title: Potent, tumor-specific gene expression in an orthotopic hepatoma rat model using a Survivin-targeted, amplifiable adenoviral vector.
abstract: Ideal cancer gene therapies should have high tumor specificity and efficacy, and allow systemic administration to target metastases. We recently developed a bi-directional, two-step transcriptional amplification (TSTA) system driven by the tumor-specific Survivin promoter (pSurv) to amplify the correlated expression of both the reporter gene firefly luciferase (FL) and therapeutic gene tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we compare the specificity and potency of an adenovirus carrying this system (Ad-pSurv-TSTA-TRAIL-FL) to a nonspecific vector (Ad-pCMV-FL) in an orthotopic hepatocellular carcinoma (HCC) rat model after systemic administration. At 24 h after injection of Ad-pCMV-FL, bioluminescence imaging revealed a trend (P=0.30) towards greater FL expression in liver versus tumor. In striking contrast, Ad-pSurv-TSTA-TRAIL-FL showed increased FL activity within the tumor compared with the liver (P<0.01), a strong trend towards reduced liver expression compared with Ad-pCMV-FL (P=0.07), and importantly, similar FL levels within tumor compared with Ad-pCMV-FL (P=0.32). Hence, this vector shows potent, tumor-specific transgene expression even after extensive liver transduction and may be of significant value in avoiding hepatotoxicity in HCC patients. Future studies will explore the benefits of tumor-specific TRAIL expression in this model, the potential to target metastases and the extension of this vector for the treatment of other Survivin-positive tumors is warranted.
authors.affiliation: Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: B-C
authors.initials: BC
authors.lastname: Ahn
authors.forename: J A
authors.initials: JA
authors.lastname: Ronald
authors.forename: Y I
authors.initials: YI
authors.lastname: Kim
authors.forename: R
authors.initials: R
authors.lastname: Katzenberg
authors.forename: A
authors.initials: A
authors.lastname: Singh
authors.forename: R
authors.initials: R
authors.lastname: Paulmurugan
authors.forename: S
authors.initials: S
authors.lastname: Ray
authors.forename: L V
authors.initials: LV
authors.lastname: Hofmann
authors.forename: S S
authors.initials: SS
authors.lastname: Gambhir
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D015870:Gene Expression; D018390:Gene Targeting; D017930:Genes, Reporter; D005822:Genetic Vectors; D008113:Liver Neoplasms / Q000235:genetics*; D049409:Luciferases, Firefly / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D012680:Sensitivity and Specificity; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D019076:Transgenes
chemical_list: C516989:Birc5 protein, rat; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C505655:Tnfsf10 protein, rat; D049409:Luciferases, Firefly