Science and Technology Production
Congress
Authorship
Helga Lorena Weber
;
Manuel Gidekel
;
Santiago Werbajh
;
Edgardo Salvatierra
;
Cecilia Rotondaro
;
Leonardo Sganga
;
Gabriela Acosta Haab
;
David Curiel
;
CAFFERATA, EDUARDO GUSTAVO ALFREDO
;
Osvaldo L. Podhajcer
Date
2015
Publishing House and Editing Place
Mary Ann Liebert, inc
Summary
Information provided by the agent in
SIGEVA
Pancreaticcancer is predicted to become the second leading cause of cancer-related deatharound 2020. Early stages are usually asymptomatic and patients present withadvanced metastatic disease. The high resistance to conventional and targetedtherapies is largely due to the dense extracellular matrix devoid of anextended blood vasculature that hampers drug penetration deeply inside thetumor mass. Novel therapeutic tools designed to target the tumor stromal cellsin addition to the malignant cells ...
Pancreaticcancer is predicted to become the second leading cause of cancer-related deatharound 2020. Early stages are usually asymptomatic and patients present withadvanced metastatic disease. The high resistance to conventional and targetedtherapies is largely due to the dense extracellular matrix devoid of anextended blood vasculature that hampers drug penetration deeply inside thetumor mass. Novel therapeutic tools designed to target the tumor stromal cellsin addition to the malignant cells might then become a valuable tool. Wedesigned an oncolytic adenovirus (OAV) whose replication was driven by thecdc25B promoter. The corresponding gene is highly expressed in primary andmetastatic pancreatic cancer both in human malignant cells and cancerassociated fibroblasts. The combination of the OAV AV25CDC andgemcitabine exhibited the largest therapeutic effect on orthotopicallyimplanted human xenografts tumors in nude mice and on syngeneic tumors inSyrian hamsters.Indeed, nudemice harboring 15-days old SW19990 orthotopic tumors, treated i.t. orsystemically with AV25CDC combined with gemcitabine, exhibited 70%-80%reduction in tumor size that lasted for at least 60 days. Chemo-virotherapytreatment induced a return to normal levels of biochemical parameters ofhepatic toxicity; mice also exhibited more than 90% reduction in CA19.9 serumlevels. Chemo-virotherapy efficacy was confirmed inmice harboring Mia PaCa-2 tumors and in Syrian hamsters harboring syngeneicHaP-T1 tumors. Biosafety studies showed no evidence of toxicity exerted byAV25CDC. We observed that viral treatment disrupted the tumor architecture andinduced an increase in MMP-9 activity that might facilitate gemcitabinepenetrability.
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Key Words
PRECLINICAL MODELSONCOLYTIC ADENOVIRUSPANCREATIC CANCER