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Epidermal growth factor receptor targeting enhances adenoviral vector based suicide gene therapy of osteosarcoma
M A Witlox1, V W Van Beusechem, J Grill
1Department of Orthopedic Surgery, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
Background:
Despite improvements in the treatment of osteosarcoma (OS) there are still too many patients who cannot benefit from current treatment modalities. Therefore, new therapeutic approaches are warranted. Here we explore the efficacy of targeted adenoviral based suicide gene therapy.
Methods And Results:
Immunohistochemistry and FACS analysis detected low or absent expression levels of the primary adenovirus receptor CAR on human primary OS and human OS cell lines. These results predict a low infection efficiency and thus a reduced therapeutic effect. Targeting the adenoviruses to another receptor highly expressed on OS could overcome this limitation. We found epidermal growth factor receptor (EGFR) to be widely expressed on primary OS. Immunohistochemistry on primary tumor samples and FACS analysis on primary short-term cultures and four OS cell lines showed that EGFR was consistently expressed. The recombinant bispecific single-chain antibody 425-s11 redirects adenoviral vectors towards the EGFR. Adenovirus transduction experiments in the presence or absence of 425-s11 showed significantly enhanced gene transfer with the targeted adenoviral vector compared with the native vector (OS cell lines 2.5 to 7.2 times enhanced gene transfer and OS primary short term cultures 1.7 to 10 times enhanced gene transfer). On this basis, targeted suicide gene therapy experiments with AdCMVHSV-TK in combination with ganciclovir were performed. These experiments demonstrated up to 3.5-fold enhanced kill of OS cell lines and primary short-term cultures by the EGFR targeted vector.
Conclusions:
Suicide gene therapy with adenovirus targeted towards EGFR may have favorable therapeutic characteristics for future gene therapy applications in OS.
Insights
Targeted adenoviral suicide gene therapy shows promise for osteosarcoma (OS) treatment. By targeting the epidermal growth factor receptor (EGFR), researchers enhanced gene transfer and tumor cell kill in OS models.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Molecular oncology
Background:
- Current osteosarcoma (OS) treatments remain insufficient for many patients, necessitating novel therapeutic strategies.
- Adenoviral vectors face limitations in OS treatment due to low coxsackie adenovirus receptor (CAR) expression.
Purpose of the Study:
- To investigate the efficacy of EGFR-targeted adenoviral suicide gene therapy for osteosarcoma.
- To overcome low CAR expression by redirecting adenoviral vectors to the highly expressed EGFR.
Main Methods:
- Assessed CAR and EGFR expression on OS cells using immunohistochemistry and FACS analysis.
- Utilized a bispecific antibody (425-s11) to retarget adenoviral vectors to EGFR.
- Evaluated gene transfer efficiency and therapeutic efficacy of targeted AdCMVHSV-TK/ganciclovir in OS models.
Main Results:
- Low CAR expression was observed on human OS cells, predicting poor adenoviral infection.
- EGFR was highly and consistently expressed on primary OS samples and cell lines.
- EGFR-targeted adenoviral vectors demonstrated significantly enhanced gene transfer (1.7-10x) and up to 3.5-fold increased tumor cell kill.
Conclusions:
- EGFR-targeted adenoviral suicide gene therapy presents a promising therapeutic approach for osteosarcoma.
- This strategy may overcome limitations of traditional adenoviral vectors in OS treatment.