Key Advance in Neurofibromatosis Research Might Result in New Therapies

Researchers from the University of Plymouth and Plymouth Hospitals NHS Trust say they have shed light on the role of the normal, cellular form of prion protein (PrPC) in the development of neurofibromatosis 2 (NF2)-related tumors;The hereditary condition, which mainly affects young people, is characterized by the development of multiple tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas, each associated with mutations in a gene coding for a tumor suppressor called Merlin.

The researchers note there could also be potential benefit for other cancers with the same mutations, including mesothelioma, breast cancer, colorectal carcinoma, melanoma, glioblastoma, and spontaneous schwannomas and meningiomas occurring independently of NF2.

PrPC is normally present in the nervous system of healthy individuals and is absent in Creutzfeldt-Jakob prion disease patients who have a pathological form of prion protein called scrapie prion protein (PrPSc). While physiological levels of PrPC are important during embryogenesis and are neuroprotective in adults, highly increased concentrations were found in several cancers, such as glioblastoma, breast cancer, prostate, and gastric cancer.

Since all NF2 patients develop multiple schwannomas, the scientists have developed a human cell culture model for schwannoma, comprising of human schwannoma cells isolated from both patients and control normal healthy Schwann cells. Using this model, the research team found for the first time that PrPC is overproduced in schwannoma compared with healthy Schwann cells. This overproduction is due to Merlin deficiency and strongly contributes to tumor growth and patient prognosis.

The researchers have already identified a range of existing drugs that could manage this protein overproduction and that are used currently for other non-NF2-related conditions, such as Creutzfeldt-Jakob disease, multiple myeloma, and acute myeloid leukemia (AML). By repurposing existing drugs, an effective therapy could be made available to NF2 patients, based on the failure of Merlin tumor suppressor expression. The safety testing process for human use has already taken place for the original purpose of these drugs, which means they could be fast-tracked into clinical studies for NF2.

“By understanding the relationship between overproduction of PrPC and Merlin deficiency in the development of schwannoma and meningioma, we have made a significant stride forward in the search for a drug treatment for NF2,” said Sylwia Ammoun, Ph.D, director of the study (“Cellular Prion Protein (PrPC) in the Development of Merlin-Deficient Tumors”) that appears in Oncogene, and senior research fellow in clinical neurobiology at Plymouth University Peninsula Schools of Medicine and Dentistry. “This is a life-changing condition usually striking the young. That our discovery could also lead to hope for thousands of patients affected by other Merlin-deficient tumors adds yet more to the significance and excitement of our findings.”

“PrPC contributes to increased proliferation, cell-matrix adhesion and survival in schwannoma cells acting via 37/67 kDa non-integrin laminin receptor (LR/37/67 kDa) and downstream ERK1/2, PI3K/AKT and FAK signaling pathways,” write the investigators. “We suggest that PrPC and its interactor, LR/37/67 kDa, could be potential therapeutic targets for schwannomas and other Merlin-deficient tumors.”