Approval of Skin Cancer Drug Leads to Medulloblastoma Treatment Hopes


For more than 15 years, Tom Curran, Ph.D., FRS, deputy scientific director at CHOP Research, has worked toward a cure for medulloblastoma, the most common form of malignant brain tumor in children. While medulloblastoma can currently be treated through surgery, chemotherapy, and radiation, patients often suffer debilitating side effects. And those patients who are not successfully treated, or whose tumors return, face an extremely low cure rate.

However, the FDA’s recent approval of a drug to treat a form of skin cancer in adults could have wide-ranging implications in the fight against medulloblastoma and other pediatric cancers. Erivedge (vismodegib), developed by Genentech and Curis Inc., was recently approved to treat metastatic basal cell carcinoma (BCC), a form of skin cancer, in adults.

Erivedge, much like the compounds Dr. Curran and his team have been investigating, works by inhibiting the hedgehog (HH) pathway, which plays a critical role during the development of the cerebellum. Because Erivedge is the first HH drug to receive an FDA nod, its approval could lead to approvals for other compounds that share a similar mechanism of action.

Dr. Curran’s Pathway

Dr. Curran began working on medulloblastoma treatments after meeting a number of younger patients with the disease in 1995. One patient’s story, a 16-year-old boy who had undergone radiation and surgery to treat his tumor, particularly affected Dr. Curran.

The treatments had “severely impaired” the patient’s quality of life, Dr. Curran said. Because of damage to his cerebellum the boy had difficulty walking normally, and the radiation he had received was affecting his ability to learn. The boy, who had a great sense of humor, “was seeing the rest of his class progress while he was falling behind,” Dr. Curran said.

Dr. Curran, who has a background in brain development and cancer research, decided then that he wanted to develop a drug that could help patients without the many negative side effects.

One molecular target Dr. Curran has focused on is the sonic hedgehog (SHH) signaling pathway, which is crucial for normal development of the cerebellum and has been shown to play an important role in medulloblastoma and other cancers. Dr. Curran identified the SHH pathway as an ideal target for medulloblastoma therapies following the finding that patients with Gorlin syndrome, a disorder caused by a mutation in a gene associated with the SHH pathway, are predisposed to these brain tumors. Gorlin syndrome is also associated with a “very high instance” of BCC, according to Dr. Curran.

The mutation affects the PTCH1 transmembrane protein that acts as a receptor for SHH, and in the absence of SHH maintains inactivity of the SHH pathway by repressing Smoothened (Smo), another transmembrane protein. The PTCH1 mutation results in an inappropriately active SHH pathway, leading to increased expression of genes that influence neuronal progenitor cell proliferation.

Dr. Curran’s team engineered an animal model of medulloblastoma that precisely mimics the characteristics of disease through the PTCH1 mutation to investigate whether suppressing the overactive SHH signaling could cause tumor regression. They evaluated the effect of HhAntag, a SHH pathway inhibitor developed to block the SHH pathway by binding to Smo.

Isolated by Lee Rubin, Ph.D., director of Translational Medicine at the Harvard University Stem Cell Institute, while he was working at Curis Inc., HhAntag acts in a similar way to the naturally occurring SHH pathway inhibitor cyclopamine but is more effective and far less toxic. The study team found that treatment with HhAntag drastically decreased tumor proliferation and increased tumor apoptosis in the models of medulloblastoma, and long-term treatment eliminated all tumors. In later studies, the team found that this agent was also active against medulloblastomas in which the SHH pathway was active even though they lacked known mutations in the pathway.

Erivedge Approval Raises Hopes

The recent FDA approval of Erivedge, which Genentech developed under an agreement with Curis, to treat BCC in adults is an important first step for hedgehog pathway signaling inhibitors, and could eventually lead to other approvals.

“Our understanding of molecular pathways involved in cancer, such as the Hedgehog pathway, has enabled the development of targeted drugs for specific diseases,” Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research said.

“This approach is becoming more common and will potentially allow cancer drugs to be developed more quickly. This is important for patients who will have access to more effective therapies with potentially fewer side effects,” Pazdur added.
The recent approval of Erivedge “justifies everything we do,” Dr. Curran noted, adding that it was a rare privilege “to have an idea or concept that can lead to an approved drug.”