*3.2. Status of Oncogenic Signaling Pathways Affected in Glioblastoma*

*3.2. Status of Oncogenic Signaling Pathways Affected in Glioblastoma* Many OVs applied in glioma studies are genetically engineered or have naturally evolved to exploit oncogenic signaling pathways in cancer cells, such as the Ras, Rb, p53 or nucleotide synthesis pathways [58]. Therefore, OV efficacy could potentially be enhanced by stratification of patients based on activation status or presence of mutations in Many OVs applied in glioma studies are genetically engineered or have naturally evolved to exploit oncogenic signaling pathways in cancer cells, such as the Ras, Rb, p53 or nucleotide synthesis pathways [58]. Therefore, OV efficacy could potentially be enhanced by stratification of patients based on activation status or presence of mutations in targeted pathways.

targeted pathways. Another targeting approach is by the insertion of tumor-specific promoters to drive specific viral replication in tumor cells and avoid toxicity to normal tissue [59]. Various promoter candidates have been applied to design tumor-specific promoter-driven OVs, including nestin, survivin, cyclooxygenase-2 (COX-2), C-X-C chemokine receptor type 4 Another targeting approach is by the insertion of tumor-specific promoters to drive specific viral replication in tumor cells and avoid toxicity to normal tissue [59]. Various promoter candidates have been applied to design tumor-specific promoter-driven OVs, including nestin, survivin, cyclooxygenase-2 (COX-2), C-X-C chemokine receptor type 4 (CXCR4), hypoxia inducible factor-1 (HIF-1) and telomerase [10,60–63]. Considering the

intertumoral heterogeneity in transcription profiles of GBM, it would be expected that the response to such OVs might vary between GBM subtypes. One could hypothesize that GBM with proneural features might be more sensitive to viruses targeting cells expressing neuronal progenitor genes (e.g., nestin), whereas tumors of mesenchymal subtype may be more sensitive to viruses in which replication is driven by the inflammation-activated COX-2 or CXCR4 promoter [62–64].
