NF1 Optic Pathway Glioma & Other Brain Tumor Research
Visual loss in children with NF1-associated optic glioma
Optic pathway glioma (OPG)
While 15-20% of children with NF1 will develop a low-grade brain tumor involving the optic nerve called an optic pathway glioma, it is not known whether the patient age, gender or tumor location can be used to predict who will require treatment. Moreover, it is not clear whether some groups of children with NF1-associated optic gliomas are at higher risk for vision loss or treatment failure.
As part of an international consortium, NF Center director, David H. Gutmann, MD, PhD, and his colleagues are studying the impact of chemotherapy on vision in children with NF1. In addition, these investigations are aimed at identifying risk factors for poor outcome in children with optic pathway gliomas.
Diggs-Andrews KA, Brown JA, Gianino SM, D’Agostino McGowan L, Rubin JB, Wozniak DF, Gutmann DH. Reply. Ann Neurol. 75: 800-1, 2014.
Fisher MJ, Logudice M, Gutmann DH, Listernick R, Ferner RE, Ullrich NJ, Packer RJ, Tabori U, Hoffman RO, Ardern-Holmes SL, Hummel TR, Hargrave DR, Bouffet E, Charrow J, Bilaniuk LT, Balcer LJ, McGowan LD, Liu GT. Gender as a disease modifier in neurofibromastosis type 1 optic pathway glioma. Ann Neurol. 75: 799-800, 2014.
Diggs-Andrews KA, Brown JA, Gianino SM, D’Agostino McGowan L, Rubin JB, Wozniak DF, Gutmann DH. Sex is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann Neurol. 75: 309-16, 2014.
Fisher MJ, Avery RA, Allen JC, Arden-Holmes SL, Bilaniuk LT, Ferner RE, Gutmann DH, Listernick R, Martin S, Ullrich NJ, Liu GT. Functional outcome measures of NF1-associated optic pathway glioma clinical trials. Neurology. 19: S15-24, 2013.
Ji J, Shimony J, Gao F, McKinstry RC, Gutmann DH. Optic nerve tortuosity in children with neurofibromatosis type 1. Pediatr Radiol. 43: 1418, 2013.
Gutmann DH, Avery R. Ferner RE, Listernick R. Visual function and optic pathway glioma: A critical response. JAMA Opthalmol. 131: 120-1, 2013.
Avery RA, Ferner RE, Listernick R, Fisher MJ, Gutmann DH, Liu GT. Visual acuity of children with low grade gliomas of the visual pathway: Implications for patient care and clinical research. J Neurooncol. 110: 1-7, 2012.
Fisher MJ, Loguidice M, Gutmann DH, Listernick R, Ferner RE, Ullrich NJ, Packer RJ, Tabori U, Hoffman RO, Ardern-Holmes SL, Hummel TR, Hargrave DR, Boufet E, Charrow J, Bilaniuk LT, Balcer LJ, Liu GT. Visual outcomes in children with neurofibromatosis type 1 associated optic pathway glioma following chemotherapy: A mulit-center retrospective analysis. Neuro-Oncology. 14: 790-7, 2012.
Gutmann DH, Listernick R, Ferner RE. Screening for symptomatic optic pathway glioma in children with neurofibromatosis type 1. Eye. 25: 818, 2011.
Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: Controversies and recommendations. Ann Neurol. 61: 189-98, 2007.
Preclinical evaluation of new brain tumor therapies in Nf1 genetically-engineered mice
After the identification of the Nf1 gene and its protein (neurofibromin), it became possible to envision a time when new drug therapies for NF1-associated tumors might replace the missing function of neurofibromin. Over the past decade, several promising candidate compounds have been identified, which need to be evaluated in model organisms prior to the application to children and adults with NF1.
To this end, Dr. Gutmann and his colleagues at the Washington University NF Center have an active research program to evaluate new drugs for the treatment of optic glioma using Nf1 genetically-engineered mice. These studies are designed to rapidly test the most promising candidate drugs prior to their evaluation in children and adults with NF1. One such drug, rapamycin, is now in clinical trials for children with NF1-associated glioma. Additional compounds are currently being evaluated in several Nf1 genetically-engineered mice with optic glioma.
Banerjee S, Gianino SM, Gao F, Christians U, Gutmann DH. Interpreting mammalian target of rapamycin and cell growth inhibition in a genetically-engineered mouse model of Nf1-deficient astrocytes. Mol Cancer Ther. 10: 279-91, 2011.
