Understanding Brain Tumors in NF1
NF1-associated brain tumors
While children with NF1 are at risk for developing a low-grade brain tumor involving the optic nerve called an optic pathway glioma (OPG), it is not known how best to predict which child will develop an OPG or 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.
Optic pathway glioma (OPG
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. These investigations are aimed at identifying risk factors for vision loss in children with OPGs. In addition, Dr. Gutmann and his colleagues have spearheaded a multi-investigator study to define the genetic and genomic alterations in pediatric NF1 low-grade brain tumors (gliomas) relevant to improved patient management. Finally, Washington University NF Center investigators have developed uniform criteria for classifying brain tumors in children with NF1. These studies have led to a greater appreciation of the spectrum of brain tumors in NF1 important for optimizing the care of affected individuals.
Anastasaki C, Gao F, Gutmann DH. Commentary: Identification of Mutation Regions on NF1 Responsible for High- and Low-Risk Development of Optic Pathway Glioma in Neurofibromatosis Type I. Front Genet. 2019 Mar 1;10:115. doi: 10.3389/fgene.2019.00115. eCollection 2019. PMID: 30881378.
Freret ME, Gutmann DH. Insights into optic pathway glioma vision loss from mouse models of neurofibromatosis type 1. J Neurosci Res. 2019 Jan;97(1):45-56. doi: 10.1002/jnr.24250. Epub 2018 Apr 28. PMID: 29704429.
Griffith JL, Morris SM, Mahdi J, Goyal MS, Hershey T, Gutmann DH. Increased prevalence of brain tumors classified as T2 hyperintensities in neurofibromatosis 1. Neurol Clin Pract. 2018 Aug;8(4):283-291. doi: 10.1212/CPJ.0000000000000494. PMID: 30140579.
Campen CJ, Gutmann DH. Optic Pathway Gliomas in Neurofibromatosis Type 1. J Child Neurol. 2018 Jan;33(1):73-81. doi: 10.1177/0883073817739509. PMID: 29246098.
Anastasaki C, Morris SM, Gao F, Gutmann DH. Children with 5′-end NF1 gene mutations are more likely to have glioma. Neurol Genet. 2017 Sep 22;3(5):e192. doi: 10.1212/NXG.0000000000000192. eCollection 2017 Oct. PMID: 28955729.
de Blank PMK, Fisher MJ, Liu GT, Gutmann DH, Listernick R, Ferner RE, Avery RA. Optic Pathway Gliomas in Neurofibromatosis Type 1: An Update: Surveillance, Treatment Indications, and Biomarkers of Vision. J Neuroophthalmol. 2017 Sep;37 Suppl 1:S23-S32. doi: 10.1097/WNO.0000000000000550. PMID: 28806346.
Mahdi J, Shah AC, Sato A, Morris SM, McKinstry RC, Listernick R, Packer RJ, Fisher MJ, Gutmann DH. A multi-institutional study of brainstem gliomas in children with neurofibromatosis type 1. Neurology. 2017 Apr 18;88(16):1584-1589. doi: 10.1212/WNL.0000000000003881. Epub 2017 Mar 22. PMID: 28330960.
Porcelli B, Zoellner NL, Abadin SS, Gutmann DH, Johnson KJ. Associations between allergic conditions and pediatric brain tumors in Neurofibromatosis type 1. Fam Cancer. 2016 Apr;15(2):301-8. doi: 10.1007/s10689-015-9855-3. PMID: 26666764.
Diggs-Andrews KA, Brown JA, Gianino SM, Rubin JB, Wozniak DF, Gutmann DH. Sex Is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann Neurol. 2014 Feb;75(2):309-16. doi: 10.1002/ana.24093. Epub 2014 Feb 6. PMID: 24375753.
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. 2013 Mar;23(3):431-9. doi: 10.1101/gr.142604.112. Epub 2012 Dec 5. PMID: 23222849.
Wessel LE, Albers AC, Gutmann DH, Dunn CM. The association between hypotonia and brain tumors in children with neurofibromatosis type 1. J Child Neurol. 2013 Dec;28(12):1664-7. doi: 10.1177/0883073812460918. Epub 2012 Oct 15. PMID: 23071069.
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, Bouffet E, Charrow J, Bilaniuk LT, Balcer LJ, Liu GT. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis.Neuro Oncol. 2012 Jun;14(6):790-7. doi: 10.1093/neuonc/nos076. Epub 2012 Apr 3. PMID: 22474213.
Identification and 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, are currently being 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. Drugs like mTOR (Sirolimus) and MEK inhibitors are now in clinical trials for children with NF1-associated glioma. Additional compounds are also currently being evaluated in several Nf1 genetically-engineered mice with optic glioma to restore or prevent vision loss.
Toonen JA, Ma Y, Gutmann DH. Defining the temporal course of murine neurofibromatosis-1 optic gliomagenesis reveals a therapeutic window to attenuate retinal dysfunction. Neuro Oncol. 2017 Jun 1;19(6):808-819. doi: 10.1093/neuonc/now267. PMID: 28039362.
