Abstract
Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1. NF1 encodes neurofibromin, a negative regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic RAS gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.
Highlights
Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1
A more recent study revealed that blockade of mTOR with sapanisertib, which inhibits mTORC1 and mTORC2, with histone deacetylase (HDAC) inhibition is selectively toxic to Ras pathway-driven tumors, including human malignant peripheral nerve sheath tumors (MPNSTs) xenografts and the NPCis GEM model, by converging on the TXNIP/thioredoxin pathway [52]
If these results are validated in isogenic model systems and proper in vivo preclinical MPNST models, these drugs should be tested in vivo, possibly with the signaling inhibitors described above that leverage sensitivities from loss of NF1 expression
Summary
NF1 encodes a large GTPase activating protein (GAP) called neurofibromin. Monotherapy often leads to emergence of drug resistance, and work from our lab indicates MEK inhibition can synergize with other therapeutics, such as mTOR inhibitors [13] It is unclear if MEK inhibition will be useful in MPNST treatment, but preclinical data suggests that it may [12]. Loss of H3K27me, known to be caused by mutations in SUZ12 or EED, is an indicator of a bad prognosis in MPNST [24]. These common mutations in chromatin remodeling machinery provide unique avenues of therapeutic targeting. To determine if such therapeutic ideas might have merit in the clinic, it is critical to ensure that the very best model systems for MPNSTs are utilized
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