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Targeting trastuzumab-resistant breast cancer cells with a lentivirus engineered to bind antibodies that recognize
Kai-xin Zhang1, Connie Kim, Elaine Chow
1The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC V6H-3Z6, Canada.
Abstract:
Targeting HER-2 over-expressing breast cancer cells with trastuzumab has resulted in significant improvements in both disease-free and overall survival rates. However, despite a favorable initial response, some cancer cells become resistant and develop into fatal metastatic disease. Here we report that we can specifically target HER-2 over-expressing and trastuzumab-resistant breast cancer cells by using an engineered lentivirus which has trastuzumab bound to its envelope. In vitro, this lentiviral construct mediated both the expression of reporter genes, such as enhanced green fluorescent protein (EGFP) and firefly luciferase, as well as the therapeutic gene, herpes thymidine kinase (hTK), in HER-2 over-expressing cells. Subsequent application of the pro-drug ganciclovir selectively killed breast cancer cells in which lentivirus mediated expression of hTK. In vivo, we successfully targeted the expression of firefly luciferase to trastuzumab-resistant breast cancer tumors established in nude mice. Furthermore, we found that systemic administration of trastuzumab-bound lentivirus led to expression of EGFP in circulating trastuzumab-resistant breast cancer cells. In conclusion, HER-2 over-expressing breast cancer cells resistant to trastuzumab can be targeted for selective gene expression and destruction by viruses with envelope-proteins engineered to bind to this antibody.
Insights
Researchers engineered a lentivirus to target HER-2 over-expressing and trastuzumab-resistant breast cancer cells. This novel approach enables selective gene expression and destruction of resistant cancer cells.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Trastuzumab therapy improves survival in HER-2 over-expressing breast cancer but resistance develops.
- Trastuzumab resistance leads to fatal metastatic disease.
- Targeting resistant cancer cells remains a significant clinical challenge.
Purpose of the Study:
- To develop a targeted delivery system for HER-2 over-expressing and trastuzumab-resistant breast cancer cells.
- To utilize an engineered lentivirus for selective gene expression and therapeutic payload delivery.
- To demonstrate the efficacy of this approach both in vitro and in vivo.
Main Methods:
- Engineered a lentivirus with trastuzumab bound to its envelope for specific targeting.
- In vitro studies: assessed reporter gene (EGFP, luciferase) and therapeutic gene (hTK) expression in HER-2 over-expressing cells.
- In vitro studies: evaluated cancer cell killing using ganciclovir in hTK-expressing cells.
- In vivo studies: targeted trastuzumab-resistant breast cancer xenografts in nude mice with the lentivirus.
- In vivo studies: assessed systemic delivery and expression in circulating tumor cells.
Main Results:
- The engineered lentivirus successfully expressed reporter and therapeutic genes in HER-2 over-expressing cells in vitro.
- Ganciclovir treatment selectively killed cancer cells expressing herpes thymidine kinase (hTK) delivered by the lentivirus.
- In vivo, the lentivirus targeted luciferase expression to trastuzumab-resistant tumors in mice.
- Systemic administration of the trastuzumab-bound lentivirus resulted in EGFP expression in circulating resistant cancer cells.
Conclusions:
- Engineered lentiviruses can specifically target HER-2 over-expressing breast cancer cells resistant to trastuzumab.
- This targeted viral vector facilitates selective gene expression for potential therapeutic interventions.
- The approach demonstrates potential for selective destruction of resistant cancer cells via gene therapy.
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