Tag Archive for: pediatric brain tumor

cancer cells

Advancing immunotherapy for pediatric brain tumors

cancer cells

While immunotherapy has revolutionized cancer treatments, its efficacy remains relatively undefined in pediatric settings for brain tumors.

While immunotherapy has revolutionized cancer treatments, its efficacy remains relatively undefined in pediatric settings for brain tumors. Children’s National Hospital experts and other institutions argue in a review published in Nature Cancer that there is a need for closer collaborations between academia, industry partners, regulatory bodies and funders to progress the field.

Eugene Hwang, M.D., associate division chief of Oncology and neuro-oncologist at Children’s National, led the review that outlines immunotherapeutic hurdles and simultaneously proposes next steps for immunotherapy use in these patients. These considerations will aid pediatric oncologists make better recommendations and advances in this type of treatment.

“The promise of immunotherapy in helping to cure children with brain tumors is exciting,” Dr. Hwang said. “This type of approach has already revolutionized treatments for many different kinds of cancer, and a comprehensive review of this complicated arena, especially by leading voices in the field, can help set the stage for finally moving the needle for these patients.”

The review is especially helpful as children harbor unique elements of immunity and the brain presents distinct obstacles to immune attack that are not present in other cancers. For example, there are challenges in antigen identification, the blood-brain barrier and the tumor microenvironment. For many pediatric cancer doctors as well this novel, complex form of therapy is outside of their historical training.

To overcome these challenges, the authors encourage philanthropic organizations and patient advocacy groups to be part of the process that can help fill funding gaps in patient-focused pre-clinical and clinical research and educate patients and families.

“Multiple stakeholders around pediatric brain cancer immunotherapy must be mobilized in a concerted fashion,” Hawk et al. argue in the piece. “The need for close academic collaboration with industry partners and regulatory bodies is increasingly apparent given the unique pediatric phenotypes and complex outcomes in immunotherapeutic trials, and progress will be made at the interface of the interactions of all these key stakeholders.”

The group of internationally renowned pediatric brain tumor-focused immunotherapy experts comprehensively reviewed the advances in the major modalities of immunotherapy and the landscape of preclinical modeling for these patients to date.

Investigators at Children’s National, for example, are leading several national and international trials involving immunotherapy which have spurred international meetings with a focus in childhood brain tumor immunotherapies.

“The multiple T cell trials led by Children’s National are perfect examples of truly field-leading innovative immunotherapy, as are the other trials that are led by our own investigators,” Dr. Hwang added.

Jia-Ray Yu

Virginia Tech announces cancer biologist to launch lab at Children’s National Research & Innovation Campus

Jia-Ray Yu

Jia-Ray Yu, Ph.D., will be an assistant professor at Virginia Tech’s Fralin Biomedical Research Institute at Virginia Tech Carilion and in the Department of Biomedical Sciences and Pathobiology in the Virginia-Maryland College of Veterinary Medicine, as well as an adjunct assistant professor at Children’s National Hospital starting Sept. 1.

Every year, 790 Americans are diagnosed with a rare and deadly form of brain cancer called a diffuse midline glioma, according to the National Cancer Institute. Tragically, only 2% of children with this disease will survive five years.

Jia-Ray Yu, Ph.D., a new assistant professor joining the Fralin Biomedical Research Institute at Virginia Tech Carilion and the Department of Biomedical Sciences and Pathobiology on Sept. 1, studies these fast-growing, treatment-resistant brain tumors, which commonly affect children, with hopes of identifying new therapeutic approaches. Yu will be the first of several cancer researchers to work in Virginia Tech’s brand-new research facility on the Children’s National Research & Innovation Campus in Washington, D.C.

“This disease is fatal and there is no cure. Any hint at a potential therapeutic pathway could be helpful,” said Yu, who will also hold an adjunct faculty position in the Children’s National Hospital Center for Cancer and Immunology Research.

Michael Friedlander, Virginia Tech’s vice president for health sciences and technology, and executive director of the Fralin Biomedical Research Institute, led Yu’s recruitment.

