New research shows that a drug approved for basal cell carcinomas could also be effective for a subtype of medulloblastoma. Both cancers arise from aberrant Sonic hedgehog (SHH) pathway activity and may therefore respond to vismodegib, which blocks a key protein in the SHH signaling cascade.

According to results from phase II studies conducted through the Pediatric Brain Tumor Consortium, a subtype of the brain stem tumor medulloblastoma may respond to vismodegib (Erivedge; Genentech)—approved for basal cell carcinomas—with less toxicity than current standard therapy. Both cancers arise from aberrant Sonic hedgehog (SHH) pathway activity; vismodegib inhibits a key protein, Smoothened (SMO), in this signaling cascade.

Medulloblastoma's SHH subtype (SHH-MB) occurs in about 60% of adult and 25% of pediatric patients. Initial treatment involves a combination of surgery, radiation, and cytotoxic therapy, with a 5-year overall survival of 70%. However, patients are often left with severe long-term side effects, and a grim prognosis if the tumor recurs.

“We need a therapy that is less toxic and better honed to its target,” says corresponding author Giles Robinson, MD, a pediatric neuro-oncologist at St. Jude Children's Research Hospital in Memphis, TN.

The studies enrolled 31 adults and 12 children respectively, all with recurrent or refractory medulloblastoma (J Clin Oncol 2015;33:2646–54). Following treatment with vismodegib, a total of 13 patients experienced prolonged disease stabilization for up to 16 months. Four of these patients had significant tumor shrinkage for longer than 2 months, while another four had shorter responses. All positive responses occurred in patients with SHH-MB, and none among those with non-SHH tumors. So “while vismodegib seems like a good drug with a huge amount of potential, it's effective for only a select group,” Robinson notes.

Interestingly, the SHH-MB subtype didn't guarantee sensitivity to SMO inhibition. Molecular analyses of 26 SHH-MB tumors revealed that the location of genetic alterations along the SHH pathway plays a role: Loss-of-function mutations in PTCH1, which inhibits SMO, predicted vismodegib sensitivity, as did alterations in p53. However, tumors with pathway mutations downstream of SMO, including GLI2 and SUFU, were nonresponsive.

“These results validate findings from larger genomics studies that showed substantial numbers of SHH-MB patients had varying mutations predictive of vismodegib response,” says Yoon-Jae Cho, MD, a pediatric neuro-oncologist at California's Stanford University School of Medicine. There have been no previous pediatric trials with vismodegib, he adds, so these studies “open up our ability to combine vismodegib with other targeted therapies, or with some of the backbone chemotherapy regimens for kids, for more durable responses.”

Clinicians at St. Jude have now incorporated vismodegib into treatment regimens after patients with SHH-MB complete standard-of-care therapy. This could reduce recurrence, Robinson says; if not, new therapeutic targets may be uncovered by analyzing the molecular features of recurrent tumors.

“The idea is to look at vismodegib responses in a larger population of patients with SHH-MB,” Robinson explains. “The more specific our drugs, the better we need to understand the tumors we're targeting.”

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