**3. Combination Therapies**

Nevertheless, monotherapy with oncolytic MeV will often be insufficient to cure advanced stage malignancies. Modern medical oncology builds on effective combination therapies. Therefore, measles virotherapy has been combined with other established cancer therapies such as radiation and chemotherapy (recently reviewed in [47]). Synergistic effects of oncolytic MeV and radiotherapy against glioblastoma were observed in vitro and in a xenograft model [48]. In vitro studies have also demonstrated successful combination of oncolytic MeV with chemotherapies such as paclitaxel [49], camptothecin [50], and gemcitabine [51]. Combination with the anti-epidermal growth factor receptor (EGFR) monoclonal antibody nimotuzumab was reported to result in increased antitumor efficacy in laryngeal cancer models [52].

Several small molecules have also been shown to enhance MeV oncolysis by modulating host cell factors. MeV infection is associated with heat shock protein (Hsp) 70 upregulation. Combination treatment with a Hsp90 inhibitor, resulting in increased Hsp70 expression [53,54], led to increased apoptosis [55]. Counteracting the IFN response, e.g., with janus-associated kinase (JAK) inhibitors such as ruxolitinib, enhances MeV replication in vitro [56]. Epigenetic modulation by histone deacetylase (HDAC) inhibition was also reported to increase efficacy of oncolytic MeV by preventing induction of ISGs in hepatocellular carcinoma [57], but by a different, so far unresolved mechanism in pancreatic adenocarcinoma [58]. As MeV spread and syncytia formation involves remodeling of the actin cytoskeleton, inhibition of Rho-associated coiled-coil forming kinase (ROCK) was tested during treatment of prostate, breast, and glioblastoma cancer cells with MeV, yielding increased viral replication, spread, and tumor cell killing [59]. Compounds which modulate cellular metabolism have also been tested in combination approaches. Blocking aerobic glycolysis with dichloroacetate was shown to increase cell death upon MeV treatment [60]. Furthermore, inducing autophagy has been suggested as a combination strategy to promote MeV oncolysis [61].

Even combination with other oncolytic viruses is conceivable. Along these lines, the combination of MeV with mumps virus showed increased efficacy in a human prostate cancer xenograft model [62].
