Aggressive, defiant, disruptive, and antisocial behavior stems from externalizing behavior disorders, which are highly prevalent in school settings today.

The failure to address the emotional and behavioral problems of school-age children can have serious, life-changing ramifications, including poor grades, suspension and expulsion, and problems with the law later in life. Aggressive, defiant, disruptive, and antisocial behavior stems from externalizing behavior disorders, which are highly prevalent in school settings today.

Only 1 in 5 children with emotional and behavioral disorders receive mental health services, studies show, with low-income and ethnically diverse children lagging far behind their middle class, Caucasian counterparts. At the heart of this disparity is a shortage of specialized services in low-income communities, the high cost of these services, and the stigma attached to using such services for low-come minority families. Minority students in urban school districts are especially at risk due to the anxiety and deleterious effects of living in unsafe and deprived neighborhoods.

Unfortunately, evidence-based interventions are not successfully deployed in urban schools. Such interventions are all too often derailed by inadequate training and poor implementation by service providers in the school, and the lack of resources to contract with outside behavioral health providers.

The National Institute of Child Health and Human Development awarded Children’s Hospital a $3.1 million grant to study the level of support school personnel need to effectively implement an intervention program called School-Wide Positive Behavioral Interventions and Supports (SW-PBIS) for typically developing students as well as students with, or at risk for, externalizing or anxiety disorders.

SW-PBIS is a comprehensive service delivery strategy that combines universal and targeted interventions to address students’ emotional and behavioral issues can help improve overall school climate, perceived school safety, and student academic performance. The program focuses on preventing new cases of problem behaviors through school-wide discipline, classroom behavior management, and effective instructional practices.

The study will examine whether school personnel can implement the components of a two-tier SW-PBIS program.

The program emphasizes teaching all students key behavioral expectations and routines, and creating a proactive communication system for students and school staff. Children with or at risk for externalizing behavior problems or excessive anxiety will participate in group coping skills training.

Specifically, the study will examine whether school personnel can implement the components of a two-tier SW-PBIS program with the same level of fidelity, integrity and effectiveness when they receive a relatively low level of support from coaches and supervisors as they can with a high level of support.

Ricardo Eiraldi, PhD, is the principal investigator and program director of the Behavioral Health in Urban Schools Program (BHUSP). His line of research centers on addressing mental health services disparities by creating internal capacity for preventing and treating behavioral health disorders in urban schools. He and his team and the School District of Philadelphia have selected six schools in North Philadelphia for participation in the project. The schools will be randomly assigned to receive either a high level or a low level of training and consultation to implement SW-PBIS interventions over a five-year period.

Investigators will additionally study the impact of high and low levels of support on students’ mental health disparities and academic productivity, as well as the cost-effectiveness of the respective support levels.

“We know that school personnel can implement SW-PBIS with fidelity from a program development grant project we already conducted in two other schools located in the same area of the school,” Dr. Eiraldi said. “Now we would like to know how much support school personnel actually need in order to implement the program with fidelity and effectiveness.”

The School District of Philadelphia fully supports this project. Providing SW-PBIS strategies in school settings is ideal for identifying students with or at risk for externalizing and anxiety disorders, and for reducing service disparities because the program is available to all students. School-based services can be conveniently provided while children are attending school and often at little or no cost to their families. School-based services can also take advantage of existing infrastructure and behavioral health personnel. Finally, teachers and administrators in SW-PBIS schools spend less time to dealing with behavioral health problems.

The post Grant to Fund Behavioral Health Interventions in Philadelphia School District appeared first on CHOP Research Institute Blog.

Muscular dystrophy is a group of genetic disorders that causes muscle weakness and loss.

A new grant award will allow an investigator at The Children’s Hospital of Philadelphia to study the effectiveness of certain drugs called retinoid agonists in slowing or preventing muscle degeneration in individuals with muscular dystrophy. Findings from the study could lead to new, ground-breaking treatment for those individuals.

Muscular dystrophy is a group of genetic disorders that causes muscle weakness and loss. It causes progressive loss of muscle structure and muscle contractility, strength, and function. The disease is characterized by chronic inflammation, muscle cell death, the decrease and eventual exhaustion of satellite cells, and increase and infiltration of fat and fibrous tissue.

