The excitement surrounding the study drug, K252a, comes from its evidence that its impact on NFkappaB signaling is also precisely targeted, mild and easily reversed. In cell culture studies, Maggirwar's results suggest that K252a causes one part of the NFkappaB complex, a protein called RelA, to cluster within structures called nucleoli. Once there, RelA can no longer interact with the gene-containing chromosomes that it would otherwise influence (e.g. the one for interleukin 6).
The beauty of the study drug's proposed "RelA redistribution" mechanism would be that it allows other parts of the NFkappaB complex, like RelA relative CRel, to continue signaling. RelA and CRel work interchangeably in many pathways, but only RelA drives the expression of the gene that codes for IL6, encouraging B cell longevity. In experiments, exposure to K252a caused five times as many activated B cells, which closely resemble cancerous B cells, to undergo cell death than normal, resting B cells. Furthermore, experiments revealed that K252a keeps lymphoma-like cells from dividing and multiplying.
To extend their findings to other cancer types, the team then analyzed expression of Trk and neurotrophins in cell lines derived from breast cancer, Burkitt's lymphoma and multiple myeloma, as well as the effect of K252a on them. They found the same autocrine neutrophin signaling cascade to exist in these other cancer cells, which again encouraged abnormal survival, and which K252a countered.
In the next step, the team will test the effect of K252a in live mice with NHL in partnership with oncologists within the James P. Wilmot Cancer Center at the Medical Center, who in September 2008 won a SPORE grant from the National Cancer Institute to support the expansion of lymphoma research and clinical trials.
Along with Maggirwar, the study was led by Lynn Sniderhan, Ph.D., Tatiana Garcia-Bates, Ph.D., Michael Burgart and Richard Phipps, Ph.D., in the Department of Microbiology & Immunology, and by Steven Bernstein, M.D., co-director of Wilmot's Lymphoma Biology Program. The work was supported by the grants from the National Institutes of Health.
"The current study results provide strong evidence for the existence of vicious cycle in Non-Hodgkin Lymphoma, a loop where B cells keep secrete too many neutrophins, which interact with too many Trk receptors on their surfaces, which drive abnormal survival of these cells," Maggirwar said. "We believe the study drug broke this deadly loop in lymphoma cells."
Source: University of Rochester Medical Center