“Jia-Ray Yu is one of the rising leaders in understanding the molecular substrates of aggressive forms of pediatric brain cancer that can contribute to the identification of innovative therapeutic approaches. Moreover, his fundamental research into chromatin remodeling is at the very forefront of this area of emerging area importance in molecular biology,” Friedlander said. “We are very fortunate to have been able to attract Dr. Yu to Virginia Tech as we grow our greater cancer research community and our partnership with one of the nation’s pre-eminent children’s health care delivery and research systems, Children’s National Hospital.”

Yu studies how genes change when an ordinary brain cell develops malignant traits.

In particular, he examines changes in proteins called histones that spool strands of DNA molecules into a substance called chromatin, which forms chromosomes. In addition to packing genetic material into cells, these structures also play a key role in telling genes when to turn on or off.

Faulty histone proteins alter the chromatin’s structure, which in turn garbles the genetic instructions that regulate a cell’s behavior, growth rate, and identity. Furthermore, when this defective cell divides, its two daughter cells inherit the original cell’s chromatin, the malignant traits are passed on, and the cancer grows.

“These epigenetic features of chromatin are distinct from the DNA itself, yet they are inherited during cellular division,” said Yu.

Yu said 80% of tumors from diffuse midline gliomas begin with one cell that has a histone gene defect. He found when this tiny piece of a specific histone, called H3K27, stops working properly, it creates a series of domino-like reactions that cause normal cells to become cancerous.

Yu recently examined this molecular cascade as a postdoctoral fellow in the lab of Danny Reinberg, Terry and Mel Karmazin Professor in the NYU Grossman School of Medicine Department of Biochemistry and Molecular Pharmacology, and senior Howard Hughes Medical Institute Investigator.

The research team identified two genes, NSD1 and NSD2, appear to be the molecular fingers that tap the histone domino. When these genes are disabled, diffuse midline gliomas stop growing in a cultured lab dish, and in animal models. They also identified signaling pathways that could be targets for new drug therapies. Their findings are available in pre-print and will be published this summer in Science Advances.

Yu’s laboratory at the new Children’s National Research & Innovation Campus in Washington, D.C., will build on this fundamental question: How can chromatin-associated molecules be targeted to stop aggressive cancers?

Yu says that as he studies the molecular genesis of diffuse midline glioma, he may also identify therapeutic approaches for other diseases, such as leukemia and Sotos syndrome, that involve mutations in these chromatin-associated molecules.

His research team will combine biochemistry, single-molecule imaging, next-generation sequencing, biophysics, and preclinical research to develop and test new pharmaceutical alternatives to chemotherapy and radiation.

Yu was awarded a three-year American Cancer Society Postdoctoral Fellowship while working in Reinberg’s laboratory.

He completed a bachelor’s degree in biological science and technology at National Chiao Tung University in Taiwan, and his doctoral degree in genetics at Stony Brook University and Cold Spring Harbor Laboratory, where he studied signaling pathways in lung adenocarcinoma metastasis.

Recruitment for research positions in the Yu lab begins this summer.

Research & Innovation Campus

Virginia Tech, Children’s National Hospital award $100,000 to fund collaborative cancer research pilot projects

Research & Innovation Campus

This pilot research program represents a growing academic research partnership between Children’s National and Virginia Tech. Last year, the two institutions announced that Virginia Tech will establish a biomedical research facility on the Children’s National Research & Innovation Campus.

Children’s National Hospital and Virginia Tech have awarded two $50,000 one-year pilot grants to multi-institutional teams of scientists for pediatric brain cancer research.

The inter-institutional program, which launched in December, promotes cross-disciplinary collaborations among researchers at both institutions. At Virginia Tech, the program is part of the Virginia Tech Cancer Research Alliance. Financial support for the program was provided by the Offices of the Physician-in-Chief and Chief Academic Officer at Children’s National, and by Virginia Tech’s Office of the Vice President for Health Sciences and Technology.

“We were delighted to see so many innovative and competitive research proposals for our first round of pilot grants in the area of brain cancer. By forging new research collaborations with our partners at Children’s National, we hope to make major strides in addressing one of the most common and devastating groups of cancers in children,” said Michael Friedlander, Virginia Tech’s vice president for health sciences and technology, and the executive director of the Fralin Biomedical Research Institute at VTC. “The pilot funding will bootstrap several programs to be able to acquire ongoing sustainable funding by providing the opportunity to test novel high impact ideas for new strategies for treating these disorders. There are simply too few good options for children in this space now and this partnership can change that for the better.”

The collaborative research initiative began through an agreement between the Fralin Biomedical Research Institute and the Children’s National Research Institute. The collaborative teams formed through a series of interactive discussions among Virginia Tech’s Cancer Research Alliance faculty members from the university’s Blacksburg and Roanoke campuses, and Children’s National’s neuro-oncology researchers.

“I am extremely excited by this collaboration between VT and CNH that is focused on pediatric brain tumors which is such an area of unmet need,” said Catherine Bollard, M.D., M.B.Ch.B.,, director of Children’s National’s Center for Cancer and Immunology Research. “I am confident that the funded proposals will soon advance our understanding of pediatric brain tumors and, more importantly, facilitate more joint efforts between two world-class institutions which is especially timely with the development of the Children’s National Research & Innovation Campus.”

Yanxin Pei, Ph.D., an assistant professor in the Center for Cancer Immunology Research at Children’s National, and Liwu Li, Ph.D., a professor of biological sciences in Virginia Tech’s College of Science, were awarded one of the pilot research grants to study how white blood cells called neutrophils are involved in metastatic MYC-driven medulloblastoma, an aggressive type of brain tumor in children that often resists conventional radiation and chemotherapies.

Yuan Zhu, Ph.D., the Gilbert Family Professor of Neurofibromatosis Research at Children’s National, and Susan Campbell, Ph.D., an assistant professor of animal and poultry sciences in Virginia Tech’s College of Agriculture and Life Sciences, were awarded funds to study glioma-induced seizures in mice with a genetic mutation that inhibits the production of P53, a key protein involved in suppressing cancer cell growth and division.

The successful applicants will receive funding starting this month and are expected to deliver preliminary data to support an extramural research application by 2024.

This pilot research program represents a growing academic research partnership between Children’s National and Virginia Tech. Last year, the two institutions announced that Virginia Tech will establish a biomedical research facility on the Children’s National Research & Innovation Campus. It will be the first research and innovation campus in the nation focused on pediatrics when it opens later this year and will house newly recruited teams of pediatric brain cancer researchers.

Liwu Li, Yanxin Pei, Susan Campbell, and Yuan Zhu

Liwu Li, Ph.D., Yanxin Pei, Ph.D., Susan Campbell, Ph.D., and Yuan Zhu, Ph.D., were awarded funding through the new pilot research program.

DNA moleucle

Epigenetics and pediatric brain tumors

DNA moleucle

Over the last two decades the critical role of epigenetics in cancer biology has evolved significantly. In parallel, our understanding of the biology of many pediatric brain tumors and the central role of alterations in their epigenetic regulation has become an important area of discovery.

In an editorial in a special issue of the Journal of Neuro-Oncology, Roger Packer, M.D., senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National Hospital, looks at understanding the role of epigenetics and how they will further characterize pediatric brain tumors, open new therapeutic avenues for treatment and lead to true breakthroughs and cures for children.

person with brain tumor

Update on pediatric brain tumors

person with brain tumor

Over the last five years, there has been tremendous growth in the field of pediatric neuro-oncology with increasing understanding of the genetic and epigenetic heterogeneity of central nervous system (CNS) tumors. Attempts are underway to translate these insights into tumor-specific treatments. A recent review article in Current Neurology and Neuroscience Reports by Roger Packer, M.D., senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National Hospital, provided an update on the current landscape of pediatric brain tumors and the impact of novel molecular insights on classification, diagnostics and therapeutics.

graphic abstract for brain tumor paper

First large-scale proteogenomic analysis offers insights into pediatric brain tumor biology

graphic abstract for brain tumor paper

In the first large-scale, multicenter study of its kind, researchers conducted comprehensive analysis yielding a more complete understanding of pediatric brain tumors (PBT), which are the leading cause of cancer-related deaths in children. Researchers from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and Children’s Brian Tumor Network (CBTN) generated and analyzed proteomic data, which identifies common biological characteristics among different tumor types. The consortia consist of collaborators from the Icahn School of Medicine at Mount Sinai, National Cancer Institute, Fred Hutchinson Cancer Research Center, Children’s National Hospital and Children’s Hospital of Philadelphia. The study, published in Cell on November 25, 2020, provides a clearer understanding of the molecular basis of pediatric brain tumors and proposes new therapeutic avenues.

