Considering the biology of MPNST tumors, obvious and potential targets can be recognized. Growth and activation receptors, such as vascular endothelial growth factor receptors (VEGFR), epidermal GFR (EGFR), and platelet-derived GFR (PDGFR), activate two pivotal intracellular activation pathways, i.e., the MAPK signal transduction pathway and the P13K-AKT-mammalian target of rapamycin (mTOR). Potential targets for therapy are found on all three levels of normal signal transduction, i.e., receptor kinases, MAPK pathway, and the P13K-AKT-mTOR pathway. Currently, the most considered in NF1 disease is inhibition of the MAPK pathway via MEK inhibitors (MEKi). MEKi potentially neutralize the loss of
NF1 in controlling Ras activation. Selumetinib is a MEK1/2 inhibitor therefore can convey an anti-tumor signal by inhibiting Ras signals. In pediatric NF1 patients, selumetinib was very effective in controlling the growth of inoperable plexiform neurofibromas. Partial response was observed in 17/24 patients (71%) [
93]. Selumetinib was consequently approved in 2019 by the US FDA for treatment of pediatric patients (
> 3 years) with symptomatic or inoperable plexiform neurofibroma. In the treatment of MPNST, selumetinib has not yet been approved, but several trials including (plexiform) neurofibromas and some including MPNST are being conducted (i.e., NCT03433183, NCT02124772). Targeting of upstream tyrosine kinase receptors, alone or in combination with chemotherapy, can also de-activate the MAPK or mTOR pathways. A phase 2 randomized study of doxorubicin plus olaratumab (anti-PDGFRα antibody) compared with doxorubicin monotherapy showed a better OS and trend towards improved median progression-free survival for the combination treatment arm [
94]. The study included MPNST patients but did not report separate analyses of this subgroup. Imatinib inhibits specifically the tyrosine kinase domain in ABL (effective in BCR-ABL translocated leukemia), c-KIT, and PDGFR. Imatinib has proven activity in other (pediatric) STS, including dermatofibrosarcoma protuberans (DFSP), gastrointestinal stromal tumor (GIST), and desmoid fibromatosis. However, in MPNST, imatinib has not been found effective [
95,
96]. Other RTK inhibitors, such as erlotinib, sunitinib, sorafenib, cediranib, and dasatinib, are all potential inhibitors of NF1-related tumors but have not been found effective in few phase 1 studies with limited information on effectiveness, and they all reported on considerable side effects [
97‐
102]. Inhibition of the mTOR pathway has been effective in several tumor models [
103]. One trial in 25 adult MPNST patients administered everolimus and bevacizumab combination therapy, but found only stable disease in 3 patients [
104]. Currently, several combination therapies with mTOR inhibition are being undertaken including at least in some part of MPNST patients (NCT02584647, NCT01661283, NCT03433183, NCT02008877, NCT02601209). Anti-GD2-based immunotherapy could potentially be useful in MPNST. Gangliosides are abundantly expressed in neuro-ectodermal-derived tissues (Schwann cells) and tumors. In neurofibromas, the expression of gangliosides has been established [
105]. For MPNST, this has not yet been studied. The CH(O)14,18 chimeric mouse-human anti-GD2 antibody has proven to be safe and effective in pediatric high risk neuroblastoma tumors resulting in significantly increased OS [
106]. Dinutuximab has been FDA-approved and dinutuximab-beta has been EMA-approved for standard use in high risk neuroblastoma. So far, no studies applying anti-GD2 antibodies in MPNST or other neuro-ectodermal tumors (melanoma, non-small cell lung cancer) have been conducted. Another type of immunotherapy using anti-CTLA4 and/or anti-PD(L)-1 inhibitors has proven effectiveness in several tumors (melanoma, non-small cell lung cancer, mesothelioma and others). A recent phase 2 trial combining nivolumab with ipilimumab in advanced sarcomas yielded promising effects, although the study did not specify the included types of sarcomas [
107]. One trial is currently ongoing in MPNSTs specifically investigating the effect of pembrolizumab (NCT02691026). Oncolytic viruses have proven effective in vivo, and one trial is currently investigating the effect of oncolytic measles virus in MPNST patients (NCT02700230) [
103].