Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

Details of Gene Pathways Suggest Fine-Tuning Drugs for Child Brain Tumors

Published: Thursday, March 28, 2013
Last Updated: Thursday, March 28, 2013
Bookmark and Share
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.

Results lay foundation for multicenter clinical trials

This preclinical 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 Sievert. As this effort progresses, it will benefit from CHOP’s commitment to resources and collaborations that support data-intense research efforts.

The direction of brain tumor research over the past several years reflects some of those data-driven advances, says 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. “For years, astrocytomas have been lumped together based on similar appearance to pathologists studying their structure, cell shape and other factors,” said Resnick. “But our current discoveries show that the genetic and molecular structure of tumors provides more specific information in guiding oncologists toward customized treatments.”

Earlier this year, Children’s Hospital announced its collaboration with the gene-sequencing organization BGI-Shenzhen in performing next-generation sequencing of pediatric brain tumors at the Joint Genome Center, BGI@CHOP. The center’s sophisticated, high-throughput sequencing technology will greatly speed the discovery of specific gene alterations involved in childhood brain cancers.

This genomic discovery program dovetails with the work of the Childhood Brain Tumor Tissue Consortium, a multi-institutional collaboration recently launched by CHOP, with support from the Children’s Brain Tissue Foundation. Because even large research centers may not hold enough tumor tissue specimens to power certain research, the consortium pools samples from a group of institutions, providing an important scientific resource for cooperative studies.

“The better we understand the mutational landscape of tumors, the closer we’ll be to defining therapies tailored to a patient’s specific subtype of cancer,” added Resnick.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,600+ scientific posters on ePosters
  • More than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Scientific News
New Gene Therapy for Vision Loss From a Mitochondrial Disease
NIH-funded study shows success in targeting mitochondrial DNA in mice.
Five New Genetic Variants Linked to Brain Cancer Identified
The biggest ever study of DNA from people with glioma – the most common form of brain cancer – has discovered five new genetic variants associated with the disease.
Predictive Model for Breast Cancer Progression
Biomedical engineers have demonstrated a proof-of-principle technique that could give women and their oncologists more personalized information to help them choose options for treating breast cancer.
Fatty Liver Disease and Scarring Have Strong Genetic Component
Researchers say that hepatic fibrosis, which involves scarring of the liver that can result in dysfunction and, in severe cases, cirrhosis and cancer, may be as much a consequence of genetics as environmental factors.
Specific Variations in RNA Splicing Linked to Breast Cancer
Researchers have identified cellular changes that may play a role in converting normal breast cells into tumors. Targeting these changes could potentially lead to therapies for some forms of breast cancer.
Finding Links and Missing Genes
A catalogue of large-scale genetic changes around the world.
Scientists Test New Gene Therapy for Vision Loss from a Mitochondrial Disease
NIH-funded study shows success in targeting mitochondrial DNA in mice.
Gene Expression: A Snapshot of Stem Cell Development
New genes found that regulate development of stem cells.
Assessing Cancer Patient Survival and Drug Sensitivity
RNA editing events another way to investigate biomarkers and therapy targets.
A Natural History of Neurons
Diverse mutations reveal lineage of brain cells.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos