Researchers’ understanding of the molecular pathways involved in cancer has enabled the development of targeted drugs for diseases such as pediatric and adult recurrent medulloblastoma, a type of rare brain cancer.
Two studies reported in the Journal of Clinical Oncology assessed the efficacy of a drug called vismodegib (Erivedge) in a subgroup of patients with recurrent medulloblastoma. Tom Curran, PhD, FRS, deputy scientific director of The Children’s Hospital of Philadelphia Research Institute, contributed to the article.
“It is terrific to see this exciting application of precision medicine to brain tumors that arise in children and adults,” Dr. Curran said. “While there is a long way still to go, and drug resistance is an issue, this is an extremely promising result.”
Dr. Curran, who has a background in brain development and cancer research, has a longstanding interest in finding drugs to treat medulloblastoma with fewer long-term side effects than current surgery, chemotherapy, and radiation approaches. New therapies especially are crucial for patients with high-risk or recurrent/relapsed disease who have poor chances of survival.
Medulloblastoma is comprised of four molecular subgroups. The studies focused on the SHH-MB subgroup, which is associated with activation of the sonic hedgehog (SHH) pathway. The SHH signaling pathway is crucial for the normal development of the cerebellum, a part of the brain that helps to coordinate movements such as posture, balance, and speech. Researchers suspect that overactive SHH signaling can cause tumors to proliferate.
Previous research suggests that SHH pathway inhibitors, such as vismodegib, could be useful to treat patients in the SHH-MB subgroup. Dr. Curran identified the SHH pathway as an ideal target for medullobastoma therapies after noting that Gorlin syndrome, a disorder caused by a mutation in the gene associated with the SHH pathway, is associated with a predisposition to these brain tumors.
In the current studies, participants’ tumors were prescreened for SHH-pathway activation. Out of 20 participants with recurrent SHH-MB who received oral vismodegib daily, the researchers observed a reduction in tumor area in three adults and a child. While this disease response was seen in only a few patients, prolonged disease stabilization occurred in 41 percent of patient cases with SHH-MB, which indicates that vismodegib has favorable activity. They observed no responses in patients with recurrent non-SHH-MB.
“This work represents the culmination of efforts of a large collaborative team starting in 1995 to develop a molecular-targeted treatment for medulloblastoma,” Dr. Curran said. “The clinical results are very consistent with preclinical studies indicating that the HH pathway inhibitor, vismodegib, is efficacious in a particular molecular subtype of tumor.”
The variable response to vismodegib in patients with recurrent SHH-MB suggests the presence of additional tumor mutations that may occur downstream of the transmembrane protein called Smoothened that the drug helps to block. The investigators concluded that while SHH inhibitors “should be advanced in SHH-MB studies, molecular and genomic work remains imperative to identify target populations that will truly benefit.” T
he SHH-MB subgroup appears to be less common in the pediatric population than in the adult population, so the researchers do not have enough data yet to make any conclusions about using vismodegib for children. In future research studies, they emphasized that children exposed to vismodegib should continue to be monitored for safety and efficacy.
The studies were performed as part of the Pediatric Brain Tumor Consortium, a multidisciplinary cooperative research organization devoted to the study of correlative tumor biology and new therapies for primary central nervous system tumors of childhood. The co-investigators hold positions at St. Jude Children’s Research Hospital, Memphis; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, N.C.; Center for Neuroscience Research, Children’s National Medical Center, Washington, D.C.; Ann & Robert Lurie Children’s Hospital of Chicago; Helen Diller Cancer Center, University of California, San Francisco; Texas Children’s Cancer Center, Houston; National Cancer Institute, Bethesda, MD; and Cincinnati Children’s Hospital.