Clinical Trial Explores Potential New Treatments for Patients With Recurrent Meningiomas

The two mutations that the clinical trial targets affect the SMO gene (which makes a protein called smoothened, part of the hedgehog signaling pathway) and the NF2 gene (which makes a protein called neurofibrimin 2 or schwannomin, a cytoskeletal protein that’s also a tumor suppressor involved in neurofibromatosis type II). Above: 3-D depiction of cancer cell.
The two mutations that the clinical trial targets affect the SMO gene (which makes a protein called smoothened, part of the hedgehog signaling pathway) and the NF2 gene (which makes a protein called neurofibrimin 2 or schwannomin, a cytoskeletal protein that’s also a tumor suppressor involved in neurofibromatosis type II). Above: 3-D depiction of cancer cell.

May 25, 2017

The majority of meningiomas  are curable through surgery, radiation, or a combination of the two treatment modalities. However, in a fraction of patients, these typically benign tumors are located near critical structures. Because they can’t be completely removed, these meningiomas can grow back repeatedly—threatening quality of life and, sometimes, life itself.

However, says Chetan Bettegowda, M.D., Ph.D. , associate professor in the Department of Neurosurgery at the Johns Hopkins University School of Medicine and the director of the Johns Hopkins Meningioma Center, a new therapy for recurrent meningiomas may soon be on the horizon. In a new Johns Hopkins clinical trial that’s concurrently taking place at several other sites across the country, Bettegowda, who’s leading the trial, and other researchers are testing two medications that specifically target mutations linked to these tumors.

“The goal is to use the mutations as Achilles heels that drugs can attack, hopefully shrinking or stopping the continued growth of these tumors.” - Chetan Bettegowda

“The goal is to use the mutations as Achilles heels that drugs can attack, hopefully shrinking or stopping the continued growth of these tumors,” Bettegowda says.

The two mutations that this trial targets affect the SMO gene (which makes a protein called smoothened, part of the hedgehog signaling pathway) and the NF2 gene (which makes a protein called neurofibrimin 2 or schwannomin, a cytoskeletal protein that’s also a tumor suppressor involved in neurofibromatosis type II). Meningiomas typically harbor few mutations, Bettegowda explains. So when one of these mutations is present in a tumor, it’s thought to drive the tissue’s dangerous pattern of overgrowth.

This clinical trial recruits patients who have tumors that have enlarged or regrown despite receiving currently available treatments. Their tumor tissue, tested using archived samples resected in previous surgeries, must also have one of these two mutations. After a multidisciplinary team, including neurosurgeons, radiation oncologists, and medical oncologists carefully consider if patients have exhausted all other treatment options, study participants are offered one of two oral medications targeting their particular mutation: vismodegib for mutated SMO or GSK2256098 for NF2. Vismodegib is already FDA approved to treat various cancers that also harbor SMO mutations. GSK2256098 is currently in clinical trials to treat others cancers thought to be driven by NF2 mutations.

Patients stay on their assigned drug indefinitely, coming back to the study site for regular MRIs every two to three months to assess tumor growth. Although the trial is still in its early days, Bettegowda says, he and other researchers working on the study have hope and enthusiasm that these medications—and eventually, others on the horizon—will target different mutations involved in meningioma. Because the compounds have already been shown in other clinical trials to be potent inhibitors for these mutations in various cancers, they may offer promise for patients with meningioma.

“Despite being a surgeon,” he adds, “my goal is to minimize the need for surgery. While I don’t envision a future without surgery at all for these tumors, having alternatives if traditional treatments fail is the ultimate goal.”

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