Enrico Martin

172 Chapter 7 compared to a placebo control group. The addition of erlotinib, an EGFR inhibitor, did not significantly improve the efficacy compared to oHSV monotherapy in vivo. 70 However, additional AURKA inhibition was found to have a synergistic effect on both tumor growth and survival. 74 Immunotherapy and oncolytic viruses –trials Two ongoing trials are investigating the role of PD1 checkpoint inhibitors ( Table 3 ): one looks at PD1 inhibitors alone and includes MPNST patients only (NCT02691026), while the other study combines the PD1 inhibitor nivolumab with CTLA-4 inhibitor ipilimumab and includes patients with rare tumors, one of which is MPNST (NCT02834013). No clinical trial has yet evaluated the effect of oncolytic viruses in MPNSTs. Two trials are registered of which one will use an oMV in MPNST patients only (NCT02700230) and the other, which is complete and whose results are pending, investigated the effect of an oHSV in non-central nervous system (CNS) solid tumors including MPNSTs (NCT00931931, Table 3 ). Other targets – in vivo Eight studies investigated other types of drugs, targeting different pathways including fatty acid synthase (FAS), 76 pigment epithelium-derived factor (PEDF), 77 calcium channels, 78 survivin, 79 hyaluronan synthesis, 80 and other apoptosis-inducing pathways ( Table 1 ). 81–83 Most studies found an intermediate effect on tumor growth (6/9 cell lines), and only verticillin A and PEDF were found to have a high effect on tumor growth. 77,83 Docosahexaenoic acid (DHA) showed an intermediate effect on tumor growth, but increased survival significantly. 81 None of these drugs has yet been established in a trial setting that includes MPNST patients. Discussion MPNST still remains a highly aggressive sarcoma subtype with poor outcome despite regular cytotoxic treatment. Novel strategies to target metastatic MPNST and improve its outcomes, both in terms of survival as well as quality of life, are needed. In locally advanced disease, neoadjuvant treatment that can downsize the primary tumor and allow for subsequent surgical resection is also of value. In this review, we sought to describe new approaches to treat advanced MPNST. Multiple membrane, cytoplasmic, and nuclear actors are potential targets in the therapy of MPNST, of which mTOR inhibition is most commonly investigated in vivo and has frequently resulted in high responses on tumor growth (81.3% of cell lines) and survival (100% of cell lines). Targeted therapies In vivo , RTK inhibitors that include VEGFR inhibition have also shown intermediate to high responses. However, monotherapy with an RTK inhibitor has not shown tumor