New Treatment for Medulloblastoma Shows Promising Results in Early Clinical Trials


Patients with medulloblastoma, the most common malignant brain tumor in children, are urgently in need of new treatments. The existing therapeutic approach requires surgery, chemotherapy, and radiation, and while some patients are cured, they invariably suffer debilitating side effects such as motor coordination problems and learning disabilities. Patients who are not successfully treated with standard treatment, or whose tumors return, face a cure rate of less than 5 percent. However, a small Phase 1 clinical trial shows early indications of benefit for children whose medulloblastoma is resistant to treatment.

Presented at the American Society of Clinical Oncology annual meeting on June 5, this research finding is based squarely upon the work of Tom Curran, Ph.D., FRS, deputy scientific director at CHOP Research. Dr. Curran’s medulloblastoma research was established with the goal of developing less toxic treatment strategies directed against specific molecular targets. One molecular target he 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 this and other cancers.

The current study is the first to report that a drug developed to attack tumors by blocking the SHH pathway can be safely administered to children. Conducted by investigators in the Pediatric Brain Tumor Consortium (PBTC), including Dr. Curran and fellow CHOP Research investigator, Peter Phillips, M.D., the study evaluated 12 patients with medulloblastoma that resisted standard treatment or returned following treatment. Participants ranging in age from 4 to 21 years received one of two doses of GDC-0449 daily for 28 days or as long as their disease remained stable.

In addition to showing that the drug is well tolerated, the study has shown early indications of therapeutic benefit in patients who have remained on the treatment for almost a year with no progression of disease.

“This is the first new treatment developed for brain tumors in decades that has had such dramatic results,” says Dr. Curran. “The nature of the response of brain tumors to this drug is unlike anything we have ever seen before, and if the drug works as well as we think it will, it will revolutionize the treatment of medulloblastoma.”

The early promise of a targeted therapy to treat medulloblastoma is the result of more than 15 years of research spearheaded by Dr. Curran. He 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. 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-691, 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-691 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-691 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 lacking known mutations in the SHH pathway.

In collaboration with Curis Inc., scientists at Genentech Inc. developed a related compound for clinical use (GDC-0449) that had an almost unheard of 50 percent response rate in advanced or metastatic skin tumors in a Phase 1 study in adults. These results, and encouragement from Dr. Curran and his colleagues at CHOP Research and St. Jude Children’s Research Hospital, where he began his research, led to the development of the current pediatric Phase 1 study in treatment-resistant medulloblastoma that showed the drug can be given to children with without severe toxic side effects. Based on the results of the current study, the PBTC will soon begin a Phase II trial of GDC-0449 in children with relapsed medulloblastoma.

“This finding represents an important step in the treatment of brain tumors, which are notoriously difficult to treat, as well as the development of personalized medicine,” says Dr. Curran. “Using this agent we can achieve a predictive response in the 20 percent of medulloblastomas that have a defect in the SHH pathway. We hope that this research helps to usher in a new paradigm of identifying subsets of disease, isolating potential targets for each subset, and developing precise therapies to act on the subset’s Achilles heel.”

If the Phase II study of GDC-0449 is successful, long-term studies will be needed to address concerns raised in a study led by Dr. Curran that showed mice treated with HhAntag-691 were at risk for problems with bone development.

The PBTC trials are supported by the Division of Cancer Treatment and Diagnosis of the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement Letter of Intent between NCI and Genentech Inc.