The human capacity to repair muscle is limited, however, resulting in an inexorable worsening of the disease over time. Current treatment options are limited to symptom management.

With a $405,000, three-year grant from the Muscular Dystrophy Association (MDA), Masahiro Iwamoto, PhD, DDS, a research scientist of the Translational Research Program in Pediatric Orthopaedics at Children’s Hospital and Research Associate Professor of Orthopedics at the University of Pennsylvania School of Medicine, will test his hypothesis that a retinoic acid receptor-gamma (RARg) agonist, a synthetic retinoid which selectively activates RARg could be used to slow and even stop the disease progression of muscular dystrophy.

Retinoic acid, an active form of vitamin A, plays an important role in the functioning of numerous organs, including musculoskeletal systems.

Retinoic acid, an active form of vitamin A, plays an important role in the functioning of numerous organs, including musculoskeletal systems. However, the clinical use of natural retinoids is limited to the treatment of certain malignant tumors and skin conditions due to side effects caused by the simultaneous activation of multiple retinoid receptors. To improve drug effectiveness and reduce side effects, synthetic receptor-specific retinoid agonists have been developed.

Dr. Iwamoto and his team recently discovered that a class of selective RARg agonist block the formation of bone within muscle and prevents muscle degeneration. The findings were part of his research into heterotopic ossification (HO), the pathological formation of ectopic bone within soft tissue, primarily skeletal muscles.

More than 10 percent of patients undergoing invasive surgeries can develop a form of HO and 65 percent of seriously wounded soldiers also develop the disease, which causes chronic pain, limited motion and other complications.

With the MDA grant, Dr. Iwamoto will build on his HO research to learn more about RARg properties and how the molecule contributes to the repair and maintenance of skeletal muscle.  An RARg agonist known as R667 has already shown some promise in the lab and has been tested in humans for other conditions. Dr. Iwamoto will test whether R667 has the potential for treating muscular dystrophy in mice without serious side effects.

The post Muscular Dystrophy Association Grant Could Lead to Ground-Breaking Treatment appeared first on CHOP Research Institute Blog.

The United States has a weight problem: according to the CDC, more than one-third of American adults are obese. Moreover, as of 2010 one-third of children were either overweight or obese, with the rates of obesity doubling in children and tripling in adolescents in the past thirty years. And some groups are more inclined to be obese than others, with non-hispanic blacks 51 percent more likely than whites to be obese, for example.

A recently published study may help researchers better understand why some populations are more susceptible to obesity than others. Struan Grant, PhD, associate director of The Children’s Hospital of Philadelphia’s Center for Applied Genomics (CAG), co-authored a study that discovered new loci associated with body mass index (BMI) in adults of African ancestry.

Previous genome-wide association studies had identified 36 BMI-associated loci. While those studies mainly investigated individuals of European descent, in the current study the researchers conducted a meta-analysis to determine whether more than 3.2 million single nucleotide polymorphisms were associated with BMI in men and women of African ancestry. In all, more than 70,000 men and women of African descent were studied.

In addition to Dr. Grant, Children’s Hospital’s Hakon Hakonarson, M.D., PhD, director of CAG, Brendan Keating, PhD, CAG lead clinical data analyst and Faculty member in UPenn Pediatrics and Surgery, and CAG bioinformatics specialist Jonathan Bradfield, also contributed and co-authored the study. More than 200 researchers representing over 50 institutions, including the Broad Institute, the National Human Genome Research Institute, and Johns Hopkins University, took part in the investigation. The study was published online recently in Nature Genetics.

The research group discovered two new loci — 5q33 and 7p15 — associated with BMI in people of African ancestry, , while a third, 6q16, was found to be suggestive of an association.

The research group discovered two new loci — 5q33 and 7p15 — associated with BMI in people of African ancestry, while a third, 6q16, was found to be suggestive of an association. “These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations,” the researchers say.

“Our sizeable genetic database of African American children played a crucial role in this study, lending further support to the loci initially detected in the adult cohorts” Dr. Grant added.

Children’s Hospital researchers have been associated with a number of previous investigations related to the current study, including one that identified genes associated with childhood obesity.

