title: The combination of intravenous Reolysin and gemcitabine induces reovirus replication and endoplasmic reticular stress in a patient with KRAS-activated pancreatic cancer.
abstract: BACKGROUND
  Activating mutations in RAS are present in the majority of pancreatic cancer cases and represent an ideal therapeutic target. Reolysin is a proprietary formulation of oncolytic reovirus that is currently being evaluated in multiple clinical trials due to its ability to selectively replicate in cells harboring an activated RAS pathway. Here we report for the first time the presence of reovirus replication and induction of endoplasmic reticular (ER) stress in a primary tumor specimen collected from a pancreatic cancer patient receiving intravenous Reolysin and gemcitabine.
  
  
  METHODS
  We describe the case of a 54-year old patient diagnosed with pancreatic adenocarcinoma in February 2012. Analysis of a tumor biopsy revealed an activating KRAS mutation (G12D) and the patient was started on first-line treatment with Reolysin in combination with gemcitabine in March 2012. Stable disease was achieved with significant improvement in cancer-related pain. Following 25 cycles of treatment over 23 months, a second biopsy was collected and immunohistochemical analyses revealed the presence of reovirus replication and induction of the ER stress-related gene GRP78/BIP and the pro-apoptotic protein NOXA. Importantly, co-localization of reoviral protein and active caspase-3 was also observed in the biopsy specimen.
  
  
  CONCLUSIONS
  This is the first report of reoviral protein detection in primary tumor biopsies taken from a pancreatic cancer patient receiving intravenous Reolysin therapy. The accumulation of reoviral protein was associated with ER stress induction and caspase-3 processing suggesting that Reolysin and gemcitabine treatment exhibited direct pro-apoptotic activity against the tumor.
authors.affiliation: Division of Hematology/Oncology, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, 7979 Wurzbach Rd, San Antonio, TX, 78229, USA. Mahalingam@uthscsa.edu.
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.affiliation: Division of Hematology/Oncology, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, 7979 Wurzbach Rd, San Antonio, TX, 78229, USA. PatelS3@uthscsa.edu.
authors.forename: Sukeshi
authors.initials: S
authors.lastname: Patel
authors.affiliation: Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA. Gerard.Nuovo@osumc.edu.
authors.forename: Gerard
authors.initials: G
authors.lastname: Nuovo
authors.affiliation: Oncolytics Biotech, Inc., Calgary, AB, Canada. GMGillMD@aol.com.
authors.forename: George
authors.initials: G
authors.lastname: Gill
authors.affiliation: Oncolytics Biotech, Inc., Calgary, AB, Canada. GSelvaggi@oncolytics.ca.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Selvaggi
authors.affiliation: Oncolytics Biotech, Inc., Calgary, AB, Canada. MCoffey@oncolytics.ca.
authors.forename: Matt
authors.initials: M
authors.lastname: Coffey
authors.affiliation: Division of Hematology/Oncology, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, 7979 Wurzbach Rd, San Antonio, TX, 78229, USA. Nawrocki@uthscsa.edu.
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000473:pathology / Q000821:virology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D016283:Proto-Oncogene Proteins p21(ras); D012087:Reoviridae / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C117307:KRAS protein, human; D003841:Deoxycytidine; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine