Oncolytic Virus-Mediated Targeting of the ERK Signaling Pathway Inhibits Invasive Propensity in Human Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) cells have an exceptional ability to invade nerves through pronounced crosstalk between nerves and cancer cells; however, the mechanism of PDAC cell invasion remains to be elucidated. Here, we demonstrate the therapeutic potential of telomerase-specific oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, against human PDAC cells. Highly invasive PDAC cells exhibited higher levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) expression independent of KRAS expression; ERK1/2 inhibitor or small interfering RNA (siRNA) treatment significantly reduced the migration and invasion of PDAC cells, suggesting that the ERK signaling pathway is associated with the invasiveness of PDAC cells. OBP-702 infection suppressed ERK signaling and inhibited PDAC cell migration and invasion more efficiently than OBP-301. OBP-702 also effectively inhibited PDAC cell invasion even when invasiveness was enhanced by administration of motility stimulators, such as nerve and neurosecretory factors. Moreover, noninvasive whole-body imaging analyses showed that OBP-702 significantly suppressed tumor growth in an orthotopic PDAC xenograft model, although both viruses were equally effective against subcutaneous tumors, suggesting that OBP-702 can influence the orthotopic tumor microenvironment. Our data suggest that oncolytic virus-mediated disruption of ERK signaling is a promising antitumor strategy for attenuating the invasiveness of PDAC cells.

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

“…Iodine‐125 seeds planted in the local sites of tumors even relieved pain in PDAC patients [ 124 ]. It has also been reported that telomerase‐specific oncolytic adenoviruses might have therapeutic potential for PDAC patients [ 125 ]. Moreover, these viruses repressed the migration and invasion of pancreatic cell lines in a DRG co‐culture system [ 125 ], indicating their potential role in preventing PNI.…”

“…It has also been reported that telomerase‐specific oncolytic adenoviruses might have therapeutic potential for PDAC patients [ 125 ]. Moreover, these viruses repressed the migration and invasion of pancreatic cell lines in a DRG co‐culture system [ 125 ], indicating their potential role in preventing PNI. Overall, comprehensive multidisciplinary clinical trials are urgently needed to optimize the treatment of PDAC patients.…”

Win or loss? Combination therapy does improve the oncolytic virus therapy to pancreatic cancer

“…In addition, the OBP-702 can activate p53, while OBP-301 does not activate p53 in PC. Therefore, OBP-702, p53-armed oncolytic virotherapy, could be a promising strategy for PC [ 51 ]. Mechanically, OBP-702 effectively inhibited the invasion of PC cells by inhibiting ERK signaling.…”

Combination Immunotherapy Using Oncolytic Virus for the Treatment of Advanced Solid Tumors

“…To overcome these unfavorable TMEs in pancreatic cancer, several OVs have been investigated in preclinical in vivo models, and some OVs are already under development in phase I and II clinical trials. An oncolytic adenovirus, OBP-702, expressing tumor suppressor p53, significantly suppressed tumor growth in an orthotropic xenograft model of pancreatic cancer by disruption of extracellular signal regulated kinase (ERK) signaling [ 60 ]. Oncolytic adenovirus (ONYX-015, VCN-01, LOAd703), oncolytic HSV (T-VEC, HF10, Orien X010), and pelareorep (Reolysin) are now in phase I or phase II clinical trials [ 33 ].…”