title: Targeted oncolytic herpes simplex virus type 1 eradicates experimental pancreatic tumors.
abstract: As many other cancers, pancreatic ductal adenocarcinoma (PDAC) progression is associated with a series of hallmark changes for cancer cells to secure their own growth success. Yet, these very changes render cancer cells highly sensitive to viral infection. A promising strategy may rely on and exploit viral replication for tumor destruction, whereby infection of tumor cells by a replication-conditional virus may lead to cell destruction and simultaneous release of progeny particles that can spread and infect adjacent tumor cells, while sparing healthy tissues. In the present study, we used Myb34.5, a second-generation replication-conditional herpes simplex virus type 1 (HSV-1) mutant in which ICP6 gene expression is defective and expression of the HSV-1 γ134.5 gene is regulated by the cellular B-myb promoter. We found that B-myb is present in experimental PDAC and tumors, and is overexpressed in patients' tumors, as compared with normal adjacent pancreas. Myb34.5 replicates to high level in human PDAC cell lines and is associated with cell death by apoptosis. In experimental models of PDAC, mice receiving intratumoral Myb34.5 injections appeared healthy and tumor progression was inhibited, with evidence of tumor necrosis, hemorrhage, viral replication, and cancer cell death by apoptosis. Combining standard-of-care chemotherapy with Myb34.5 successfully led to a very impressive antitumoral effect that is rarely achieved in this experimental model, and resulted in a greater reduction in tumor growth than chemotherapy alone. These promising results warrant further evaluation in early phase clinical trial for patients diagnosed with PDAC for whom no effective treatment is available.
authors.affiliation: 1 Université Toulouse III-Paul Sabatier , UMR1037 CRCT, F-31000 Toulouse, France .
authors.forename: Marion
authors.initials: M
authors.lastname: Gayral
authors.forename: Hubert
authors.initials: H
authors.lastname: Lulka
authors.forename: Naima
authors.initials: N
authors.lastname: Hanoun
authors.forename: Coline
authors.initials: C
authors.lastname: Biollay
authors.forename: Janick
authors.initials: J
authors.lastname: Sèlves
authors.forename: Alix
authors.initials: A
authors.lastname: Vignolle-Vidoni
authors.forename: Hervé
authors.initials: H
authors.lastname: Berthommé
authors.forename: Pascal
authors.initials: P
authors.lastname: Trempat
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Epstein
authors.forename: Louis
authors.initials: L
authors.lastname: Buscail
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Béjot
authors.forename: Pierre
authors.initials: P
authors.lastname: Cordelier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005818:Genetic Engineering; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015552:Injections, Intralesional; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods*; D010179:Pancreas / Q000473:pathology / Q000821:virology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C064352:MYBL2 protein, human; D015534:Trans-Activators; D014764:Viral Proteins; C054366:herpes simplex virus type 1-protein ICP6; D003841:Deoxycytidine; D000093542:Gemcitabine