Navigation Links
Details of gene pathways suggest fine-tuning drugs for child 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, M.D., M.P.H., an oncologist in the Cancer Center at The Children's Hospital of Philadelphia.

Sievert, working with co-first author Shih-Shan Lang, M.D., in the translational laboratory of neurosurgeon Phillip Storm, M.D., and Adam Resnick, Ph.D., published a study ahead of print today in the Proceedings of the National Academy of Sciences.

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 worsevia 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.

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.

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, Ph.D., 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.

Contact: John Ascenzi
Children's Hospital of Philadelphia

Related medicine news :

1. Report Details Steps to Boost Patient Safety
2. ANY LAB TEST NOW®’s Terri McCulloch Details the Misconceptions about Drug and DNA Testing to Legal Investigators
3. New details on the molecular machinery of cancer
4. Scans Show Details of Damage to Soldiers With Head Injuries
5. Institute of Medicine report details for monitoring safety of childhood immunization schedule
6. IOM report details strategy for monitoring safety of childhood immunization schedule
7. MyPuress Releases Details About Groundbreaking New Product
8. Report Details Start of Steroid Meningitis Outbreak
9. Study details bullying involvement for adolescents with autism spectrum disorder
10. Stanford/Intel study details power of new chip to diagnose disease, analyze protein interactions
11. Researchers unveil molecular details of how bacteria propagate antibiotic resistance
Post Your Comments:
(Date:12/1/2015)... ... December 01, 2015 , ... For the millions of people ... Incorporated has launched the VaPro Plus Pocket™ touch free hydrophilic intermittent catheter. “Hollister ... free catheter portfolio,” said Michael Gresavage, Vice President North America. "We designed our ...
(Date:12/1/2015)... ... December 01, 2015 , ... Lutronic, a leading innovator of aesthetic and ... to the devices for sale in the United States. Clarity is a Superior ... nm Nd:YAG lasers, into a single platform that is easy to own and operate. ...
(Date:12/1/2015)... ... December 01, 2015 , ... With FCPX Overlay: Grit ... full control over customization, the possibilities are truly endless, all with a click of ... depth position, vertical flip, horizontal flip, depth of field and more, all within Final ...
(Date:11/30/2015)... , ... November 30, 2015 , ... ... engine optimization companies, announced today that it has officially launched a sleek, mobile-ready ... SEO, explained that his company’s new website clearly outlines the benefits that its ...
(Date:11/30/2015)... NY (PRWEB) , ... December 01, 2015 , ... ... a 2015-2016 inductee into its VIP Woman of the Year Circle. She is recognized ... nation’s leading networking organization exclusively for professional women, boasting more than 850,000 members and ...
Breaking Medicine News(10 mins):
(Date:12/1/2015)... , Dec. 01, 2015 ... of the "Medical Alert Systems/Personal Emergency Response ... by Geography - Global Forecas" report to ... announced the addition of the "Medical Alert ... by End-User and by Geography - Global Forecas" ...
(Date:12/1/2015)... 2015 ) ... Delivery Technology Market 2015 - Forecast to 2020" ... ) has announced the addition of the ... to 2020" report to their offering. ... has announced the addition of the "Drug ...
(Date:12/1/2015)... and UPPSALA, Sweden , December 1, ... selected by the International Breast Cancer Study Group (IBCSG, ... Brussels ) to be part of a ... a promising new cancer drug.  --> ... with advanced breast cancer being treated with anti-hormonal therapy in ...
Breaking Medicine Technology: