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Combining virotherapy and angiotherapy for the treatment of breast cancer
M Bazan-Peregrino1, R C A Sainson, R C Carlisle
1Department of Oncology, Old Road Campus, University of Oxford, Oxford, UK.
Abstract:
A breast cancer-selective oncolytic adenovirus was engineered to express antagonists of vascular endothelial growth factor (VEGF) and Notch signaling to combine direct anticancer activity with disruption of tumor-associated angiogenesis. Replication of the parental virus, AdEHE2F, is stimulated by estrogen receptor (ER), E2F1 and hypoxia, and it mediates selective lysis of breast cancer cells in vitro and in vivo. Here, we encoded soluble Flt-1 (sFlt1) and soluble Dll4 (sDll4) under control of the E3 promoter. sFlt1 (the extra-cellular domain of VEGF receptor 1) binds VEGF-A and inhibits stimulation of VEGFR2, decreasing angiogenic stimulus. Conversely, sDll4 (the extracellular domain of Delta-like 4) antagonizes Notch signaling to prevent endothelial maturation. We hypothesized that these agents might show additive or synergistic activity. In vitro, sFlt1 inhibited endothelial cell proliferation and sprouting, whereas sDll4 increased the number of vascular branchpoints. In ER-positive ZR75.1 tumors in vivo AdEHE2F showed the potent direct virotherapy with no augmentation owing to sFlt1 or sDll4; however, in ER-negative MDA-231 tumors efficacy was enhanced by encoding sFlt1 or sDll4, with survival time extending to double that of controls. There was also a dramatic decrease in the total number of tumour blood vessels, as well as the number of perfused vessels, suggesting that improved efficacy reflects combined anti-tumour and anti-vascular effects.
Insights
Engineered oncolytic adenovirus targets breast cancer by inhibiting vascular endothelial growth factor (VEGF) and Notch signaling. This dual approach enhanced efficacy in ER-negative tumors, doubling survival time and reducing tumor vascularization.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Tumor angiogenesis
Background:
- Oncolytic adenoviruses offer selective cancer cell lysis.
- Tumor growth is supported by angiogenesis (new blood vessel formation).
- VEGF and Notch signaling pathways are crucial for angiogenesis.
Purpose of the Study:
- To engineer an oncolytic adenovirus expressing VEGF and Notch antagonists.
- To evaluate the combined anti-cancer and anti-angiogenic effects.
- To assess efficacy in estrogen receptor-positive and negative breast cancer models.
Main Methods:
- Engineered AdEHE2F adenovirus to express soluble Flt-1 (sFlt1) and soluble Dll4 (sDll4).
- Assessed in vitro effects on endothelial cells.
- Evaluated in vivo efficacy in ER-positive (ZR75.1) and ER-negative (MDA-231) breast cancer xenografts.
Main Results:
- In vitro, sFlt1 inhibited endothelial proliferation, while sDll4 increased vascular branching.
- In ER-positive tumors, AdEHE2F showed virotherapy alone; sFlt1/sDll4 did not augment efficacy.
- In ER-negative tumors, AdEHE2F encoding sFlt1 or sDll4 doubled survival and reduced tumor vascularization.
Conclusions:
- Combined anti-VEGF and anti-Notch strategies enhance oncolytic adenovirus efficacy in ER-negative breast cancer.
- The enhanced efficacy is attributed to synergistic anti-tumor and anti-vascular effects.
- This dual-targeting approach holds promise for treating specific breast cancer subtypes.
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