Hegedus B, Banerjee D, Yeh T-H, Rothermich S, Perry A, Rubin JB, Garbow JR, Gutmann DH. Preclinical cancer therapy in a mouse model of neurofibromatosis-1 optic glioma. Cancer Res. 68: 1520-8, 2008.
Gutmann DH, Hunter-Schaedle K, Shannon KM. Harnessing preclinical mouse models to inform human clinical cancer trials. J Clin Invest. 116: 847-52, 2006.
Understanding the role of the tumor microenvironment in brain tumor formation and growth
Brain tumors are composed of both cancerous and non-cancerous cells. Previous studies in Dr. Gutmann’s laboratory revealed that the non-cancerous cells may play a critical role in the development and growth of optic gliomas in Nf1 genetically-engineered mice.
To further define the contribution of these non-cancerous cells to glioma growth, investigators at the Washington University NF Center are working together to combine their individual expertise. Dr. Gutmann and his colleagues showed that immune system-like cells, called microglia, are abundant in both human and mouse optic gliomas and that these cells are critical for optic glioma growth in Nf1 genetically-engineered mice. These exciting findings suggest that new targets for therapeutic drug design might result from the identification of the factors made by glioma-associated microglia.
Teaming with Drs. Elaine Mardis, Joshua Rubin, Jeffrey Leonard and David Piwnica-Worms, Dr. Gutmann is directing studies aimed at discovering these critical microglia growth factors using advanced RNA sequencing methods developed at the McDonnell Genome Institute at Washington University. The results from these studies may one day lead to treatments that target these non-cancerous cells in the tumor microenvironment.
Pong WW, Walker J, Wylie T, Magrini V, Luo J, Emnett RJ, Choi J, Cooper ML, Griffith M, Griffith OL, Rubin JB, Fuller GN, Piwnica-Worms D, Feng X, Hambardzumyan D, DiPersio JF, Mardis ER, Gutmann DH. F11R is a novel monocyte prognostic biomarker for malignant glioma. PLoS One. 8: e77571, 2013.
Pong WW, Higer SB, Gianino SM, Emnett RJ, Gutmann DH. Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann Neurol. 73: 303-8, 2013.
Simmons GW, Pong WW, Emnett RJ, White CR, Gianino SM, Rodriguez FJ, Gutmann DH. Neurofibromatosis-1 heterozygosity increases microglia in a spatially-and temporally-restricted pattern relevant to mouse optic glioma formation and growth. J Neuropathol Exp Neurol. 70: 51-62, 2011.
Daginakatte GC, Gianino SM, Zhao NW, Parsadanian AS, Gutmann DH. Increase JNK signaling in Neurofibromatosis-1 (Nf1) heterozygous microglia activation and promotes optic glioma proliferation. Cancer Res. 68: 10358-66, 2008.
Daginakatte GC, Gutmann DH. Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum Mol Genet. 16: 1098-112, 2007.
Defining the role of the NF1 gene in normal brain development
The observation that children with NF1 have learning, memory and behavioral problems suggests that the Nf1 gene neurofibromin is important in brain development and function.
To better understand the role of neurofibromin in normal brain development, Dr. Gutmann and his colleagues are using novel strains of genetically-engineered mice. These studies are aimed at determining the mechanism by which neurofibromin regulates the growth of progenitor cells (neural stem cells) and their differentiation into neurons, astrocytes and oligodendrocytes. The goal of these studies is to determine exactly how neurofibromin regulates normal brain development and function with an eye towards future treatments that leverage these new insights.
Hegedus B, Yeh T-H, Lee DY, Emnett RJ, Li J, Gutmann DH. Neurofibromin regulates somatic growth through the hypothalamic-pituitary axis. Hum Mol Genet. 17: 2955-66, 2008.
Hegedus B, Dasgupta B, Shin JE, Emnett RJ, Hart-Mahon EK, Elghazi L, Bernal-Mizrachi E, Gutmann DH. Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo by both cAMP and Ras-dependent mechanisms. Cell Stem Cell. 1: 443-57, 2007.
Dasgupta B, Gutmann DH. Neurofibromin regulates neural stem cell proliferation, survival and astroglial differentiation in vitro and in vivo. J Neurosci. 25: 5584-94, 2005.
Understanding the cellular origins of brain tumors
Research over the past decade has shown that brain tumors can arise from a number of different types of cells in the brain. Determining where these come from in children with NF1 may yield new insights into how best to prevent their formation.
