Limits...
The combination of intravenous Reolysin and gemcitabine induces reovirus replication and endoplasmic reticular stress in a patient with KRAS-activated pancreatic cancer.

Mahalingam D, Patel S, Nuovo G, Gill G, Selvaggi G, Coffey M, Nawrocki ST - BMC Cancer (2015)

Bottom Line: 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.Importantly, co-localization of reoviral protein and active caspase-3 was also observed in the biopsy specimen.

View Article: PubMed Central - PubMed

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.

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.

Case presentation: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

CT scans of pancreatic cancer patient. CT scan imaging at baseline (left) and at time of biopsy (right) demonstrates stability of hypovascular pancreatic mass. White bar indicates 1 cm
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4496814&req=5

Fig1: CT scans of pancreatic cancer patient. CT scan imaging at baseline (left) and at time of biopsy (right) demonstrates stability of hypovascular pancreatic mass. White bar indicates 1 cm

Mentions: The patient was placed on a clinical trial with first-line treatment of Reolysin and gemcitabine, receiving cycle one day one on March 2012. Reolysin was administered at a dose of 1 × 1010 TCID50 IV on days 1, 2, 8, and 9 (immediately after gemcitabine on days 1 and 8) in combination with 800 mg/m2 IV gemcitabine on days 1 and 8, with 21-day cycles. The patient displayed a clinical response with improvement in cancer-related pain. The best radiographical response was documented as stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (Fig. 1) [11].Fig. 1


The combination of intravenous Reolysin and gemcitabine induces reovirus replication and endoplasmic reticular stress in a patient with KRAS-activated pancreatic cancer.

Mahalingam D, Patel S, Nuovo G, Gill G, Selvaggi G, Coffey M, Nawrocki ST - BMC Cancer (2015)

CT scans of pancreatic cancer patient. CT scan imaging at baseline (left) and at time of biopsy (right) demonstrates stability of hypovascular pancreatic mass. White bar indicates 1 cm
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4496814&req=5

Fig1: CT scans of pancreatic cancer patient. CT scan imaging at baseline (left) and at time of biopsy (right) demonstrates stability of hypovascular pancreatic mass. White bar indicates 1 cm
Mentions: The patient was placed on a clinical trial with first-line treatment of Reolysin and gemcitabine, receiving cycle one day one on March 2012. Reolysin was administered at a dose of 1 × 1010 TCID50 IV on days 1, 2, 8, and 9 (immediately after gemcitabine on days 1 and 8) in combination with 800 mg/m2 IV gemcitabine on days 1 and 8, with 21-day cycles. The patient displayed a clinical response with improvement in cancer-related pain. The best radiographical response was documented as stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (Fig. 1) [11].Fig. 1

Bottom Line: 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.Importantly, co-localization of reoviral protein and active caspase-3 was also observed in the biopsy specimen.

View Article: PubMed Central - PubMed

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.

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.

Case presentation: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus