Neuro-Oncology Research

Our Neuro-Oncology Research Program is included in the Childhood Brain Tumor Network. The Center for Cancer and Immunology Research's (CCIR) Medulloblastoma Special Interest Group focuses on understanding the causative mechanism and improving the treatment of medulloblastoma, which is a cancerous tumor that starts in the region of the brain at the base of the skull.

Neuro-Oncology

The Neuro-Oncology Program at the Children’s National Research Institute continues to have robust translational and basic research components. Javad Nazarian, Ph.D., M.Sc., leads the basic research activities and currently serves as Scientific Director of the Brain Tumor Institute. Laboratory efforts underway include:

• Those focusing on systemic detections of intracranial lesions (liquid biopsies)
• The biology and the molecular therapeutic targets of high-grade gliomas, including pontine gliomas and new therapeutics for Group 3 medulloblastomas with MYC amplifications

Basic science efforts have expanded nationally and internationally with the program’s inclusion in the Childhood Brain Tumor Network (CBTN) of which Brian Rood, M.D., was recently named the Co-Executive Chair. The translational program remains robust as Children’s National remains an active member of the Pediatric Brain Tumor Consortium (PBTC), the Pediatric (Pacific) Neuro-Oncology Consortium (PNOC), the Sunshine Network and the CONNECT Consortium. All these consortiums are focusing on novel means to treat childhood brain tumors with an emphasis on molecular-targeted therapy and immunologic approaches.

Over the past year, translational trials have been opened utilizing check-point inhibitors, vaccine studies for high-grade gliomas and diffuse intrinsic pontine gliomas (DIPG), and molecularly-targeted trials for medulloblastomas, brainstem gliomas and low-grade gliomas are also being conducted. The low-grade glioma study utilizing a MEK inhibitor has progressed to the point that the MEK inhibitor is part of a Phase III study for newly diagnosed patients with low-grade gliomas. Roger Packer, M.D., director of the Brain Tumor Institute, has led multiple international consensus conferences on pediatric low-grade gliomas, which have resulted in new guidelines published for the evaluation and potential management of such tumors. He has also been named Scientific Director of the National Brain Tumor Society’s Defeat Pediatric Brain Tumor initiative.

Our Team

• Gene Hwang, M.D.
• Lindsay Kilburn, M.D.
• Javad Nazarian, Ph.D.
• Roger Packer, M.D.
• Yanxin Pei, Ph.D.
• Brian Rood, M.D.
• Yuan Zhu, Ph.D.

Medulloblastoma

1. Generating diverse preclinical mouse models of medulloblastoma. Medulloblastoma is a heterogeneous disease that has been classified into four major molecular groups (WNT, SHH, Group 3 and Group 4), each characterized by distinct genetic and molecular alterations and clinical features. Despite this heterogeneity, most medulloblastoma patients currently receive the same therapy, resulting in over-treatment and toxic side effects for those with good prognosis and insufficient treatment for patients with more malignant tumors who ultimately succumb to their disease. A major goal of our research is to generate diverse preclinical mouse models for each subgroup of medulloblastoma and discover new therapeutic strategies that are tailored to the specific subgroups. To this end, we have used an orthotopic transplantation approach to generate mouse models of both Group 3 medulloblastoma associated with MYC amplification and SHH medulloblastoma associated with GLI2 amplification. Using our newly developed models, we have identified novel therapeutic targets that are specific to the corresponding subgroup of medulloblastoma.
2. Elucidating the molecular mechanisms of metastasis, therapeutic resistance and tumor relapse. Approximately one-third of patients with Group 3 medulloblastoma present with metastases at diagnosis, and nearly all have metastatic disease at relapse. Treatment-resistant, metastatic medulloblastoma tumors pose a daunting therapeutic challenge as they are neither amenable to surgical resection nor responsive to radiation or currently available chemotherapy. Identifying the signaling pathways involved in metastatic progression will facilitate the development of an effective strategy to prevent and treat metastasis. Using patient-derived xenograft mouse models of Group 3 medulloblastoma, we have isolated treatment resistant metastatic tumor cells and discovered that a subpopulation of OLIG2+ tumor cells in primary tumors have a unique ability to metastasize along the leptomeninges. We are currently testing several novel therapeutic approaches to eliminate the metastatic tumor cells, including targeted drug therapy and cellular immunotherapy with CAR T cells and adoptive NK cells.
3. Exploring novel approaches to enhance delivery of therapeutic drugs to the central nervous system. The blood-brain barrier (BBB) is a major obstacle to the delivery of effective therapies for brain tumors. To address this problem, we are collaborating with bioengineers specializing in nanotechnology. By encapsulating drugs in nanoparticles and delivering them directly to the central nervous system, we hope to improve the delivery of sufficient, effective concentrations of drugs to the brain tumor site and reduce accumulation of the drugs in other tissues, thereby mitigating systemic side effects. Additionally, we are collaborating with bioengineers using either High-Frequency Irreversible Electroporation (H-FIRE) or ultrasound to transiently disrupt the BBB in order to deliver effective intratumoral concentrations of anticancer drugs. We have already identified several drugs that effectively kill medulloblastoma cells in vitro; if we can develop strategies to effectively deliver these drugs to tumors, we can markedly improve outcomes for patients with medulloblastoma.

Our Team

• Catherine Bollard, M.B.Ch.B., M.D.
• C. Russell Cruz, M.D., Ph.D.
• Gene Hwang, M.D.
• Roger Packer, M.D.
• Yanxin Pei, Ph.D.
• Brian Rood, M.D.
• Yuan Zhu, Ph.D.

Gift From a Child Initiative

Families have the ability to directly support and advance pediatric brain tumor research. As a member of the Gift from a Child initiative, our post-mortem tissue donation team helps families through this decision making process and provides them with the opportunity to impact the future of childhood brain cancer treatments. For inquiries, please contact Augustine Eze or Javad Nazarian, Ph.D., M.Sc.