Challenges and future directions in therapeutics for pancreatic ductal adenocarcinoma

Haddad, Amal H. I. Al; Adrian, Thomas E.

doi:10.1517/13543784.2014.933206

Cited by 16 publications

(11 citation statements)

References 110 publications

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“…Pancreatic cancer death rates have been increasing in the US over the past several years, as compared with the downward trend in death rates for most other major cancers (5, 6). The overall 5-year survival rate of patients with pancreatic cancer is less than 6% and this dismal prognosis has not improved in recent years resulting in an increasing number of deaths (7).…”

Section: Introductionmentioning

confidence: 99%

Pancreatic Cancer–Specific Cell Death Induced In Vivo by Cytoplasmic-Delivered Polyinosine–Polycytidylic Acid

et al. 2014

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Polyinosine-polycytidylic acid (pIC) is a synthetic dsRNA that acts as an immune agonist of TLR3 and RLR to activate dendritic and NK cells that can kill tumor cells. pIC can also trigger apoptosis in pancreatic ductal adenocarcinoma cells but its mechanism of action is obscure. In this study, we investigated the potential therapeutic activity of a formulation of pIC with polyethylenimine ([pIC]PEI) in PDAC and investigated its mechanism of action. [pIC]PEI stimulated apoptosis in PDAC cells without affecting normal pancreatic epithelial cells. Mechanistically, [pIC]PEI repressed XIAP and survivin expression and activated an immune response by inducing MDA-5, RIG-I and NOXA. Phosphorylation of AKT was inhibited by [pIC]PEI in PDAC and this event was critical for stimulating apoptosis through XIAP and survivin degradation. In vivo administration of [pIC]PEI inhibited tumor growth via AKT-mediated XIAP degradation in both subcutaneous and quasi-orthotopic-models of PDAC. Taken together, these results offer a preclinical proof-of-concept for the evaluation of [pIC]PEI as an immunochemotherapy to treat pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

Pancreatic Cancer–Specific Cell Death Induced In Vivo by Cytoplasmic-Delivered Polyinosine–Polycytidylic Acid

et al. 2014

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“…Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the fourth leading cause of cancer-related mortality, with a 5-year overall survival (OS) rate for patients with metastatic PDAC at 8%, which is the lowest OS rate among all types of cancer (5,6). Although new therapies have been introduced, there has not been a notable improvement in OS rates for patients with PDAC (7). Thus, there is an urgent need to elucidate the underlying mechanisms of pancreatic cancer metastasis.…”

Section: Introductionmentioning

confidence: 99%

Asparaginyl endopeptidase enhances pancreatic ductal adenocarcinoma cell invasion in an exosome-dependent manner and correlates with poor prognosis

et al. 2018

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Pancreatic cancer is one of the most lethal types of cancer; owing to low early detection rates and high metastasis rates, it is associated with an extremely poor prognosis. Therefore, a better understanding of the molecular mechanisms that underlie its metastasis and the identification of potential prognostic biomarkers are urgently required. Although high expression levels of asparaginyl endopeptidase (AEP) have been detected in various types of solid tumor, the expression and functions of AEP in pancreatic carcinomas have yet to be determined. The present study aimed to examine the putative functions of AEP in pancreatic carcinoma. Immunohistochemical analysis revealed that AEP was highly expressed in pancreatic cancer tissues compared with adjacent normal tissues. Patients with high AEP expression exhibited a significantly shorter overall survival time. Results from multivariate Cox regression analysis revealed that AEP was an independent prognostic factor for overall survival. Gain- and loss-of-function experiments demonstrated that knockdown of AEP expression significantly reduced the invasive ability of pancreatic cancer cells, whereas overexpression of AEP increased the invasive ability. In addition, AEP was detected in exosomes that were derived from cultured pancreatic ductal adenocarcinoma cells (PDACs) and in the serum from patients with PDAC. The Matrigel-Transwell invasion assay revealed that exosomes enriched with AEP were able to enhance the invasive ability of PDAC cells, whereas exosomes lacking AEP decreased the invasive ability. Furthermore, results from the present study suggested that AEP may be crucial for activation of the phosphoinositide 3-kinase/RAC‑α serine/threonine-protein kinase signaling pathway in PDAC cells. The present study data indicated that high AEP expression may be important for pancreatic carcinoma progression in an exosome-dependent manner, and that AEP may be an independent indicator of poor prognosis in patients with PDAC and may be a novel prognostic biomarker or therapeutic target in pancreatic carcinoma.

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“…The mean survival time after diagnosis is about five months and even the subgroup (less than 20% of patients), in whom potentially curative surgery is an option, rarely survive more than two or three years [ 2 ]. Until recently, gemcitabine was the mainstay of therapy for pancreatic cancer patients in neoadjuvant, adjuvant and palliative treatment protocols [ 3 ]. While this drug improved quality of life, it has proved to have little effect on survival [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer

et al. 2016

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The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of ~1 µM. Frondoside B was less potent (EC50 ~2.5 µM). Frondoside C and the aglycone had no effect. At 100 µg/kg, frondoside A administered to CD2F1 mice as an i.v. bolus, the Cpmax was 129 nM, Cltb was 6.35 mL/min/m2, and half-life was 510 min. With i.p. administration the Cpmax was 18.3 nM, Cltb was 127 mL/min/m2 and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 µg/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.

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Challenges and future directions in therapeutics for pancreatic ductal adenocarcinoma

Cited by 16 publications

References 110 publications

Pancreatic Cancer–Specific Cell Death Induced In Vivo by Cytoplasmic-Delivered Polyinosine–Polycytidylic Acid

Pancreatic Cancer–Specific Cell Death Induced In Vivo by Cytoplasmic-Delivered Polyinosine–Polycytidylic Acid

Asparaginyl endopeptidase enhances pancreatic ductal adenocarcinoma cell invasion in an exosome-dependent manner and correlates with poor prognosis

Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer

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