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The Children's Research Institute

Neurofibromatosis and Brain Tumor Research Program

Neurofibromatosis is a genetic disease caused by mutation of either NF1 or NF2 genes. Patients with either mutation are predisposed to cancer, learning disability and other life-long morbidities. The research team is led by Dr. Yuan Zhu, PhD, who has developed mouse models with NF1 mutations, which are highly reminiscent of human diseases conditions, and is using the model to test novel therapeutic approach to treat major illness associated with the NF1 mutations, including both cancer and learning disabilities.

Dr. Zhu’s research group is interested in understanding the role of NF1 in developing neural stem and progenitor cells and how its loss causes developmental abnormalities, leading to the structural brain defects associated with severe learning disabilities in humans, and the development of benign peripheral nerve sheath tumor, such as plexiform neurofibroma in the peripheral nervous system (PNS) and optic pathway glioma in the central nervous system (CNS). Dr. Zhu’s research group is investigating the mechanism underlying these NF1-associated diseases and performing preclinical studies with animal models. Our goal is to integrate basic, translational and clinical research to develop novel preventive and treatment therapies for NF1-associated diseases.

NF1 tumor suppressor gene is one of the most frequently mutated genes in glioblastoma (GBM) – the most frequent and lethal brain cancer in humans. However, the development of GBM in individuals afflicted with NF1 is not common. Using GEM models, we have demonstrated that inactivation of NF1 is not a robust oncogenic event unless it occurs in the context of p53 loss. Thus, sequential inactivation of tumor suppressor genes p53 and NF1 is required for effectively transforming neural stem and progenitor cells in the subventricular zone (SVZ) of the lateral ventricle. These studies have established NF1 as a context-dependent tumor suppressor gene in GBM, providing the mechanism by which most individuals with NF1 have no increased risk of developing GBM. They are exploring these mouse models to address:

  • How the tumor suppressor genes p53 and NF1 regulate growth and transformation of neural stem/progenitor cells in vivo and in vitro.
  • What is the lineage relationship between neural stem and progenitor cells or differentiated cells and tumors in the nervous system.
  • What is the molecular mechanism(s) underlying the development of astrocytomas/GBM and malignant peripheral nerve sheath tumors (MPNSTs) from normal neural stem and progenitor cells.

Brain tumors are the most common solid tumor in children, with an estimated 3,750 new patients diagnosed every year. Children’s National has one of the largest and most active programs in the United States for the diagnosis and treatment of children with brain tumors. Through a multidisciplinary team approach that includes the specialties of neuro-oncology, neurology, neurosurgery, neuropathology, neuropsychology, and neuroradiology, Children’s National not only provides state-of-the-art clinical care, but also performs cutting-edge research investigating the genetic causes, biology, and new treatments of these tumors.

Dr. Zhu’s research group seeks to understand molecular and cellular mechanisms underlying the development of normal neural stem and progenitor cells as well as tumorigenesis in the nervous system. They are using the mouse as a model system to develop genetic engineering mouse (GEM) tumor models, which recapitulate human nervous system tumors both genetically and phenotypically. Particularly, Dr. Zhu’s laboratory have been focused on the role of tumor suppressor genes in the nervous system.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Based on extensive genomic analysis, MB has been classified into four major subtypes. Among these, tumors associated with overexpression or amplification of MYC has the poorest prognosis. Even with an intensive regimen of surgery, radiation and chemotherapy, 30 to 40 percent of patients exhibit tumor recurrence and die from their disease. One important cause of relapse is the small number of tumor cells that are initially resistant to radiation and chemotherapy. These cells may become activated and expand into a therapy-resistant and ultimately lethal tumor.

The laboratory led by Yanxin Pei, PhD, is interested in understanding the mechanisms of therapy resistance and finding ways to target the resistant tumor cells, using both mouse MYC-driven MB model and human MYC-driven MB xenografts. Dr. Pei is also interested in investigating how oncogenes initiate and sustain tumorigenesis in MYC-driven MB. They have developed model systems whereby we can conditionally alter the expression of oncogenes in tumor cells. We are using these model systems to study whether inactivation of one oncogene can be sufficient to cause complete tumor regression, whether some tumor cells escape dependence on oncogene and acquire additional genetic mutations during oncogene inactivation, and whether these mutations can be new therapeutic targets to combine with oncogene inactivation to prevent tumor recurrence in MB.

HIC1 is a tumor suppressor gene that is frequently inactivated in neural tumors. The laboratory of Brian Rood, MD, employs a novel protein constructed to inactivate the product of the HIC1 gene to gain an understanding of its tumor promoting mechanisms. Recently, in collaboration with Dominique Leprince, MD, at the Centre National de la Recherche Scientifique in Lille, France, the research team has discovered that the expression of the cytokine receptor CXCR7 is under HIC1's direct control, potentially influencing pro-migrational tumor-host interactions.

Dr. Rood and Yetrib Hathout, PhD, work to characterize the cerebrospinal fluid (CSF) proteome in patients with medulloblastoma. CSF is uniquely suited to this because of its continuous turnover, availability, and its relatively low protein complexity. Current diagnostic and therapeutic monitoring studies are limited in their ability to accurately characterize a brain tumor’s biological response to therapy and detect tumor recurrence. Using cutting-edge proteomics technology, Dr. Rood and Hathout are working to develop a means to:

  • Augment the ability of MRI scanning to differentiate tumor tissue from post-surgical or post-radiation effects
  • Assess treatment response to small molecule inhibitors and anti-angiogenic agents
  • Detect early disease recurrence
  • Identify pharmacodynamic biomarkers that predict response to specific molecularly targeted therapies

The systematic evaluation of CSF of patients with brain tumors is building the foundation for reliable biomarker discovery. In collaboration with investigators from the Pediatric Brian Tumor Consortium, the investigators have been able to collect relevant samples from around the United States, creating a unique and powerful resource. The identification of CSF PGD2S as a biomarker of medulloblastoma was recently reported as a result of this work.

Investigators in the program