Personalizing Treatments for NF1

Developing small-animal models to promote personalized medicine

An ongoing initiative in the Washington University NF Center is focused on developing preclinical models of brain tumors and attention deficits that incorporate the specific NF1 genetic mutations observed in people with NF1. These unique mouse and other animal strains will be employed to develop more individualized treatments for children and adults with NF1-associated clinical problems, including optic glioma.

Suggested Reading

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.

Isakson SH, Rizzardi AE, Coutts AW, Carlson DF, Kirstein MN, Fisher J, Vitte J, Williams KB, Pluhar GE, Dahiya S, Widemann BC, Dombi E, Rizvi T, Ratner N, Messiaen L, Stemmer-Rachamimov AO, Fahrenkrug SC, Gutmann DH, Giovannini M, Moertel CL, Largaespada DA, Watson AL. Genetically engineered minipigs model the major clinical features of human neurofibromatosis type 1. Commun Biol. 2018 Oct 2;1:158. doi: 10.1038/s42003-018-0163-y. eCollection 2018. PMID: 30302402.

Monroe CL, Dahiya S, Gutmann DH. Dissecting Clinical Heterogeneity in Neurofibromatosis Type 1.Annu Rev Pathol. 2017 Jan 24;12:53-74. doi: 10.1146/annurev-pathol-052016-100228. PMID: 28135565.

Li K, Turner AN, Chen M, Brosius SN, Schoeb TR, Messiaen LM, Bedwell DM, Zinn KR, Anastasaki C, Gutmann DH, Korf BR, Kesterson RA. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I. Dis Model Mech. 2016 Jul 1;9(7):759-67. doi: 10.1242/dmm.025783. Epub 2016 Jun 2. PMID: 27482814.

Toonen JA, Anastasaki C, Smithson LJ, Gianino SM, Li K, Kesterson RA, Gutmann DH. NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1. Hum Mol Genet. 2016 May 1;25(9):1703-13. doi: 10.1093/hmg/ddw039. Epub 2016 Feb 16. PMID: 26908603.

Chen YH, McGowan LD, Cimino PJ, Dahiya S, Leonard JR, Lee DY, Gutmann DH. Mouse low-grade gliomas contain cancer stem cells with unique molecular and functional properties. Cell Rep. 2015 Mar 24;10(11):1899-912. doi: 10.1016/j.celrep.2015.02.041. Epub 2015 Mar 12. PMID: 25772366.

Kaul A, Toonen JA, Gianino SM, Gutmann DH. The impact of coexisting genetic mutations on murine optic glioma biology. Neuro Oncol. 2015 May;17(5):670-7. doi: 10.1093/neuonc/nou287. Epub 2014 Sep 21. PMID: 25246427.

Individualizing therapies for NF1 malignant peripheral nerve sheath tumors (MPNST)

MPNSTOne area of study is focused on identifying the genetic changes that predict malignant transformation and spread (metastasis) or MPNSTs using advanced genomic sequencing strategies. A second area of investigation aims to develop better small-animal models of MPNST development and metastasis to provide a platform to find better treatment strategies for these deadly cancers.

Suggested reading

Hirbe AC, Zhang X, Dahiya S, Godec A, Chrisinger J, Tao Y, Luo J, Gutmann DH. β-III-spectrin immunohistochemistry as a potential diagnostic tool with high sensitivity for malignant peripheral nerve sheath tumors. Neuro Oncol. 2018 May 18;20(6):858-860. doi: 10.1093/neuonc/noy038. PMID: 29596596.

Reilly KM, Kim A, Blakely J, Ferner RE, Gutmann DH, Legius E, Miettinen MM, Randall RL, Ratner N, Jumbé NL, Bakker A, Viskochil D, Widemann BC, Stewart DR. Neurofibromatosis Type 1-Associated MPNST State of the Science: Outlining a Research Agenda for the Future. J Natl Cancer Inst. 2017 Aug 1;109(8). doi: 10.1093/jnci/djx124. PMID: 29117388.

Hirbe AC, Kaushal M, Sharma MK, Dahiya S, Pekmezci M, Perry A, Gutmann DH. Clinical genomic profiling identifies TYK2 mutation and overexpression in patients with neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Cancer. 2017 Apr 1;123(7):1194-1201. doi: 10.1002/cncr.30455. Epub 2016 Nov 22. PMID: 27875628.

Hirbe AC, Dahiya S, Miller CA, Li T, Fulton RS, Zhang X, McDonald S, DeSchryver K, Duncavage EJ, Walrath J, Reilly KM, Abel HJ, Pekmezci M, Perry A, Ley TJ, Gutmann DH. Whole Exome Sequencing Reveals the Order of Genetic Changes during Malignant Transformation and Metastasis in a Single Patient with NF1-plexiform Neurofibroma. Clin Cancer Res. 2015 Sep 15;21(18):4201-11. doi: 10.1158/1078-0432.CCR-14-3049. Epub 2015 Apr 29. PMID: 25925892.

Hirbe AC, Pekmezci M, Dahiya S, Apicelli AJ, Van Tine BA, Perry A, Gutmann DH. BRAFV600E mutation in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumors. Neuro Oncol. 2014 Mar;16(3):466-7. doi: 10.1093/neuonc/not248. Epub 2013 Dec 22. PMID: 24366910.