To understand the origins of optic pathway gliomas in NF1, Dr. Gutmann and his colleagues are using novel strains of genetically-engineered mice. These studies are focused on finding which cells in the developing brain give rise to optic pathway gliomas in children. In addition, similar studies are underway to identify the cells in the developing brain responsible for childhood brain tumors in people without NF1.
Solga AC, Gianino SM, Gutmann DH. NG2-cells are not the cell of origin for murine neurofibromatosis-1 (Nf1) optic glioma. Oncogene. 33: 283-99, 2014.
Lee DY, Gianino SM, Gutmann DH. Innate neural stem cell heterogeneity determines the patterning of glioma formation in children. Cancer Cell. 22: 131-8, 2012.
Lee DY, Yeh T-H, Emnett RJ, White CR, Gutmann DH. Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes & Development. 24: 2317-29, 2010.
Yeh T-H, Lee DY, Giannino SM, Gutmann DH. Microarray analyses reveal regional astrocyte heterogeneity with implications for neurofibromatosis type 1 regulated glial proliferation. GLIA. 57: 1239-49, 2009.
Identifying new treatments for NF1-associated tumors
With the identification of the Nf1 gene in 1990, it became possible to define the mechanism by which the Nf1 protein (neurofibromin) controls cell growth. Over the past decade, Dr. Gutmann and his colleagues have focused on determining the precise way neurofibromin regulates the growth of brain cells.
Using a team effort involving numerous investigators at the Washington University NF Center, we aim to discover new drugs for the treatment of tumors arising in children and adults with NF1. Drs. David Piwnica-Worms, Joshua Rubin, Jason Weber and David Gutmann have been working together for the past seven years to identify such promising compounds and determine how they block NF1-associated tumor growth. These studies have already led to the identification of rapamycin drugs now in clinical trial for plexiform neurofibromas and brain tumors as well as compounds that restore normal cyclic AMP signaling in NF1-associated tumors in mice. We continue to refine these targeted treatments to optimally inhibit tumor growth with minimal effects on the normal brain.
Banerjee S, Crouse NR, Emnett RJ, Gianino SM, Gutmann DH. Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner. Proc Natl Sci USA. 108: 15996-6001, 2011.
Warrington NM, Gianino SM, Jackson E, Goldhoff P, Garbow JR, Piwnica-Worms D, Gutmann DH, Rubin JB. Cyclica AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res. 70: 5717-27, 2010.
Sun T, Gianino SM, Jackson E, Piwnica-Worms D, Gutmann DH, Rubin JB. CXCL12 alone is insufficient for gliomagenesis in Nf1 mutant mice. J Neuroimmunol. 224: 108-13, 2010.
Banerjee S, Byrd JN, Gianino SM, Harpstrite SE, Rodriguez FJ, Tuskan RG, Reilly KM, Piwnica-Worms D, Gutmann DH. Neurofibromin controls cell growth by regulating STAT3 activity in vitro and in vivo. Cancer Res. 70: 1356-66, 2010.
Warrington NM, Woener BM, Daginakatte GC, Dasgupta B, Perry A, Gutmann DH, Rubin JB. Spatiotemporal differences in CXCL12 expression and cyclic AMP underlie the unique pattern of optic pathway glioma growth in neurofibromatosis type 1. Cancer Res. 67: 8588-95, 2007.
Sandsmark DK, Zhang H, Hegedus B, Pelletier CL, Weber JD, Gutmann DH. Nucleophosmin mediates mammalian target of rapamycin-dependent actin cytoskeleton dynamics and proliferation in neurofibromin-deficient astrocytes. Cancer Res. 67: 4790-9, 2007.
Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH. Proteomic analysis reveals hyperactivation of the mTOR pathway in NF1-associated human and mouse brain tumors. Cancer Res. 65: 2755-60, 2005.
Understanding the genetics of NF1-associated brain tumors
The development of new drugs for NF1-associated brain tumors requires a comprehensive analysis of these tumors in both mice and humans.
To accomplish this goal, Dr. Gutmann and his colleagues are preforming detailed studies to identify types of cells present in mouse optic gliomas and the interactions between these various cells in controlling brain tumor growth. In addition, Dr. Elaine Mardis and her team at the McDonnell Genome Institute at Washington University are applying advanced whole genome sequencing methods to NF1-associated human tumors to comprehensively define the genetic changes present in these complex tumors.
