Mantle cell lymphoma has one of the worst clinical outcomes among the B-cell lymphomas, with a median survival rate of three to four years with standard therapy.
To develop a more effective therapy, UNMC investigators wanted a better understanding of the underlying mechanisms that regulate mantle cell lymphoma proliferation and survival.
Their answers have been published in the cover story of the June issue of “Molecular Cancer Therapeutics,” a preeminent journal published by the American Association for Cancer Research. The journal focuses on basic research studies that have implications for cancer therapeutics.
The findings present the first report on the role of sonic hedgehog (Shh)-GLI signaling in the proliferation of mantle cell lymphoma. Although Shh-GLI signaling has been shown to be important in the pathogenesis of different cancers, until now, no such study was reported for mantle cell lymphoma.
“Along with our unpublished preclinical in vivo studies, targeting of hedgehog signaling is promising and could translate into medicines that improve therapies for mantle cell lymphoma,” said Ganapati Hegde, Ph.D., a postdoctoral research associate and the first author of the paper.
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The study, funded by the Lymphoma Research Foundation, showed that targeting the molecules associated with Shh-GLI signaling is a potential therapeutic approach that could improve the treatment for mantle cell lymphoma.
“Targeting of hedgehog signaling may have therapeutic potential in clinic for the treatment of mantle cell lymphoma and other B-cell malignancies as hedgehog signaling inhibitors are being investigated in clinical trials for other cancers,” said Julie Vose, M.D., professor, internal medicine-section of oncology/hematology, Center for Research in Leukemia and Lymphoma at UNMC.
Mantle cell lymphoma — which accounts for 6 percent to 10 percent of all non-Hodgkin’s lymphomas — is a malignancy of cells located in the mantle zone of the lymph node, a thin area surrounding individual follicles. The disease, which predominantly affects older males, was first well-defined more than 20 years ago by Dennis Weisenburger, M.D., professor in the department of pathology and microbiology at UNMC.
Although, mantle cell lymphoma patients currently are treated with high dose chemotherapy and a stem cell transplant, diseased cells remain behind.
“We think these are the tumor stem cells and we can stop them from proliferating with a molecular — targeting approach,” Dr. Joshi said.
In the study, UNMC researchers found that molecules associated with the Shh-GLI signaling were expressed in the mantle cell lymphoma. Deviation of the signaling influenced the proliferation of these cells, Dr. Joshi said, while down-regulation of GLI resulted in decreased proliferation and increased susceptibility to the chemotherapeutic drug doxorubicin.
“That suggests the key molecules might be regulated by GLI in mantle cell lymphoma,” Dr. Joshi said.
To improve treatment, further preclinical studies in mantle cell lymphoma are needed to determine the feasibility and efficacy of approaches targeting Shh-GLI signaling molecules. In addition, other hematologic malignancies including leukemia and multiple myeloma also might benefit from testing of the strategy.
The recently published article, titled “Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma,” is available on the Molecular Cancer Therapeutics Web site at http://mct.aacrjournals.org.
In addition to Dr. Joshi, other UNMC participants included:
- Ganapati Hegde, Ph.D., genetics, cell biology and anatomy;
- Corey Munger, Ph.D., genetics, cell biology and anatomy;
- Katy Emanuel, a BRIN scholar from Nebraska Wesleyan University who works in the department of genetics, cell biology and anatomy at UNMC;
- Avadhut Joshi, Ph.D., genetics, cell biology and anatomy;
- Timothy Greiner, M.D., pathology and microbiology;
- Dennis Weisenburger, M.D., pathology and microbiology; and
- Julie Vose, M.D., internal medicine-section of oncology/hematology.
Subsequent gene-targeting experiments in animal models have eliminated tumors, Dr. Joshi said, noting those findings soon will be submitted for possible publication.