Challenges and Progress for Treatment of Malignant Peripheral Nerve Sheath Tumors in the Context of Recent Successes for Sarcoma Therapy.

Malignant peripheral nerve sheath tumors (MPNSTs) are one of the most difficult sarcomas to treat. Due to the rarity of MPNSTs, many of the therapeutic approaches used are from treatment guidelines for soft tissue sarcoma. Besides surgery, little success has been achieved using these therapies. Traditional chemotherapy and radiation therapy regimens designed to treat sarcoma have unclear efficacy when used to treat MPNSTs. Targeted therapeutics that succeeded in other sarcomas failed to produce positive results in MPNSTs. Moreover, investigational agents that have shown efficacy in preclinical models have produced disappointing outcomes in clinical trials. While therapeutic options for patients with MPNST have remained relatively stagnant, dramatic improvements in therapeutic outcomes of other rare sarcomas have been made. This difference in success is likely caused by the complex heterogeneity of MPNSTs that hinders drug development, although many MPNSTs are associated with neurofibromatosis type 1 (NF1), a genetic disorder resulting from mutations in the NF1 gene that encodes the negative RAS regulator neurofibromin. The development of new agents for MPNST treatment has shifted away from solely targeting RAS pathway gene products to stimulating the immune system and manipulating other MPNST driver mutations such as