Urokinase-type plasminogen activator receptor transcriptionally controlled adenoviruses eradicate pancreatic tumors and liver metastasis in mouse models.
Treatment options for pancreatic cancer have shown limited success mainly owing to poor selectivity for pancreatic tumor tissue and to a lack of activity in the tumor. In this study, we describe the ability of the urokinase-type plasminogen activator receptor (uPAR) promoter to efficiently and selectively target pancreatic tumors and metastases, which enables the successful management of pancreatic cancer. We have generated a replication-defective reporter adenovirus, AduPARLuc, and a conditionally replicating adenovirus, AduPARE1A, and we have studied the selectivity and antitumoral efficacy in pancreatic tumors and metastases. Toxicity was studied on intravascular delivery. We demonstrate that the uPAR promoter is highly active in pancreatic tumors but very weak in normal tissues. Tumor specificity is evidenced by a 100-fold increase in the tumor-to-liver ratio and by selective targeting of liver metastases (P < .001). Importantly, the AduPARE1A maintains the oncolytic activity of the wild-type virus, with reduced toxicity, and exhibits significant antitumoral activity (25% tumor eradication) and prolonged survival in pancreatic xenograft models (P < .0001). Furthermore, upon intravascular delivery, we demonstrate complete eradication of liver metastasis in 33% of mice, improving median survival (P = 5.43 x 10(-5)). The antitumoral selective activity of AduPARE1A shows the potential of uPAR promoter-based therapies in pancreatic cancer treatment.
Huch
Meritxell
M
Programa Gens i Malaltia, Centre de Regulació Genòmica-CRG, UPF, Parc de Recerca Biomèdica de Barcelona-PRBB, Barcelona, Spain.
Gros
Alena
A
José
Anabel
A
González
Juan Ramon
JR
Alemany
Ramon
R
Fillat
Cristina
C
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008114:Liver Neoplasms, Experimental / Q000556:secondary / Q000628:therapy* / Q000821:virology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D011401:Promoter Regions, Genetic / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D055293:Receptors, Urokinase Plasminogen Activator; D049452:Green Fluorescent Proteins; D008156:Luciferases