Genetic Study Suggests Fine-Tuning Drugs for Pediatric Brain Tumors

A new genetic study offers glimpses into how scientists might use gene-sequencing data to customize pediatric patients’ cancer treatments. While investigating the biology of brain tumors in children, researchers at The Children’s Hospital of Philadelphia found that crucial differences in how genes are mutated in a tumor may call for different treatments. “

By better understanding the basic biology of these tumors, such as how particular mutations in the same gene may respond differently to targeted drugs, we are moving closer to personalized medicine for children with cancer,” said the study’s co-first author, Angela J. Sievert, MD, MPH, an oncologist in Children's Hospital's Cancer Center. The study was published recently in the Proceedings of the National Academy of Sciences.

The study focused on a type of astrocytoma, the most common type of brain tumor in children. When surgeons can fully remove an astrocytoma (also called a low-grade glioma), a child can be cured. However, many astrocytomas are too widespread or in too delicate a site to be safely removed, and others may recur. So pediatric oncologists have been seeking better treatment options — ideally, a drug that can selectively and definitively kill the tumor with low toxicity to healthy tissue.

The current study focuses on mutations in the BRAF gene, one of the most frequently mutated genes in human cancers. Because the same gene is also mutated in certain adult cancers, the pediatric researchers were able to make use of recently developed drugs known as BRAF inhibitors that were already being tested in adults.

Reaffirming Cancer’s Complexity

Dr. Sievert and her colleagues at Children’s Hospital were among several research groups who reported almost simultaneously in 2008 and 2009 that mutations in the BRAF gene were highly prevalent in astrocytomas in children.

“These were landmark discoveries, because they suggested that if we could block the action of that mutation, we could develop a new, more effective treatment for these tumors,” said Dr. Sievert. However, follow-up studies in animal models were initially disappointing.

In addition, the current study provided another example of the complexity of cancer: in the same gene, different mutations were found to behave differently. Moreover, drugs were not found to be universally effective. For example, some BRAF inhibitors that were effective in BRAF-driven adult melanomas made brain tumors worse, via an effect called paradoxical activation.

But by examining the molecular mechanisms behind drug resistance and working with the pharmaceutical industry, Dr. Sievert and her colleagues identified a new, experimental second-generation BRAF inhibitor that did not cause the paradoxical activation in the cell cultures and animal models.

This new work result lays a foundation for multicenter clinical trials to test the mutation-specific targeting of tumors by this class of drugs in children with astrocytomas, said Dr. Sievert.

“For years, astrocytomas have been lumped together based on similar appearance to pathologists studying their structure, cell shape and other factors,” said Adam C. Resnick PhD, the senior author of the current paper and principal investigator of the astrocytoma research team in the Division of Neurosurgery at Children’s Hospital. “But our current discoveries show that the genetic and molecular structure of tumors provides more specific information in guiding oncologists toward customized treatments.”

To learn more about this study, see the full press release here.