Last year CHOP investigators, as part of the Early Growth Genetics Consortium, helped identify two new gene variants that increase the risk of childhood obesity. After performing a meta-analysis of 14 previous studies, the study’s authors identified two novel loci and the suggestion of an association for two other gene variants, none of which had previously been implicated in obesity. CAG’s Struan Grant was the senior author of the study while Jonathan Bradfield acted as co-first author, which was published in Nature Genetics.

The current study’s findings, meanwhile, “demonstrate the importance of conducting genetic studies in diverse populations to identify new susceptibility loci for common traits,” the investigators note.

The post Study Identifies BMI-Associated Loci in Individuals of African Descent appeared first on CHOP Research Institute Blog.

This new model cell system will allow neuroscientists to investigate normal brain development, as well as to identify specific disruptions in biological signals that may contribute to neuropsychiatric diseases.

The research, conducted by scientists from The Children’s Hospital of Philadelphia and Memorial Sloan-Kettering Cancer Center, harnesses human embryonic stem cells, which differentiate into a broad range of different cell types. The investigators directed the stem cells into becoming cortical interneurons — a class of brain cells that, by releasing the neurotransmitter GABA, controls electrical firing in brain circuits.

“Interneurons act like an orchestra conductor, directing other excitatory brain cells to fire in synchrony,” said study co-leader Stewart A. Anderson, MD, a research psychiatrist at Children’s Hospital. “However, when interneurons malfunction, the synchrony is disrupted, and seizures or mental disorders can result.”

Dr. Anderson and his study co-leader Lorenz Studer, MD, of the Center for Stem Cell Biology at Sloan-Kettering, derived interneurons in a laboratory model that simulates how neurons normally develop in the human forebrain.

“Unlike, say, liver diseases, in which researchers can biopsy a section of a patient’s liver, neuroscientists cannot biopsy a living patient’s brain tissue,” said Dr. Anderson.

It is therefore important to produce a cell culture model of brain tissue for studying neurological diseases, he added. Significantly, the human-derived cells in the current study also “wire up” in circuits with other types of brain cells taken from mice, when cultured together. Those interactions, Dr. Anderson said, allowed the study team to observe cell-to-cell signaling that occurs during forebrain development.

Dr. Anderson and his colleagues are using their cell model to better define molecular events that occur during brain development. By selectively manipulating genes in the interneurons, they hope to better understand how gene abnormalities may disrupt brain circuitry and give rise to particular diseases.

Those studies could ultimately help inform drug development by identifying molecules that could offer therapeutic targets for more effective treatments of neuropsychiatric diseases.

The post Turning Stem Cells into Brain Cells Sheds Light on Neural Development appeared first on CHOP Research Institute Blog.

Please click image to enlarge.

Motor vehicle crashes remain the leading cause of death for children older than 4 years and resulted in 952 fatalities in 2010 for children age 15 and younger. Children and adolescents are the most common occupants in the rear seat of passenger vehicles, and a new research report from The Children’s Hospital of Philadelphia Research Institute provides specific recommendations for optimizing the rear seat to better protect them.

By bringing technologies already protecting front seat passengers to the rear seat and modifying the geometry of the rear seat to better fit this age group, the U.S. could achieve important reductions in serious injury and death, according to the report.

Kristy Arbogast, PhD, director of engineering at the Center for Injury Research and Prevention at CHOP, led the report, which reviewed the current science and data regarding rear seat occupant safety. The investigators found clear evidence that use of a child restraint system (CRS) is protective for younger children.

“However, older children who have outgrown child safety seats and booster seats are at greater risk of injury,” said Dr. Arbogast. “Many technologies that protect front seat passengers, such as load limiters and pretensioners, are not commonly found in the rear seat even though sled tests and computer modeling suggest that these seat belt features have the potential to reduce the risk of serious head and chest injury for rear seated occupants.”

In addition to front seat restraints, the researchers suggest that cues can be taken from booster seat design to determine how to keep kids who have outgrown boosters properly positioned in vehicle seat belts so the restraint can perform properly. They propose that adjustments to the geometry of the rear seat — including shorter seat cushions, lower seat belt anchorages and contoured seats — could increase comfort, keep the shoulder belt in position and, in side impact crashes, reduce lateral movement.

“For children under age 13, the rear seat is still the safer seating position as compared to the front seat of passenger vehicles,” said Dr. Arbogast. “But we can do a better job at protecting children who have outgrown add-on restraints.”

