The most common tumors seen in individuals with NF1 are peripheral nerve sheath tumors (cutaneous and plexiform neurofibromas). These tumors are typically slow growing, but can transform into malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are highly aggressive cancers, which frequently metastasize to other organs.
Research in the laboratories of Dr. Angela Hirbe and Dr. Corina Anastasaki are focused on generating new models of these tumors using a combination of genetically engineered mice and patient-derived cancers. Dr. Angela Hirbe and Dr. Aadel Chaudhuri are using advanced DNA detection methods to monitor cancer development and progression, whereas Dr. Corina Anastasaki is working to understand how nerves control neurofibroma growth.
- Genetics of malignant peripheral nerve sheath tumors
- Developing next-generation models of nerve sheath tumors
- Role of nerves in nerve sheath tumor development
- Developing novel treatments for nerve sheath tumors
Genetics of malignant peripheral nerve sheath tumors
In order to discover new therapeutic approaches for MPNSTs, Dr. Angela Hirbe and her colleagues are using advanced genetic and genomic methods to define the molecular changes responsible for MPNST development and metastasis.
Dehner C, Moon CI, Zhang X, Zhou Z, Miller C, Xu H, Wan X, Yang K, Mashl J, Gosline SJ, Wang Y, Zhang X, Godec A, Jones PA, Dahiya S, Bhatia H, Primeau T, Li S, Pollard K, Rodriguez FJ, Ding L, Pratilas CA, Shern JF, Hirbe AC. Chromosome 8 gain is associated with high-grade transformation in MPNST. JCI Insight. 2021 Mar 22;6(6):e146351. doi: 10.1172/jci.insight.146351. PMID: 33591953
Godec A, Jayasinghe R, Chrisinger JSA, Prudner B, Ball T, Wang Y, Srihari D, Kaushal M, Dietz H, Zhang X, Pekmezci M, Dahiya S, Tao Y, Luo J, Van Tine BA, Ding L, Gutmann DH, Hirbe AC. Whole exome sequencing reveals the maintained polyclonal nature from primary to metastatic malignant peripheral nerve sheath tumor in two patients with NF1. Neurooncol Adv. 2019 Sep 10;2(Suppl 1):i75-i84. doi: 10.1093/noajnl/vdz026. eCollection 2020 Jul. PMID: 32642734
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
Developing next-generation models of peripheral nerve sheath tumors
Using a combination of approaches, including mouse and human cellular engineering, Dr. Angela Hirbe and Dr. Corina Anastasaki are developing next-generation models of plexiform neurofibroma and malignant peripheral nerve sheath tumors.
Mo J, Anastasaki C, Chen Z, Shipman T, Papke J, Yin K, Gutmann DH, Le LQ. Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins. J Clin Invest. 2021 Jan 4;131(1):e139807. doi: 10.1172/JCI139807. PMID: 33108355
Inoue A, Janke LJ, Gudenas BL, Jin H, Fan Y, Paré J, Clay MR, Northcott PA, Hirbe AC, Cao X. A genetic mouse model with postnatal Nf1 and p53 loss recapitulates the histology and transcriptome of human malignant peripheral nerve sheath tumor. Neurooncol Adv. 2021 Sep 10;3(1):vdab129. doi: 10.1093/noajnl/vdab129. eCollection 2021 Jan-Dec. PMID: 34647023
Hirbe AC, Dahiya S, Friedmann-Morvinski D, Verma IM, Clapp DW, Gutmann DH. Spatially- and temporally-controlled postnatal p53 knockdown cooperates with embryonic Schwann cell precursor Nf1 gene loss to promote malignant peripheral nerve sheath tumor formation. Oncotarget. 2016 Feb 16;7(7):7403-14. doi: 10.18632/oncotarget.7232. PMID: 26859681
Role of nerves in peripheral nerve sheath tumor development
Neurofibromas also form and grow in an environment rich in nerves. While not conventionally thought to control tumor development and progression, recent studies have revealed that nerve cells are important drivers of plexiform neurofibroma growth.
Dr. Gutmann, Dr. Anastasaki and colleagues are focused on defining the mechanisms by which nerves control neurofibroma growth, and identifying therapies that safely block neuron activity-driven tumor expansion. Dr. Yuan Pan is working with Dr. Angela Hirbe to determine how nerves and neuronal hyperactivity control MPNST growth.
Anastasaki C, Mo J, Chen JK, Chatterjee J, Pan Y, Scheaffer SM, Cobb O, Monje M, Le LQ, Gutmann DH. Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1. Nat Commun. 2022 May 19;13(1):2785. doi: 10.1038/s41467-022-30466-6. PMID: 35589737
Developing novel treatments for peripheral nerve sheath tumors
One of the areas of intense study in the laboratory of Dr. Angela Hirbe is the development and evaluation of promising drugs for the treatment of malignant peripheral nerve sheath tumors. In collaboration with Dr. Aadel Chaudhuri, Dr. Hirbe and her team are also investigating the use of circulating tumor DNA in the blood as an early marker of malignant transformation.
Borcherding DC, Amin NV, He K, Zhang X, Lyu Y, Dehner C, Bhatia H, Gothra A, Daud L, Ruminski P, Pratilas CA, Pollard K, Sundby T, Widemann BC, Hirbe AC. MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors. Clin Cancer Res. 2023 Apr 14;29(8):1592-1604. doi: 10.1158/1078-0432.CCR-22-3722. PMID: 36799629
Wang J, Calizo A, Zhang L, Pino JC, Lyu Y, Pollard K, Zhang X, Larsson AT, Conniff E, Llosa N, Wood DK, Largaespada DA, Moody SE, Gosline SJ, Hirbe AC, Pratilas CA. CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon restoration of RB function in malignant peripheral nerve sheath tumors. bioRxiv. 2023 Feb 3:2023.02.02.526674. doi: 10.1101/2023.02.02.526674. Preprint. PMID: 36778419
Szymanski JJ, Sundby RT, Jones PA, Srihari D, Earland N, Harris PK, Feng W, Qaium F, Lei H, Roberts D, Landeau M, Bell J, Huang Y, Hoffman L, Spencer M, Spraker MB, Ding L, Widemann BC, Shern JF, Hirbe AC, Chaudhuri AA. Cell-free DNA ultra-low-pass whole genome sequencing to distinguish malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion: A cross-sectional study. PLoS Med. 2021 Aug 31;18(8):e1003734. doi: 0.1371/journal.pmed.1003734. eCollection 2021 Aug. PMID: 34464388