study of Blood Diseases, the Bloom Family Chair in Lymphoma Research, and associate director for translational research at the USC Norris Comprehensive Cancer Center and Hospital. Joining him as the first author of the study is his former postdoctoral fellow, Yanqiang Yang, Ph.D.
Scientists long have known that in the early stages of myeloma, cancer cells depend on interleukin 6 (IL6) — a protein growth factor produced by myeloma cells and by certain cells of the bone marrow — to survive and proliferate. But when the disease progresses, spreading from the bone marrow to the bloodstream and other parts of the body, the cancer cells become independent of IL6.
“The question was, ‘What happens during the transition to make them IL6-independent?’” Chaudhary said. “We found that activation of a set of proteins known as Nuclear Factor kappa B, or NF-kB, in the plasma cells [white blood cells] provides a mechanism to bypass IL6.”
The study built upon Chaudhary’s previous research, which found that a protein expressed by the human herpes virus 8, known as K13, activated the NF-kB pathway. In the latest investigation, Chaudhary’s team used cancerous plasma cells from mice that were still dependent on IL6, and expressed the herpes virus protein in them, activating the NF-kB pathway. The plasma cells then became independent of IL6.
In addition, they found that NF-kB makes the cancerous plasma cells resistant to dexamethasone (Decadron), a drug commonly used to treat myeloma, as well as to other agents currently being tested for myeloma treatment.
“The results suggest that finding an inhibitor of the NF-kB pathway may help prevent the progression of myeloma as well as treat advanced cases of the disease,” Chaudhary said. “They may also have significance for the development of targeted agents to treat other disorders in which IL-6 is involved, such as various forms of lymphoma.”
Chaudhary and his research team have just begun the process of searching for chemical agents that could target the NF-kB pathway in myeloma. He said they have screened a library of compounds and have identified some promising leads.
The research was supported by grants from the National Institutes of Health, the Leukemia & Lymphoma Society and the Multiple Myeloma Research Foundation.
Yang, Yanqiang, Groshong, Jason S., Matta, Hittu, Gopalakrishnan, Ramakrishnan, Yi, Han and Chaudhary, Preet M., “Constitutive NF-κB Activation Confers Interleukin 6 (IL6) Independence and Resistance to Dexamethasone and Janus Kinase Inhibitor INCB018424 in Murine Plasmacytoma Cells, The Journal of Biological Chemistry, Vol. 286, Issue 32, 27988-27997, Aug. 12, 2011