The report authors recommend the development of regulatory procedures or vehicle performance assessment programs for consumers that evaluate protection of rear seat occupants. Common vehicle rating systems do not evaluate the safety of rear seat occupants in frontal crashes. In addition to engineering solutions, the report also recommends policies and programs to increase rear seat restraint use, which remains lower than front seat restraint use and is a key risk factor for dying in a crash. Additional research is needed to further inform these priorities.

The full report (in PDF form) is available here, and made possible with support from Global Automakers. Additional materials, including a one-page overview of CIRP’s recommendations, are available at http://injury.research.chop.edu.

The post Report Recommends Changes to Best Protect Children in Car Crashes appeared first on CHOP Research Institute Blog.

Researchers from The Children’s Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, along with colleagues at the Botswana-Baylor Children’s Clinical Centre of Excellence, conducted the first large-scale comparison the two drugs, efavirenz and nevirapine. The investigators found efavirenz more effective in suppressing the virus in children ages 3 to 16.

However, the less effective nevirapine is currently used much more often in countries with a high prevalence of HIV. The results of the study of more than 800 children were published recently in the Journal of the American Medical Association.

There are more than 3 million HIV-positive children in the world, with more than 90 percent of them live in sub-Saharan Africa. Currently, the World Health Organization recommends both efavirenz and nevirapine for first-line pediatric use in resource-limited settings like sub-Saharan Africa.

Lead author Elizabeth Lowenthal, MD, MSCE, of Children’s Hospital, said this study has the potential to change the standard of care in the parts of the world where most HIV-infected children live. “Because nevirapine costs less than efavirenz and is more widely available in pediatric formulations, it is currently the more frequent choice for initial treatment in these children. However, our study suggests that efavirenz produces better outcomes,” she said.

Senior author Robert Gross, MD, MSCE, an associate professor of Infectious Diseases and Epidemiology at Penn Medicine, adds, “Given this evidence, it is very reasonable to adjust pediatric HIV treatment guidelines. However, as we move towards such changes, more work should be done to make efavirenz a more financially viable option for children on anti-retroviral therapy in these resource-limited settings.”

Previous studies favoring efavirenz over nevirapine in adults have resulted in treatment guidelines for adults in many countries, including a few in resource-limited settings, to recommend the use of efavirenz over nevirapine. “In these low-resource settings, Non-Government Organizations typically work with countries’ medical programs to forecast their HIV-related drug needs and lobby companies to lower prices for bulk purchases,” explained Dr. Lowenthal. “Through such programs, drugs that were once more expensive can become cost-effective.”

Drs. Lowenthal and Gross applauded the work that the government of Botswana has done to both bring high-quality HIV treatment to its citizens and to facilitate the generation of knowledge to help improve treatment options.

“Botswana has been extremely supportive of clinical trials and epidemiological studies, and is very forward thinking in its willingness to inform the world,” they said. “For such a small country, the amount of research that comes out of Botswana on HIV and tuberculosis is tremendous, which has not only benefitted their public health, but public health for all.”

The post CHOP, Penn Study Shows Less-Used HIV Drug More Effective for Infected Children appeared first on CHOP Research Institute Blog.

The corrective gene is injected into the eyes of adult and pediatric study subjects.

A groundbreaking clinical trial of gene therapy for a form of congenital blindness, sponsored by The Children’s Hospital of Philadelphia in collaboration with Penn Medicine, was recently recognized with the Distinguished Clinical Research Achievement Award from the Clinical Research Forum, an organization of clinical research centers, industry, and volunteer groups.

Based in Washington, D.C., the Clinical Research Forum (CRF) provides “leadership to the national clinical and translational research enterprise,” and promotes “understanding and support for clinical research and its impact on health.”

That recent award given to CHOP and Penn is the second highest in the CRF’s annual Top 10 Clinical Research Achievement Awards. Recognizing studies published in 2012, the CRF focused on a Feb. 2012 article in Science Translational Medicine, co-authored by researchers from CHOP and the Perelman School of Medicine at the University of Pennsylvania. The authors reported on the most recent phase of a clinical trial for Leber’s congenital amaurosis, a rare retinal disease that progresses to total blindness by adulthood.

The study team reported on further improvements in vision in three adult patients previously treated in one eye who then received the same innovative gene therapy in the second eye.

