Enrico Martin

173 Emerging therapeutic targets regression clinically in MPNSTs except for a modest prolongation of median progression free survival in case of pazopanib treatment in all types STS. 84 Apart from two in vivo studies using cabozantinib, no other study has yet investigated the effect of MET inhibition, although it is a known contributor to malignancy in MPNSTs. RTK inhibitors targeting both the VEGF pathway as well as other pathways, or combinations with other treatment types might therefore be of interest. Unfortunately, although MPNSTs are Ras-driven tumors, no drug has yet been found to successfully target Ras. Ras inhibitors are difficult to create due to a lack of well-defined druggable pockets and cavities on its surface. 85 Targeting upregulated downstream targets of Ras is nevertheless possible. Besides upregulation of the PI3K/Akt/mTOR pathway, upregulation of the MAPK pathway in NF1 tumors has been described several times. 6 In this review we described the potential of mTOR inhibitors, which might be increased by the current development of more specific inhibitors of elements of the mTOR pathway. Although single agent MEK inhibition has not resulted in tumor suppression, 45–47 combinations with mTOR inhibitors might prove potent in terms of anti-tumorigenic effects, but at the cost of increased toxicity. 30,41 The, translationally controlled tumor protein (TCTP), a downstream effector of both the MAPK and mTOR, can be successfully inhibited leading to cell death in NF1-associated tumors. 86 and was found to increase mTOR activity when upregulated, indicating a positive feedback loop. In vivo studies on MPNST models are, however, still warranted. Other targets of interest identified in this review are PAK1 inhibitors, 49–51 as well as PI3K inhibitors. ERK inhibitors are being developed as well, which may have less toxicity, but their effect on MPNST cells is still unknown. 87 Immunotherapy While checkpoint inhibitors are gaining interest in other types of tumors, they have yet to be extensively studied in STS. Two ongoing trials will hopefully elucidate the role of these types of drugs in MPNST (NCT02691026, NCT02834013). Oncolytic viruses are showing efficacy without severe toxicity in various cancers including MPNSTs. 88,89 Moreover, as demonstrated for other tumors, an additional pathway inhibitor may give a synergistic effect when combined with oncolytic viruses. 74 Overall, while therapies with oncolytic viruses appear promising in MPNST, more in vivo studies are needed to better understand their role as well at the role for any treatment combinations. Progress in systemic treatment The lack of progress in the treatment of MPNST is multi-factorial. First, adequate preclinical models representing both NF1-associated MPNSTs as well as sporadic MPNSTs are lacking. The causal mechanisms behind NF1-associated MPNST may differ from those in sporadic MPNST, resulting in different sensitivity for treatment. This is supported by the fact that in conventional chemotherapy, NF1 patients are known to have a lower response rate. 2,17,90 However, only few in vivo studies show a difference in response on tumor growth between NF1 and sporadic patient-derived models, while others show no difference. Thus, clinical translation of these differences might 7