New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

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.

Keywords: Schwann cells; genetically engineered mouse models; malignant peripheral nerve sheath tumors; neurofibromatosis type 1 syndrome; neurofibromin 1; plexiform neurofibromas.

Figure 1

Synthetic lethality if the genetic incompatibility of the loss of two independent gene products results in cell death. Whereas a hypothetical cell can survive with either loss of Gene A or Gene B, it cannot live with loss of both simultaneously. A prime example of this being exploited therapeutically is in BRCA1/2 mutated cancers and their sensitivity to PARI inhibitors such as olaprarib. Similarly, loss of NF1 could render human Schwann cells sensitive to pharmacologic intervention with novel agents.

Figure 2

Screening scheme utilizing NF1-deficeint immortalized or iPSC derived human Schwann cells. NF1 −/− cells (of either origin) and their isogenic match parental lines can be used in selective lethal pharmacologic screens or synthetic lethal genetic screens. Compounds found to only kill NF1-deficient cells could be then prioritized for further preclinical testing, using in vivo models of MPNST for example. Novel genetic targets identified from genome-wide synthetic lethal genetic screens could provide the basis for additional drug discovery efforts.