This Leber’s congenital amaurosis research is an ongoing collaboration among Jean Bennett, MD, PhD, F.M. Kirby professor of Ophthalmology at the University of Pennsylvania School of Medicine, CHOP’S Katherine A. High, MD, director of the Center for Cellular and Molecular Therapeutics (CCMT), and Albert M. Maguire, MD, of Penn Medicine and CHOP.

Dr. High, a pioneering gene therapy researcher, directs the CCMT, which is sponsoring the clinical trial in Leber’s congenital amaurosis, and which manufactured the genetically engineered virus used to carry the therapeutic gene. Dr. Maguire, a retina specialist, injected the corrective gene into the eyes of adult and pediatric study subjects at Children’s Hospital.

As widely reported in October 2009, this clinical trial of gene therapy achieved dramatic results in children with LCA. Building on their previous work, the research team is now conducting the first Phase 3 gene therapy study for genetic disease in the U. S. This is also the world’s first Phase 3 gene therapy study for a non-lethal disorder. If successful, it could lead to the first approved gene therapy product in the United States.

The post CHOP, Penn Gene Therapy Trial for Blindness Honored appeared first on CHOP Research Institute Blog.

In addition to serving as leaders in their respective fields, many of the investigators at The Children’s Hospital of Philadelphia Research Institute help pave the way for the next generation of researchers and physician-scientists through mentoring and teaching activities. A pediatric cardiologist at Children’s Hospital was recently recognized for his teaching efforts by the American College of Cardiology (ACC).

Pediatric cardiologist Paul M. Weinberg, MD, FAAC, received the 2013 Distinguished Teacher Award at the American College of Cardiology’s national conference, called ACC.13, on March 11 in San Francisco.

The annual award recognizes a fellow of the ACC for “innovative, outstanding teaching characteristics and compassionate qualities” resulting in “major contributions to the field of cardiovascular medicine at the national and/or international level.”

Dr. Weinberg has served as director of the Fellowship Training Program in Pediatric Cardiology at Children’s Hospital for the past 22 years, a position that has allowed him to exert significant influence on innumerable pediatric cardiologists and cardiac surgeons. Dr. Weinberg conducts weekly teaching conferences on cardiac structure and has frequently lectured on that topic at national and international meetings. He has made extensive contributions to the scientific literature, including numerous chapters in prominent cardiology textbooks.

A member of the CHOP medical staff since 1977, Dr. Weinberg also is a professor of Pediatrics and of Pediatric Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania.

He has previously received the Robert Dunning Drips Award for excellence in graduate medical education from Penn, the Blockley-Osler Teaching Award, and a Teacher of the Year Award from Children’s Hospital. His other honors include the CHOP Cardiac Center Alumni Achievement Award and the Jefferson Medical College Alumni Achievement Award.

Additional details about the award, and presentations at the ACC conference on new research findings by other CHOP cardiologists are available here.

The post CHOP Cardiologist Receives Major Teaching Award at American College of Cardiology Conference appeared first on CHOP Research Institute Blog.

A new genetic study may shed light on the causes of the rare childhood disease biliary atresia. The leading cause of liver transplantation in children, biliary atresia (BA) is a rare, life-threatening condition in which the ducts that carry bile from the liver to the gallbladder become blocked.

Children’s Hospital’s Randy Matthews, MD, PhD, led this new collaborative genetic study of BA, a condition occurring exclusively in neonatal livers. A relatively rare disease, BA affects approximately one out of every 15,000 infants, and is more common in Asians and African Americans. If left untreated, BA can lead to liver damage and cirrhosis of the liver, and patients with BA often require liver transplants.

The study’s publication, in the May 2013 issue of Gastroenterology, coincides with Children’s Hospital’s 9^th annual Biliary Atresia Education Day. Scheduled this year for Sunday, April 28, from 1 to 5 pm in CHOP’s Abramson Research Center, BA education day is free for healthcare professionals and families of children with BA, and “features speakers on a variety of topics related to biliary atresia treatment and research, as well as tips to improve day-to-day living with the disease.”

