Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies

Abstract

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST.

mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors

“…MPNSTs that arise in individuals with NF1 are inherently more homogeneous as compared to lung cancer, in that they are initiated by NF1 mutations and progress due to a specific set of additional genetic alterations (47–49). In contrast, lung cancers are much more genetically and biologically heterogeneous (50,51).…”

Malignant peripheral nerve sheath tumor: The need to get it right first time around

“…The role of NF1 gene loss in both spontaneous and NF-1-associated MPNSTs suggests that NF1 is an important tumor suppressor. 8 In all MPNSTs, other genomic alterations such as CDKN2A and TP53 are important driver genes, again associated with both sporadic and radiation-induced MPNSTs and, indeed, in NF-1 patients. 9 This is of course maybe simplifying the picture as there is probably a role for the "epigenetic switch" and other genomic phenomena.…”

“…This is of course maybe simplifying the picture as there is probably a role for the “epigenetic switch” and other genomic phenomena. This of course leads to the potential of epigenetic‐based therapeutic strategies, especially now that there are multiple drugs that alter the epigenetic pathway via both inhibition and antagonism …”

“…This of course leads to the potential of epigenetic-based therapeutic strategies, especially now that there are multiple drugs that alter the epigenetic pathway via both inhibition and antagonism. 8,9 In NF1 subjects there is probably a transformation from plexiform neuromas to distinct nodular lesions (DNLs) and then to malignant peripheral nerve sheath tumors. As half of all MPNSTs are in the NF1 population, perhaps a better understanding of NF1 lesions and their progression to MPNST could serve as a model for further therapeutic intervention and, in particular, offer us an opportunity to screen these patients in order to try to detect small lesions, in particular those that are more likely on imaging such as magnetic resonance imaging and fluorodeoxyglucose positron emission tomography to be DNLs, remove them, and hopefully prevent their development into MPNSTs.…”

Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/P38 signaling

“…Even though CNFs and PNFs share identical histology, they are pathophysiologically distinct. NF1-related PNFs are associated with the development of high grade malignant peripheral nerve sheath tumors, which are the leading cause of death of NF1 patients(1). In contrast, CNFs exhibit slower growth rates and are not associated with malignant potential(2-4).…”