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Better treatments possible for child brain cancer

More than 4,000 children and teens are diagnosed with brain cancer yearly, killing more children than any other cancer. Researchers targeted an aggressive pediatric brain tumor — CNS-PNET — using a zebrafish model. And, in about 80% of cases, eliminated the tumor using existing drugs.


Writing in the journal Cell Reports, researchers at Huntsman Cancer Institute (HCI) at the University of Utah report they have identified an existing group of drugs that appear to reduce or eliminate a certain subgroup of childhood brain cancers while sparing normal brain tissue.


"For many pediatric brain tumors no cell or animal model exist to test targeted, or personalized, medications that could significantly improve survival and alleviate the harmful side effects of conventional therapies.

"Indeed, children with rare brain tumors have few options for life-saving treatment. Our hope is by creating this animal model we will be a step closer to finding effective therapies."


Rodney Stewart PhD, Assistant Professor, Department of Oncological Sciences, University of Utah, USA, an HCI investigator.


The researchers studied a particularly aggressive pediatric brain tumor, known as primitive neuroectodermal tumors of the central nervous system (CNS-PNET) for which few animal or cell line models exist. Without an animal model or cell lines, Stewart explained, treatments could not be tested. Over the course of seven years, Stewart and his team worked to develop a model which, at the genomic level, closely modeled the human condition they hoped to study.

"We spent a lot of time comparing brain tumors arising in fish with related human brain cancers at the molecular genetic level," Stewart says. "This is important because these childhood brain cancers are rare and as a result, there are few patient samples to study for comparisons."

Human tissue samples were necessary, however, in order to construct a reliable model. "We needed to reach out to several groups," he explains, including Primary Children's Hospital in Salt Lake City and The Hospital for Sick Children in Toronto.

Dr. Stewart credits discoveries announced by two other groups studying similar cancers that opened the way for his group to move forward. "They were able to re-classify CNS-PNET tumors into distinct subgroups at the molecular level. That opened up a new avenue for our team because that stratification made it possible for us to really nail down what the zebrafish brain tumor model represents."

Using the model, Stewart's lab was able to test already existing compounds to see if they could find a targeted therapy that would work on one of the newly identified subgroups: the oligoneural or NB_FOXR2 CNS-PNET subgroup. Through work they had done to create the tumor model, they knew that a particular drug already in human clinical trials might work.


"When we treated the fish with MEK inhibitors — drugs that inhibit an enzyme — they exhibited a remarkable response.

"Not only was the tumor burden reduced, it completely eliminated the tumor in about 80% of the fish and those tumors have not come back.

"This is a durable response from a transient treatment. It's what we look for in cancer therapy, an effective drug that can be taken for a certain amount of time but, after the cancer is gone, patients can stop taking the drug and go on living their lives."


Rodney Stewart PhD


Stewart is careful to emphasize that while the brain tumor type between fish and humans is similar, more studies are needed to determine if the results can be translated into the clinic. He would like to see his discovery in the hands of physicians as soon as possible.

Stewart: "Currently, the outcome for children with these cancers is deplorable. We don't want to wait much longer."

Abstract Highlights
•Subsets of CNS-PNETs express oligodendrocyte precursor cell genes SOX10 and OLIG2
•Activating NRAS/MAPK signaling in OPCs generates CNS-PNET-like tumors in zebrafish
•Cancer genomes of zebrafish and human NB-FOXR2 CNS-PNETs are highly conserved
•MEK inhibitors are identified as a potential treatment for oligoneural/NB-FOXR2 CNS-PNETs

Summary
Malignant brain tumors are the leading cause of cancer-related deaths in children. Primitive neuroectodermal tumors of the CNS (CNS-PNETs) are particularly aggressive embryonal tumors of unknown cellular origin. Recent genomic studies have classified CNS-PNETs into molecularly distinct subgroups that promise to improve diagnosis and treatment; however, the lack of cell- or animal-based models for these subgroups prevents testing of rationally designed therapies. Here, we show that a subset of CNS-PNETs co-express oligoneural precursor cell (OPC) markers OLIG2 and SOX10 with coincident activation of the RAS/MAPK (mitogen-activated protein kinase) pathway. Modeling NRAS activation in embryonic OPCs generated malignant brain tumors in zebrafish that closely mimic the human oligoneural/NB-FOXR2 CNS-PNET subgroup by histology and comparative oncogenomics. The zebrafish CNS-PNET model was used to show that MEK inhibitors selectively eliminate Olig2+/Sox10+ CNS-PNET tumors in vivo without impacting normal brain development. Thus, MEK inhibitors represent a promising rationally designed therapy for children afflicted with oligoneural/NB-FOXR2 CNS-PNETs.

This study was done in partnership with collaborators at HCI including University of Utah faculty from the departments of pediatrics, pathology, neurosurgery, and oncological sciences; ARUP laboratories, Primary Children's Hospital, Salt Lake City; and the Hospital for Sick Children, Toronto. Funding for this work was provided by the Canadian Institute of Health Research, the American Cancer Society, National Institute of Health NIH P30 CA042014, and the Huntsman Cancer Foundation.

About Huntsman Cancer Institute at the University of Utah
Huntsman Cancer Institute (HCI) is one of the world's top academic research and cancer treatment centers. HCI manages the Utah Population Database -- the largest genetic database in the world, with more than 16 million records linked to genealogies, health records, and vital statistics. Using this data, HCI researchers have identified several cancer-causing genes, including the genes responsible for melanoma, colon and breast cancer. HCI is a member of the National Comprehensive Cancer Network (a 27-member alliance of the world's leading cancer centers) and is a National Cancer Institute-Designated Comprehensive Cancer Center. HCI treats patients with all forms of cancer and operates several high-risk clinics that focus on melanoma and breast, colon, and pancreas cancers. The HCI Cancer Learning Center for patient and public education contains one of the nation's largest collections of cancer-related publications. The institute is named after Jon M. Huntsman, a Utah philanthropist, industrialist, and cancer survivor.

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Nov 9, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



Anatomy of the inside of the brain, showing the cerebrum, cerebellum,
brain stem, spinal cord, optic nerve, hypothalamus, and other parts of the brain.

Image Credit:
National Cancer Institute Childhood Central Nervous System Embryonal Tumors Treatment (PDQ®)–Patient Version


 


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