Enrico Martin

168 Chapter 7 Cytoplasmic targets – in vivo Cytoplasmic targets were investigated in 25 in vivo studies ( Table 1 ). Most studies (n = 22) focused on a target within the MAPK or the PI3K/Akt/mTOR pathway. In those targeting the PI3K/Akt/mTOR pathway, a high effect on tumor growth (14/17 cell lines) and survival was observed (3/3 cell lines). Targeting mTOR in combination with membrane targets, 37–39 other cytoplasmic targets, 40–42 or an epigenetic target 43 showed high effect on tumor growth (8/8 cell lines) and survival (3/3 cell lines). One study found a higher effect of pexidartinib compared to imatinib as an addition to mTOR inhibition. 38 The addition of sorafenib (targets include VEGFR, PDGFR, and Raf) to an mTOR inhibitor showed the best effect on tumor size in NF1-mutated xenografts, while the addition of doxorubicin showed best effects in sporadic patient xenografts. 39 The addition of a proteasome inhibitor to mTOR inhibition was only effective if radiotherapy was administered as well. 44 The addition of a mitogen-activated protein kinase (MEK) inhibitor to mTOR inhibition did not prolong survival in a murine model, but did decrease toxicity compared to single agent usage. 42 MEK inhibition itself did not show high effects on tumor growth; 45–48 however in combination with other target inhibitors the effect on tumor growth improved (5/5 cell lines). 8,30,49 The addition of silmasertib, an epigenetic modulator of CK2, did not have a superior effect over MEK-inhibiting monotherapy. 47 PAK1 influences the MAPK pathway by activating MEK and ERK. In multiple studies, inhibition of PAK1 resulted in intermediate to high effects on tumor growth as a single drug. 49–51 One study showed that the addition of a MEK inhibitor to a PAK1 inhibitor increased its effect in both NF1 and sporadic cell lines. 49 Although EGFR inhibitors in MPNST have shown poor results in clinical studies, downstream inhibition of Janus kinase 2/signal transducer and activator of transcription 3 ( JAK2/STAT3) showed intermediate to high effect in vivo . 52,53 Cytoplasmic targets – trials One trial evaluating the effect of mTOR inhibition in combination with bevacizumab, a VEGF inhibitor, demonstrated stable disease in 3/25 patients. 54 A total of three trials that were ongoing at the time of this review were investigating the role of an mTOR inhibitor in combination with a MEK inhibitor (NCT03433183), pazopanib (NCT02601209), or heat shock protein 90 (Hsp90) inhibitor (NCT02008877, Table 3 ). The latter trial was completed, although its results were not yet published. Nuclear targets – in vivo The effect of nuclear target inhibitors was investigated in twelve studies, identifying this class of drugs to have intermediate to high effects on tumor growth ( Table 1 ). Multiple studies found a high effect on survival (4/4 cell lines) or tumor growth (5/15 cell lines) via in vivo inhibition of several epigenetic pathways. 55–63 Aurora kinase A (AURKA) is one of these epigenetic regulators, which regulates centrosome maturation and chromosome separation. Alisertib, an AURKA inhibitor was found to have a higher effect on tumor growth and survival compared to a combination of doxorubicin and ifosfamide in vivo . 63