TYK2 as a Biomarker and Therapeutic Target for NF1-Associated Malignant Peripheral Nerve Sheath Tumors
Abstract
The most common malignant cancer affecting people with neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft tissue cancer (sarcoma) that commonly develops from a benign precursor tumor. In this regard, 8%-13% of adults with NF1 will develop MPNSTs. Currently, there are no effective treatments for these cancers, and the vast majority of people with MPNST will die within 5 years of initial diagnosis. Because these cancers arise from benign tumors, there is also a pressing need to be able to diagnose and distinguish true MPNSTs from non-cancerous precursors, which appear similar on advanced imaging studies such as MRI or PET scans. Using DNA sequencing technologies, we recently identified a frequently mutated gene in NF1-associated MPNSTs called TYK2. This mutation is not found in the benign precursors, however. Furthermore, in our previous experiments, we showed that mutations in this gene are critical for tumor cell survival, both in petri dishes and in tumors from mice. Thus, we propose that TYK2 mutations drive tumor growth by preventing cell death. In this manner, TYK2 mutations may suggest a poor prognosis for those MPNSTs that harbor them. Furthermore, drugs that block the effects of TYK2 may prove to be useful in the battle against this aggressive cancer. In this project, we aim to clarify the role of TYK2 in MPNST development and growth by performing experiments in previously engineered tumor cell lines in petri dishes as well as brand new tumor cells derived by our laboratory from patient samples and grown in mice. In addition, we will determine whether TYK2 mutations can reliably determine the likelihood of a poor prognosis or future tumor progression. Finally, we will assess whether drugs that block TYK2 prevent MPNST growth both in the petri dish and in mouse tumors. These experiments have the potential to lead to a markedly better treatment, which is desperately needed for these aggressive sarcomas.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010148
Entities
People
- Angela Hirbe
Organizations
- United States Army
- Washington University in St. Louis