Genetic pathways may suggest more effective targeted therapies for childhood brain tumors
Pediatric researchers investigating the biology of brain tumors in children are finding that crucial differences in how the same gene is mutated may call for different treatments. A new study offers glimpses into how scientists will be using the ongoing flood of gene-sequencing data to customize treatments based on very specific mutations in a child's tumor.
"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 first author, Angela J. Sievert, MD, MPH, an oncologist in the Cancer Center at The Children's Hospital of Philadelphia in Pennsylvania.
The study, performed in cell cultures and animals, 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's cancer can be cured. However, many astrocytomas are too widespread or in too delicate a site to be safely removed. Others may recur. So pediatric oncologists have been seeking better options—ideally, they want a drug that can selectively and definitively kill the tumor with low toxicity to nearby healthy tissue.
The current study focuses on mutations in the BRAF gene, one of the most commonly mutated genes in human cancers. The study was published in the Proceedings of the National Academy of Sciences (2013; doi:10.1073/pnas.1219232110). Because the same gene is also mutated in certain adult cancers, such as melanoma, the pediatric researchers were able to make use of recently developed drugs, BRAF inhibitors, which were already being tested with some success against melanoma in adults.
This study provides another example of the complexity of cancer: in the same gene, different mutations behave differently. Previous work found that mutations in the BRAF gene were highly prevalent in astrocytomas in children. However, follow-up studies in animal models were initially disappointing. BRAF inhibitors that were effective in BRAF-driven adult melanomas made brain tumors worse via an effect called paradoxical activation.
Further investigation revealed how tumor behavior depended on which type of BRAF mutation was involved. The first-generation drug that was effective in adult melanoma acted against point mutations in BRAF called V600E alterations. However, in most astrocytomas the mutation in the BRAF gene was different; it produced a fusion gene, designated KIAA1549-BRAF. When used against the fusion gene, the first-generation drug activated a cancer-driving biological pathway, the MAPK signaling cascade, and accelerated tumor growth.
"For years, astrocytomas have been lumped together based on similar appearance to pathologists studying their structure, cell shape, and other factors," said senior author Adam C. Resnick, PhD. "But our current discoveries show that the genetic and molecular structure of tumors provides more specific information in guiding oncologists toward customized treatments."