Toonen JA, Solga AC, Ma Y, Gutmann DH. Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal pathology. J Exp Med. 2017 Jan;214(1):17-25. doi: 10.1084/jem.20160447. Epub 2016 Dec 6. PMID: 27923908.
Smithson LJ, Gutmann DH. Proteomic analysis reveals GIT1 as a novel mTOR complex component critical for mediating astrocyte survival. Genes Dev. 2016 Jun 15;30(12):1383-8. doi: 10.1101/gad.279661.116. PMID: 27340174.
Kaul A, Toonen JA, Cimino PJ, Gianino SM, Gutmann DH. Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth. Neuro Oncol. 2015 Jun;17(6):843-53. doi: 10.1093/neuonc/nou329. Epub 2014 Dec 21. PMID: 25534823.
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 Acad Sci U S A. 2011 Sep 20;108(38):15996-6001. doi: 10.1073/pnas.1019012108. Epub 2011 Sep 6. PMID: 21896734.
Warrington NM, Gianino SM, Jackson E, Goldhoff P, Garbow JR, Piwnica-Worms D, Gutmann DH, Rubin JB. Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res. 2010 Jul 15;70(14):5717-27. doi: 10.1158/0008-5472.CAN-09-3769. Epub 2010 Jun 15. PMID: 20551058.
Understanding the role of the tumor microenvironment in brain tumor formation and growth
Brain tumors are composed of both cancerous and non-cancerous cells. Studies in Dr. Gutmann’s laboratory have 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 and T cells, are found 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.
Guo X, Pan Y, Gutmann DH. Genetic and genomic alterations differentially dictate low-grade glioma growth through cancer stem cell-specific chemokine recruitment of T cells and microglia. Neuro Oncol. 2019 Oct 9;21(10):1250-1262. doi: 10.1093/neuonc/noz080. PMID: 31111915.
Pan Y, Xiong M, Chen R, Ma Y, Corman C, Maricos M, Kindler U, Semtner M, Chen YH, Dahiya S, Gutmann DH. Athymic mice reveal a requirement for T-cell-microglia interactions in establishing a microenvironment supportive of Nf1 low-grade glioma growth. Genes Dev. 2018 Apr 1;32(7-8):491-496. doi: 10.1101/gad.310797.117. Epub 2018 Apr 9. PMID: 29632086.
Solga AC, Pong WW, Kim KY, Cimino PJ, Toonen JA, Walker J, Wylie T, Magrini V, Griffith M, Griffith OL, Ly A, Ellisman MH, Mardis ER, Gutmann DH. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth. Neoplasia. 2015 Oct;17(10):776-88. doi: 10.1016/j.neo.2015.10.002. PMID: 26585233.
Pong WW, Higer SB, Gianino SM, Emnett RJ, Gutmann DH. Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann Neurol. 2013 Feb;73(2):303-8. doi: 10.1002/ana.23813. Epub 2013 Feb 19. PMID: 23424002.
Daginakatte GC, Gianino SM, Zhao NW, Parsadanian AS, Gutmann DH. Increased c-Jun-NH2-kinase signaling in neurofibromatosis-1 heterozygous microglia drives microglia activation and promotes optic glioma proliferation. Cancer Res. 2008 Dec 15;68(24):10358-66. doi: 10.1158/0008-5472.CAN-08-2506. PMID: 19074905.
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 and human induced pluripotent stem cell models. 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, Toonen JA, Pan Y, Cimino PJ, Ma Y, Castillon GA, Gianino SM, Ellisman MH, Lee DY, Gutmann DH. The cell of origin dictates the temporal course of neurofibromatosis-1 (Nf1) low-grade glioma formation. Oncotarget. 2017 Jul 18;8(29):47206-47215. doi: 10.18632/oncotarget.17589. PMID: 28525381.
Solga AC, Gianino SM, Gutmann DH. NG2-cells are not the cell of origin for murine neurofibromatosis-1 (Nf1) optic glioma. Oncogene. 2014 Jan 16;33(3):289-99. doi: 10.1038/onc.2012.580. Epub 2013 Jan 14. PMID: 23318450.
Lee DY, Gianino SM, Gutmann DH. Innate neural stem cell heterogeneity determines the patterning of glioma formation in children. Cancer Cell. 2012 Jul 10;22(1):131-8. doi: 10.1016/j.ccr.2012.05.036. PMID: 22789544.
Dahiya S, Lee DY, Gutmann DH. Comparative characterization of the human and mouse third ventricle germinal zones. J Neuropathol Exp Neurol. 2011 Jul;70(7):622-33. doi: 10.1097/NEN.0b013e31822200aa. PMID: 21666496.
Lee DY, Yeh TH, Emnett RJ, White CR, Gutmann DH. Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes Dev. 2010 Oct 15;24(20):2317-29. doi: 10.1101/gad.1957110. Epub 2010 Sep 28. PMID: 20876733.
Payton JE, Schmidt J, Yu J, Lusis EA, Watson MA, Gutmann DH. Genome-wide polymorphism analysis demonstrates a monoclonal origin of pilocytic astrocytoma. Neuropathol Appl Neurobiol. 2011 Apr;37(3):321-5. doi: 10.1111/j.1365-2990.2010.01109.x. PMID: 20646217.