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.
Sievert, working with co-first author Shih-Shan Lang, MD, in the translational laboratory of neurosurgeon Phillip Storm, MD, and Adam Resnick, PhD, published a study ahead of print today in the Proceedings of the National Academy of Sciences.
Studying mutation behavior in the BRAF gene in astrocytoma
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 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, 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 commonly mutated genes in human cancers. 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.
The current study provides another example of the complexity of cancer: in the same gene, different mutations behave differently. 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 Sievert.
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.
Newly identified second-generation BRAF inhibitor disrupted cancer-promoting signals without adverse effects
By examining the molecular mechanisms behind drug resistance and working with the pharmaceutical industry, the current study’s investigators identified a new, experimental second-generation BRAF inhibitor that disrupted the cancer-promoting signals from the fusion gene, and did not cause the paradoxical activation in the cell cultures and animal models.