Enrico Martin

163 Emerging therapeutic targets vivo studies were found that used numerous genetically engineered mouse models (GEMM), (non)-cultured NF1 and sporadic patient xenografts, allografts from GEMMs, and one zebrafish model ( Table 1 ). Nineteen trials were identified, of which six have already been published ( Table 2 ), and thirteen are ongoing ( Table 3 ). Figure 2 presents the most important target pathways identified in MPNSTs. Membrane targets – in vivo Eight studies investigated membrane targets in vivo ( Table 1 ). Six used receptor tyrosine kinase (RTK) targeted treatments with intermediate to high effect on tumor growth. 25– 30 The addition of verteporfin (TAZ/YAP inhibitor) to sorafenib yielded intermediate effects on tumor growth in an allograft model, while monotherapy of either drugs had significantly worse effects. 28 The chemokine receptor CXCR4 stimulates cell cycle progression through PI3K and β-catenin signalling. In one in vivo study, inhibition of CXCR4 showed intermediate effect on tumor growth and increased survival of mice. 29 Two in vivo studies investigated the effect of estrogen receptor blockade; one found a low effect on tumor growth, 31 and another showed that the addition of a calmodulin inhibitor enhanced the effect on tumor growth. 32 Membrane targets – trials Four published clinical trials investigating the effect of an RTK inhibitor, of which one 33 specifically examined MPNST patients ( Table 2 ), were identified. None of the trials found an appreciable clinical response in MPNST patients, with only 0-20% of the patients achieving stable disease. 33–36 Four additional trials were still ongoing at the time this review was written, one of which will only include MPNST patients. This study will evaluate the efficacy of the multikinase inhibitor pexidartinib in combination with mTOR inhibitor sirolimus (NCT02584647, Table 3 ). Multiple other trials were identified that will enroll patients with soft tissue sarcomas (NCT02584309, NCT02180867) and CD56 expressing tumors (NCT02452554) targeting additional membrane targets. One of these trials will investigate the effect of doxorubicin and ifosfamide with the addition of pazopanib, currently the only registered RTK inhibitor for STS, in a neoadjuvant setting including patients with resectable soft tissue sarcomas (NCT02180867). 7