Abstract PO-017: Application of oncolytic adenovirus to desmoplastic pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the highly malignant tumors with the poorest prognosis worldwide. The five-year survival rate of pancreatic cancer patients is 5%. PDAC comprises a dense fibrotic stroma with an extracellular matrix produced by activated-human pancreatic stellate cells (HPSC), which helps tumor growth, infiltration and metastasis. It is the main reason for chemotherapy resistance since fibrotic stroma is impenetrable for drug delivery. AU-rich elements (ARE) are RNA elements commonly present in the 3’-UTR of certain mRNAs that encode many early response genes or growth-related genes such as proto-oncogenes. ARE enhances the rapid decay of mRNAs, and the fate of ARE-mRNA is controlled by ARE-binding proteins HuR. ARE-mRNA is stabilized in most types of cancers mediate by binding with HuR, which exports target ARE-mRNA to the cytoplasm. We have developed E4orf6-deficient adenovirus dl355 as an oncolytic virus. E4orf6 is a viral gene essential for viral replication and contributes to viral replication by stabilizing ARE-mRNA in infected cells. Therefore, dl355 can replicate only in cancer cells in which ARE-mRNA is stabilized and lyses the cells. If ARE-mRNA is stabilized not only in PDAC but also in the activated-HPSC, dl355 may be effective for surrounding fibrosis. We found that HuR was relocalized in the cytoplasm of human PDAC and HPSC activated by TGFβ-1. The co-culture enhanced HuR export of MIA PaCa-2 with activated-HPSC. Inhibition of HuR function using CMLD-2 reagent inactivated the growth, invasion and metastasis activities of PDAC. The proliferative and cytopathic effects of dl355 were very high with PDAC and even with activated-HPSC compared to quiescent cells. These results indicate that oncolytic adenovirus dl355 shows potentiality to kill both pancreatic cancer cells and activated-pancreatic stellate cells where an abundance of HuR in the cytoplasm. dl355 has the potential to overcome several critical hurdles proposed by the tumor microenvironment of desmoplastic pancreatic tumors. Citation Format: Elora Hossain, Fumihiro Higashino. Application of oncolytic adenovirus to desmoplastic pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-017.