The role of survivin in the progression of pancreatic ductal adenocarcinoma (PDAC) and a novel survivin-targeted therapeutic for PDAC.

Matthew Brown,Daniel Delitto,Kien Pham,Rajath Kenath,Wanbin Zhang,Le Le,Deyue Yan,Keith Robertson,He Wang,David Ostrov,Chen Liu,Andrei L Gartel

doi:10.1371/journal.pone.0226917

Abstract

Treating pancreatic ductal adenocarcinoma (PDAC) remains a major hurdle in the field of oncology. Less than half of patients respond to frontline chemotherapy and the pancreatic tumor microenvironment limits the efficacy of immunotherapeutic approaches. Targeted therapies could serve as effective treatments to enhance the clinical response rate. One potential therapeutic target is survivin, a protein that is normally expressed during embryonic and fetal development and has a critical impact on cell cycle control and apoptosis. In adulthood, survivin is not present in most normal adult cells, but is significantly re-expressed in tumor tissues. In PDAC, elevated survivin expression is correlated with treatment resistance and lower patient survival, although the underlying mechanisms of survivin's action in this type of cancer is poorly understood. Using patient derived xenografts of PDAC and their corresponding primary pancreatic cancer lines (PPCL-46 and PPCL-LM1) possessing increased expression of survivin, we aimed to evaluate the therapeutic response of a novel survivin inhibitor, UFSHR, with respect to survivin expression and the tumorigenic characteristics of PDAC. Cell viability and apoptosis analyses revealed that repressing survivin expression by UFSHR or YM155, a well-known inhibitor of survivin, in PPCLs effectively reduces cell proliferation by inducing apoptosis. Tumor cell migration was also hindered following treatment with YM155 and UFSHR. In addition, both survivin inhibitors, particularly UFSHR, effectively reduced progression of PPCL-46 and PPCL-LM1 tumors, when compared to the untreated cohort. Overall, this study provides solid evidence to support the critical role of survivin in PDAC progression and proposes a novel survivin inhibitor UFSHR that can become an alternative strategy for this type of cancer.

Highlights

Selecting effective therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC) continue to be a major challenge in modern oncology
We examined the efficacy and efficiency of UFSHR, a novel synthetic derivative of YM155, in inhibiting survivin expression and in regulating both in vitro tumorigenic activities and in vivo tumor progression, using our primary pancreatic cancer lines (PPCLs) established from patient-derived tumor xenografts from primary PDAC tumors (PPCL-46) and hepatic metastases (PPCL-LM1) [34]
Survivin is overexpressed in pancreatic adenocarcinoma and patientderived xenograft models of PDAC

Summary

Introduction

Selecting effective therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC) continue to be a major challenge in modern oncology. In an attempt to improve the efficacy of chemotherapy for advanced PDAC, many phase III clinical trials of combination strategies have emerged [2]. Two such combination regimens are FOLFIRINOX (a cocktail of folinic acid (calcium folinate), fluorouracil, irinotecan, and oxaliplatin) and gemcitabine in combination with albumin-bound paclitaxel [3]. Therapies targeting immune checkpoints such as PD-1 and CTLA-4 have seen minimal success in PDAC. This is primarily due to a reduced antigenicity of the tumor itself and an immunosuppressive microenvironment rich with tumor-infiltrated desmoplastic stromal elements [3]. One potential and attractive molecular target is survivin, a member of the Inhibitor of Apoptosis Protein (IAP) family

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