TY - JOUR
T1 - Targeting tumor neoangiogenesis via targeted adenoviral vector to achieve effective cancer gene therapy for disseminated neoplastic disease
AU - Lee, Myungeun
AU - Lu, Zhi Hong
AU - Li, Jie
AU - Kashentseva, Elena A.
AU - Dmitriev, Igor P.
AU - Mendonca, Samir A.
AU - Curiel, David T.
N1 - Funding Information:
We thank Dr. Arbeit for providing critical precedent research. We also appreciate Dr. Summers's laboratory for providing HSVtk antibody essential to this study. We also thank Dr. Toth's laboratory for providing SHPC6 (Syrian Hamster Pancreatic Carcinoma) cells essential to this study. We especially thank Amanda Baker Wilms-meyer for extensive advice on the article and the scientific graphics. This study was funded by the NIH (RO1's CA211096, to principle investigator D.T. Curiel) research grants.
Funding Information:
We thank Dr. Arbeit for providing critical precedent research. We also appreciate Dr. Summers's laboratory for providing HSVtk antibody essential to this study. We also thank Dr. Toth's laboratory for providing SHPC6 (Syrian Hamster Pancreatic Carcinoma) cells essential to this study. We especially thank Amanda Baker Wilmsmeyer for extensive advice on the article and the scientific graphics. This study was funded by the NIH (RO1's CA211096, to principle investigator D.T. Curiel) research grants.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/3
Y1 - 2020/3
N2 - The application of cancer gene therapy has heretofore been restricted to local, or locoregional, neoplastic disease contexts. This is owing to the lack of gene transfer vectors, which embody the requisite target cell selectivity in vivo required for metastatic disease applications. To this end, we have explored novel vector engineering paradigms to adapt adenovirus for this purpose. Our novel strategy exploits three distinct targeting modalities that operate in functional synergy. Transcriptional targeting is achieved via the hROBO4 promoter, which restricts transgene expression to proliferative vascular endothelium. Viral binding is modified by incorporation of an RGD4C peptide in the HI loop of the fiber knob for recognition of cellular integrins. Liver sequestration is mitigated by ablation of factor X binding to the major capsid protein hexon by a serotype swap approach. The combination of these technologies into the context of a single-vector agent represents a highly original approach. Studies in a murine model of disseminated cancer validated the in vivo target cell selectivity of our vector agent. Of note, clear gains in therapeutic index accrued these vector modifications. Whereas there is universal recognition of the value of vector targeting, very few reports have validated its direct utility in the context of cancer gene therapy. In this regard, our article validates the direct gains that may accrue these methods in the stringent delivery context of disseminated neoplastic disease. Efforts to improve vector targeting thus represent a critical direction to fully realize the promise of cancer gene therapy.
AB - The application of cancer gene therapy has heretofore been restricted to local, or locoregional, neoplastic disease contexts. This is owing to the lack of gene transfer vectors, which embody the requisite target cell selectivity in vivo required for metastatic disease applications. To this end, we have explored novel vector engineering paradigms to adapt adenovirus for this purpose. Our novel strategy exploits three distinct targeting modalities that operate in functional synergy. Transcriptional targeting is achieved via the hROBO4 promoter, which restricts transgene expression to proliferative vascular endothelium. Viral binding is modified by incorporation of an RGD4C peptide in the HI loop of the fiber knob for recognition of cellular integrins. Liver sequestration is mitigated by ablation of factor X binding to the major capsid protein hexon by a serotype swap approach. The combination of these technologies into the context of a single-vector agent represents a highly original approach. Studies in a murine model of disseminated cancer validated the in vivo target cell selectivity of our vector agent. Of note, clear gains in therapeutic index accrued these vector modifications. Whereas there is universal recognition of the value of vector targeting, very few reports have validated its direct utility in the context of cancer gene therapy. In this regard, our article validates the direct gains that may accrue these methods in the stringent delivery context of disseminated neoplastic disease. Efforts to improve vector targeting thus represent a critical direction to fully realize the promise of cancer gene therapy.
UR - http://www.scopus.com/inward/record.url?scp=85081114337&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-19-0768
DO - 10.1158/1535-7163.MCT-19-0768
M3 - Article
C2 - 31907220
AN - SCOPUS:85081114337
SN - 1535-7163
VL - 19
SP - 966
EP - 971
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 3
ER -