KEY POINTS
- The investigators studied breast cancer and patient-derived glioblastoma cell lines alongside subcutaneous, orthotopic mammary and intracranial mouse models. The oncolytic herpes simplex virus rHSVQ shares its viral backbone with clinical candidates CAN-3110 and G207.
- Oncolytic HSV1 increased IGF1R and AKT phosphorylation and promoted Ki67-positive tumour-cell proliferation near sites of viral replication. Activation occurred in both infected cells and neighbouring uninfected tumour cells.
- Combining oncolytic HSV1 with the IGF1R inhibitor OSI-906 modestly increased cytotoxicity but was mainly additive rather than synergistic. OSI-906 concentrations of at least 0.5 µM also inhibited viral replication, and poor blood-brain-barrier penetration limited activity in intracranial glioblastoma models.
- With the brain-penetrant IGF1R inhibitor picropodophyllin, oncolytic HSV1 increased median survival from 26 to 41 days in GBM12 and from 62 to 76 days in GBM28 models (p = 0.0109 and p = 0.0347).
- Dual oncolytic HSV1 and radiotherapy increased tumour-cell killing but also amplified IGF1R activation and YAP1 expression and nuclear localization. In intracranial GBM12 models, median survival was 40 days with dual treatment versus 31 days with oncolytic HSV1 and 26 days with radiotherapy.
- Triple treatment with oncolytic HSV1, radiotherapy and IGF1R inhibition showed synergistic activity, reduced IGF1R-AKT signalling, suppressed YAP1 and its target genes CCN1 and CCN2, and reduced tumour-cell proliferation, self-renewal and colony formation.
- In orthotopic breast cancer xenografts, mean tumour volume at day 22 was 49.6 mm³ with triple therapy versus 432.2 mm³ in controls, with complete regression in 5 of 8 mice. Intracranial GBM12 median survival reached 50 days, versus 32.5–40 days with the tested dual combinations (p < 0.0001); YAP1 also increased after oncolytic HSV1 in 7 of 12 human recurrent glioblastoma samples.
CLINICAL TAKEAWAY
IGF1R-YAP1 signalling appears to be an adaptive resistance mechanism shared by oncolytic HSV1 and radiotherapy and may become therapeutically exploitable after the two treatments are combined. Translation remains distant: the results depend on preclinical models, systemic IGF1R inhibitors have known toxicity and blood-brain-barrier limitations, and treatment sequencing requires formal optimization.