The molecular characterization of brain tumors has largely hinged upon the presence of unique alterations in the tumor genome ignoring the many layers of regulation that exist between DNA and the functional biology of the tumor cell that is actuated by proteins. The integration of proteomic data identifies common biological themes that span histologic boundaries, suggesting that treatments used for one histologic type may be applied effectively to other tumors sharing similar proteomic features.

Brian Rood, M.D., medical director of the Brain Tumor Institute and associate professor of pediatrics in the Center for Cancer and Blood Disorders at Children’s National Hospital, participated in this study and explains the importance of what the team discovered.

Q: Why was it important that researchers came together to do this work?

A: Comprehensive characterization of the fundamental biology of pediatric brain tumors, including the proteogenomic analysis done in this study, is essential to better understand and treat pediatric brain tumors.

Our study is based on the recognition that proteomics and phosphoproteomics needs to be integrated with other omics data to gain an improved systems biology view of the molecular features of brain tumors. In addition, characterizing biological themes that cross histologic boundaries and cells of origin can suggest extending treatments shown to be effective in one type of tumor to other histologically disparate tumors sharing the same proteomic features.

Proteomic data further reveal the functional impacts of somatic mutations and copy number variations (CNVs) not evident in transcriptomic data alone. Further, kinase-substrate network analyses identify activated biological mechanisms of tumor biology.

This work was only possible because of a unique collaboration between the CPTAC program of the NCI and the CBTN, of which Children’s National is a member.

Q: How will this work advance understanding and treatment of pediatric brain tumors?

A: Pediatric brain tumors have not benefitted from molecularly targeted drugs as much as other tumor types largely because they harbor relatively few gene mutations. Therefore, identifying key pathways to target in these patients’ tumors has been a challenge. The integration of proteomic and phosphoproteomic data with genomic data allows for the construction of a more comprehensive model of brain tumor biology and nominates specific key pathways to be targeted.

Q: What did you find that excites you?

A: Proteomic data revealed a number of findings that were not present in the genomic data. We found evidence to support a molecularly targeted approach to treating craniopharyngioma, a tumor that has previously been unresponsive to chemotherapy. We also found a prognostic marker for high grade gliomas that do not have a mutation in the H3 histone. We were able to identify specific kinases that may dictate the aggressive nature of certain ependymoma tumors. Importantly, we demonstrated the potential of proteomic studies to uncover unique tumor biology, paving the way for more extensive investigations using this approach.

You can find the full study published in Cell. Learn more about the Brain Tumor Institute at Children’s National.


Dr. Rood recently joined a live panel discussion with researchers from the Children’s Brain Tumor Network and the Clinical Proteomic Tumor Analysis Consortium to explore the impact of their landmark study.

Stat Madness 2019

Vote for Children’s National in STAT Madness

Stat Madness 2019

Children’s National Health System has been selected to compete in STAT Madness for the second consecutive year. Our entry for the bracket-style competition is “Sensitive liquid biopsy platform to detect tumor-released mutated DNA using patient blood and CSF,” a new technique that will allow kids to get better treatment for an aggressive type of pediatric brain tumor.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

“Children’s National researchers collaboratively work across divisions and departments to ensure that innovations discovered in our laboratories reach clinicians in order to improve patient care,” says Mark Batshaw, M.D., Children’s Executive Vice President, Chief Academic Officer and Physician-in-Chief. “It’s gratifying that Children’s multidisciplinary approach to improving the lives of children with brain tumors has been included in this year’s STAT Madness competition.”

Pediatric brain cancers are the leading cause of cancer-related death in children younger than 14. Children with tumors in their midline brain structures have the worst outcomes, and kids diagnosed with diffuse midline gliomas, including diffuse intrinsic pontine glioma, have a median survival of just 12 months.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The Children’s team searches for the histone 3.3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy. The multi-institutional team published findings online Oct. 15, 2018, in Clinical Cancer Research.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M, ” says Lindsay B. Kilburn, M.D., a Children’s neuro–oncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers, children do not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients that had undergone a tumor biopsy.”

“With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously,” Nazarian adds.

The STAT Madness round of 64 brackets opened March 4, 2019, and the championship round voting concludes April 5 at 5 p.m. (EST).

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D. and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital; John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Matthew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.