Low grade gliomas (LGG) develop in ~20% of children with NF1, occurring most commonly within the optic pathway (optic pathway glioma; OPG). While the majority of these tumors are indolent pilocytic astrocytomas (Pas) which do no necessitate medical intervention, 30-50% of the NF1-OPGs cause visual impairment, precocious puberty, or neurological symptoms. The identification of prognostic factors to identify those tumors that are likely to require intervention is crucial to minimizing the morbidity of these tumors as well as to limit treatment to only at-risk tumors. In addition, the time-honored therapies for symptomatic NF1-LGG entail the use of genotoxic drugs (e.g., carboplatin, vincristine, vinblastine) that can also damage dividing cells in germinal zones critical for normal brain development in children. As such, there is a pressing need to identify molecular risk factors and treatments targeted to the cellular and molecular properties unique to NF1-LGG. Progress in this area has been hampered by the paucity of human tumors available for analysis in any one institution, reflecting the relative infrequency of biopsy/surgical resection, and the difficulty in establishing patient-derived xenograft models from those rare specimens obtained for study. In striking contrast, there has been an explosion in our understanding of the genetic and epigenetic events associated with sporadic PA, where surgical specimens are frequently obtained. In these studies, the most common genomic changes identified involve genomic rearrangements in which the kinase domain of the BRAF gene is fused to numerous other proteins. Similar to NF1-PA, sporadic PA tumors bearing BRAF variants exhibit ERK/mTOR signaling pathway hyperactivation. Based on these studies, targeted therapies using MEK and mTOR inhibitors are now being evaluated in clinical trials.
In order to accelerate progress aimed at identifying the cell-intrinsic and cell-extrinsic molecular changes that dictate NF1-LFF biology and evaluate their functional significance relevant to the design of future NF1-LGG-specific targeted therapies, we have assembled a highly interactive and independently accomplished team of investigators with expertise in low-grade glioma mouse modeling (Gutmann, Weiss, Pfister), multi-scale genomic analyses (Pfister, Jones), tumor microenvironment influences (Phillips, Gutmann), signaling pathway growth control (Gutmann, Weiss, Resnick, Waanders), and the clinical management of children with NF1 and sporadic LGG (Fisher, Gutmann, Witt).
What are the goals of this project?
In this project, we will identify the molecular mechanisms involved in LGG development and maintenance by leveraging sporadic and NF1-LGG clinical samples, in vitro engineered human and mouse LGG platforms, and complementary in vivo transplantable and genetically-engineered mouse models.
What is the impact of this project?
Collectively, these approaches will elucidate new targets for the treatment of NF1-LGG that incorporate cooperating genetic changes, stromal influences, and tumor escape mechanisms.
The Children's Brain Tumor Network contributed to this project by providing germline and tumor DNA and tumor RNA.
David H. Gutmann
William A. Weiss
David T. Jones
Michael J. Fisher, MD
Michael J. Fisher, MD, is Chief of the Section of Neuro-Oncology, Director of the Neuro-Oncology Fellowship Program and Director of the Neurofibromatosis Program at Children's Hospital of Philadelphia. He has a special interest in brain tumors and neurofibromatosis.Areas of Experti
Children’s Hospital of Philadelphia
Joanna Phillips, MD, PhD
I am an Associate Professor in the UCSF Departments of Neurological Surgery and Pathology, Director of the UCSF Brain Tumor Research Center Tissue Biorepository and Histology Core, Co-Director of the UCSF Neuropathology BTRC Biomarkers Laboratory, Co-Director of the UCSF Brain Tumor SPORE Biorepo
UCSF Benioff Children's Hospital
Angela Waanders, MD, MPH
Specialties:Hematology, Oncology, Neuro-Oncology & Stem Cell TransplantationEducation: Tulane University School of Medicine, 2003Postgr
Ann & Robert H. Lurie Children’s Hospital of Chicago
Adam Resnick, PhD
Adam Resnick is the Director of Data Driven Discovery in Biomedicine (D3b) at Children’s Hospital of Philadelphia (CHOP) responsible for leading a multidisciplinary team to build and support a scalable, patient-focused healthcare and educational discovery ecosystem on behalf of all children. He i
Children’s Hospital of Philadelphia
Low-Grade astrocytomas are the most common cancer of the central nervous system in children. They represent a heterogeneous group of tumors that can be discovered anywhere within the brain or spinal cord. Although surgical resection may be curative, up to 20% of children still suffer from the eff