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Published on: March 22, 2011
Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding
Selvarangan Ponnazhagan1, Gandham Mahendra, Sanjay Kumar
1Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. sponnazh@path.uab.edu
Abstract:
Angiogenesis is characteristic of solid tumor growth and a surrogate marker for metastasis in many human cancers. Inhibition of tumor angiogenesis using antiangiogenic drugs and gene transfer approaches has suggested the potential of this form of therapy in controlling tumor growth. However, for long-term tumor-free survival by antiangiogenic therapy, the factors controlling tumor neovasculature need to be systemically maintained at stable therapeutic levels. Here we show sustained expression of the antiangiogenic factors angiostatin and endostatin as secretory proteins by recombinant adeno-associated virus 2 (rAAV)-mediated gene transfer. Both vectors provided significant protective efficacy in a mouse tumor xenograft model. Stable transgene persistence and systemic levels of both angiostatin and endostatin were confirmed by in situ hybridization of the vector-injected tissues and by serum ELISA measurements, respectively. Whereas treatment with rAAV containing either endostatin or angiostatin alone resulted in moderate to significant protection, the combination of endostatin and angiostatin gene transfer from a single vector resulted in a complete protection. These data suggest that AAV-mediated long-term expression of both endostatin and angiostatin may have clinical utility against recurrence of cancers after primary therapies and may represent rational adjuvant therapies in combination with radiation or chemotherapy.
Insights
Sustained delivery of antiangiogenic factors, angiostatin and endostatin, using recombinant adeno-associated virus (rAAV) gene transfer completely protected mice against tumor recurrence. Combination therapy showed superior efficacy in controlling tumor growth.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Angiogenesis, the formation of new blood vessels, is crucial for solid tumor growth and metastasis.
- Current antiangiogenic therapies require stable systemic levels of therapeutic factors for long-term tumor control.
- Controlling tumor neovasculature is essential for preventing cancer recurrence.
Purpose of the Study:
- To investigate the sustained expression of antiangiogenic factors, angiostatin and endostatin, via recombinant adeno-associated virus (rAAV) gene transfer.
- To evaluate the therapeutic efficacy of rAAV-mediated gene transfer of angiostatin and endostatin in a preclinical cancer model.
- To determine if combination therapy with both factors provides superior tumor protection.
Main Methods:
- Utilized rAAV vectors for sustained, secretory expression of angiostatin and endostatin.
- Employed a mouse tumor xenograft model to assess protective efficacy.
- Confirmed stable transgene persistence using in situ hybridization and systemic protein levels via serum ELISA.
Main Results:
- rAAV vectors successfully achieved sustained systemic expression of angiostatin and endostatin.
- Both single-factor (angiostatin or endostatin) gene transfer provided significant tumor protection.
- Combined transfer of angiostatin and endostatin from a single rAAV vector resulted in complete tumor protection.
Conclusions:
- AAV-mediated long-term expression of angiostatin and endostatin demonstrates significant therapeutic potential.
- Combination gene therapy targeting tumor neovasculature may be a promising strategy for preventing cancer recurrence.
- This approach could serve as an effective adjuvant therapy alongside conventional treatments like radiation and chemotherapy.
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