Gutmann DH, McLellan MD, Hussain I, Wallis JW, Fulton LL, Fulton RS, Magrini V, Demeter R, Wylie T, Kandoth C, Leonard JR, Guha A, Miller CA, Ding L, Mardis ER. Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma. Genome Res. 23: 431-9, 2013.
Ho CY, Bar E, Giannini C, Marchionni L, Karajannis MA, Zagzag D, Gutmann DH, Eberhart CG, Rodriguez FJ. MicroRNA profiling in pediatric pilocytic astrocytoma reveals biologically relevant targets, including PBX3, NFIB, and METAP2. Neuro Oncol. 15: 69-82, 2013.
Kim K-Y, Ju WK, Hegedus B, Gutmann DH, Ellisman ME. Ultrastructural characterization of the optic pathway in a mouse model of neurofibromatosis-1 optic glioma. Neuroscience. 170: 178-88, 2010.
Tibbetts KM, Emnett RJ, Gao F, Perry A, Gutmann DH, Leonard J. Histopathologic predictors of pilocytic astrocytoma event-free survival. Acta Neuropathologica. 117: 657-65, 2009.
Rodriguez FJ, Giannini C, Asmann YW, Sharma MK, Perry A, Tibbetts KM, Jenkins RB, Sheithauer BW, Anant S, Jenkins S, Eberhart EG, Sarkaria JN, Gutmann DH. Gene expression profiling of NF1-associated and sporadic pilocytic astrocytomas identifies ALDH1L1 as an underexpressed candidate biomarker in aggressive astrocytoma subtypes. J Neuropath Exp Neurol. 67: 1194-204, 2008.
Rodriguez FJ, Perry A, Gutmann DH, O’Neill BP, Leonard J, Bryant S, Giannini C. Gliomas in neurofibromatosis type 1: A clinical study of 100 patients. J Neuropath Exp Neurol. 67: 240-9, 2008.
Advanced imaging of optic gliomas in mice and children with NF1
While current brain imaging can clearly identify brain tumors in children with NF1, they do not provide predictive information about the clinical behavior of the tumor. Over the past several years, new imaging modalities have been developed which offer the potential to identify brain tumors with more aggressive clinical behavior.
Dr. Joshua Shimony in the Department of Radiology is currently employing one of these novel imaging methods, called functional connectivity MRI, to determine whether this advanced imaging technique can predict optic glioma growth and vision decline in children with NF1. Dr. Shimony and his colleagues are currently enrolling new patients in this exciting study. In addition, Dr. Joel Garbow in the Department of Chemistry is working with investigators at the Washington University NF Center to discover more refined imaging modalities using Nf1 mouse strains which one day might be evaluated in children with NF1.
Dorward IG, Luo J, Perry A, Gutmann DH, Mansur DB, Rubin JB, Leonard JR. Post-operative imaging surveillance in pediatric pilocytic astrocytomas. J. Neurosurg. Ped. 6: 346-52, 2010.
Jost SC, Ackerman JW, Garbow JR, Manwaring LP, Gutmann DH, McKinstry RC. Diffusion-weighted and dynamic contrast-enhanced imaging as markers of clinical behavior in children with optic pathway glioma. Pediatric Radiology. 38: 1293-9, 2008.
Banerjee D, Hegedus B, Gutmann DH, Garbow JR. Detection and measurement of neurofibromatosis-1 mouse optic glioma in vivo. Neuroimage. 35: 1434-7, 2007.
Genetic predictors of brain tumor formation in children with NF1
While current genetic testing can determine with great accuracy whether a child has NF1, it cannot provide prognostic information regarding the development of specific features of the condition. In this regard, we are unable to identify children with NF1 at highest risk for the development of brain tumors (optic pathway gliomas).
Dr. Joshua Rubin in the Department of Pediatrics is spearheading an international study using advanced genomic methods to identify subtle DNA changes that predict the development of brain tumors in children with NF1. His pioneering efforts have begun to reveal genomic regions associated with NF1 glioma formation. Future studies may lead to the development of DNA markers for predictive genetic testing in children with NF1.
Johnson KJ, Fisher MJ, Listernick RL, North KN, Schorry EK, Viskochil D, Weinstein M, Rubin JB, Gutmann DH. Parent-of-origin in individuals with familial neurofibromatosis type 1 and optic pathway glioma. Fam Cancer. 11: 653-6, 2012.