*4.3. Transforming Growth Factor-β TGF-β Inhibition*

During cancer progression, cross-talk of EGFR signaling occurs with another important signaling cascade, which is centered around the cytokine family of TGF-β [248,249]. The effects of TGF-β are very diverse and affect many signaling pathways of numerous cell types in vivo, including cancer cells [249]. Due to the interaction complexity, the effect of TGF-β evolves throughout the progression of cancer. Initially, it has a suppressing effect by triggering cell cycle arrest [250]. However, as cancer progresses, tumor cells become resistant to this response and TGF-β signaling results in epithelial–to-mesenchymal transition and increased cell migration with subsequent metastases [250,251]. TGF-β also contributes to an immunosuppressive TME [252], which impedes any anti-tumor immune response that is elicited during OV treatment [253]. Indeed, when a small-molecule inhibitor of TGF-β receptor 1 (TGF-βR1), known as A8301 [254], was combined with oncolytic HSV as treatment for murine rhabdomyosarcoma, an increased efficacy was seen due to an improved anti-tumor T cell response [255]. During non-canonical TGF-β signaling, crosstalk occurs with numerous other signaling pathways, such as PI3K, JNK and NF-κB [249]. As described above, these signaling pathways can have inhibiting effects on the replication and potency of OVs. In certain tumor settings an indirect inhibition of the pathways through TGF-β blockage could also promote OV replication. Indeed, in glioblastoma (GBM) the TGF-βRI kinase inhibitors, galunisertib [256], SB431542 and LY2109761 facilitated an increase in HSV replication through indirect inhibition of JNK-MAPK signaling [257]. Interestingly, SB431542 also inhibited oncolytic reovirus-mediated cell lysis, contrary to A8301 and galunisertib (LY2157299), indicating TGF-β signaling independent mechanisms further to be elucidated [258].
