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

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.

Identification of an autophagy-related gene signature predicting overall survival for hepatocellular carcinoma

“…In a study on the anticancer properties of FZD7 after pharmacological inhibition of HCC, it was suggested that the mechanism may be associated with PRKCD mutations (32). BIRC5 has been described as a negative regulator of apoptosis, and its expression was reported to be higher in most tumors including HCC (33)(34)(35)(36), which is consistent with our findings indicating that the expression of BIRC5 is higher in the high-risk group of HCC prognosis. Moreover, the potential influence of BIRC5, HMOX1, and VEGFA in the prognosis of HCC had been reported in studies by Wang et al(37), Shen et al (38), and…”

Schlafen 5 as a novel therapeutic target in pancreatic ductal adenocarcinoma

“…Nevertheless, we provide evidence that the anti-tumor effects observed after SLFN5 depletion are mediated, at least in part, by interfering with cell cycle progression. This is important, as PDAC tumors are characterized by the presence of cell cycle dysregulation, a hallmark of several types of cancer, 36 , 37 and the identification of SLFN5 as a new promoting factor of S phase progression may help expand the currently available armory of cell cycle inhibitors 38 , 39 .…”

Pancreatic Cancer and Immunotherapy: A Clinical Overview

“…Survivin Survivin is physiologically expressed during embryonic and fetal development and plays a critical role in cell cycle control and apoptosis. In PDAC it is re-expressed in about 80% of patients [202], with elevated expression associated with worse prognosis and treatment resistance [203]. Shima et al [178,179] utilized a survivin 2B-vaccine (SVN-2B) in a phase 2 clinical trial with randomization design in which 83 advanced PDAC patients were included, all pre-treated with at least one line of chemotherapy.…”