With this study, Dr. Matthews and other CHOP researchers, including Nancy B. Spinner, PhD, hoped to better understand BA’s etiology, which, while still poorly understood, is “believed to involve exposure of a genetically susceptible individual to certain environmental factors.” Both Drs. Matthews and Spinner are members of Children’s Hospital’s Fred and Suzanne Biesecker Pediatric Liver Center.

“Despite recent inroads into the understanding the mechanisms leading to fibroinflammatory damage to the biliary tree, uncovering the cause of BA continues to be a major challenge,” Dr. Matthews noted. Because BA is so rare, and because there have been few documented cases showing clear familial inheritance, studies into the condition’s possible genetic causes have been difficult, Dr. Matthews said.

Studies of other possible BA-associated genes are currently underway in the Spinner lab, and Dr. Matthews noted that any future investigations into BA’s causes — and possible treatments — would make use of that work.

After searching for copy number variations (CNVs) — losses or gains in DNA sequence — in patients with BA compared to healthy individuals, Dr. Spinner and her team identified a candidate gene, GPC1. Moving to an animal model, Dr. Matthews and his team then studied reducing the expression of gpc1 in zebrafish, a type of tropical freshwater fish commonly used in scientific and medical studies.

The researchers showed that disruption of gpc1 (as the gene is known in zebrafish) led to biliary defects in zebrafish. This finding, combined with the fact that the investigators also found “GPC1 abnormalities in all BA patient liver samples examined,” support “a potential role for GPC1 as a susceptibility gene for BA,” Dr. Matthews said.

This study builds on previous work by Dr. Spinner’s lab, which associated a region of chromosome 2 with BA. Studies of other possible BA-associated genes are currently underway in the Spinner lab, and Dr. Matthews noted that any future investigations into BA’s causes — and possible treatments — would make use of that work.

While “the ability to test infants for genetic susceptibility to BA is clearly far off,” future studies that shed light on biliary atresia’s pathogenesis could help “identify treatments that are more effective than the existing therapy,” Dr. Matthews said. That said, once tests for BA genetic susceptibility are developed, they will likely include testing for GPC1 defects, he added.

To learn more about Children’s Hospital’s liver disease services and research, see the Fred and Suzanne Biesecker Pediatric Liver Center. For more information about Biliary Atresia Education day see the Hospital’s website, or email Jessi Erlichman, MPH, coordinator of the Liver Center.

The post Genetic Study Offers Clues About Rare Liver Disease Biliary Atresia appeared first on CHOP Research Institute Blog.

Astrocytoma,a low-grade glioma, is the most common type of brain tumor in children.

A new genetic study offers glimpses into how scientists might use gene-sequencing data to customize pediatric patients’ cancer treatments. While investigating the biology of brain tumors in children, researchers at The Children’s Hospital of Philadelphia found that crucial differences in how genes are mutated in a tumor may call for different treatments.

“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 co-first author, Angela J. Sievert, MD, MPH, an oncologist in Children’s Hospital’s Cancer Center. The study was published recently in the Proceedings of the National Academy of Sciences.

The study 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, and others may recur. So pediatric oncologists have been seeking better treatment 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 frequently mutated genes in human cancers. Because the same gene is also mutated in certain adult cancers, the pediatric researchers were able to make use of recently developed drugs known as BRAF inhibitors that were already being tested in adults.

Reaffirming Cancer’s Complexity

Dr. 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 Dr. Sievert. However, follow-up studies in animal models were initially disappointing.

In addition, the current study provided another example of the complexity of cancer: in the same gene, different mutations were found to behave differently. Moreover, drugs were not found to be universally effective. For example, some BRAF inhibitors that were effective in BRAF-driven adult melanomas made brain tumors worse, via an effect called paradoxical activation.

But by examining the molecular mechanisms behind drug resistance and working with the pharmaceutical industry, Dr. Sievert and her colleagues identified a new, experimental second-generation BRAF inhibitor that did not cause the paradoxical activation in the cell cultures and animal models.

This new 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 Dr. Sievert.

“For years, astrocytomas have been lumped together based on similar appearance to pathologists studying their structure, cell shape and other factors,” said 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. “But our current discoveries show that the genetic and molecular structure of tumors provides more specific information in guiding oncologists toward customized treatments.”

To learn more about this study, see the full press release here.

The post Genetic Study Suggests Fine-Tuning Drugs for Pediatric Brain Tumors appeared first on CHOP Research Institute Blog.