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Cancers 2018, 10(3), 77;

Should We Keep Walking along the Trail for Pancreatic Cancer Treatment? Revisiting TNF-Related Apoptosis-Inducing Ligand for Anticancer Therapy

Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany
Department of Translational Genomics, University Hospital Cologne, Weyertal 115b, 50931 Cologne, Germany
Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann Straße 26, 50931 Cologne, Germany
Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany
Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
Author to whom correspondence should be addressed.
Received: 28 February 2018 / Revised: 13 March 2018 / Accepted: 14 March 2018 / Published: 18 March 2018
(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)
PDF [1673 KB, uploaded 3 May 2018]


Despite recent advances in oncology, diagnosis, and therapy, treatment of pancreatic ductal adenocarcinoma (PDAC) is still exceedingly challenging. PDAC remains the fourth leading cause of cancer-related deaths worldwide. Poor prognosis is due to the aggressive growth behavior with early invasion and distant metastasis, chemoresistance, and a current lack of adequate screening methods for early detection. Consequently, novel therapeutic approaches are urgently needed. Many hopes for cancer treatment have been placed in the death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) since it was reported to induce apoptosis selectively in tumor cells in vitro and in vivo. TRAIL triggers apoptosis through binding of the trans-membrane death receptors TRAIL receptor 1 (TRAIL-R1) also death receptor 4 (DR4) and TRAIL receptor 2 (TRAIL-R2) also death receptor 5 (DR5) thereby inducing the formation of the death-inducing signaling complex (DISC) and activation of the apoptotic cascade. Unlike chemotherapeutics, TRAIL was shown to be able to induce apoptosis in a p53-independent manner, making TRAIL a promising anticancer approach for p53-mutated tumors. These cancer-selective traits of TRAIL led to the development of TRAIL-R agonists, categorized into either recombinant variants of TRAIL or agonistic antibodies against TRAIL-R1 or TRAIL-R2. However, clinical trials making use of these agonists in various tumor entities including pancreatic cancer were disappointing so far. This is thought to be caused by TRAIL resistance of numerous primary tumor cells, an insufficient agonistic activity of the drug candidates tested, and a lack of suitable biomarkers for patient stratification. Nevertheless, recently gained knowledge on the biology of the TRAIL-TRAIL-R system might now provide the chance to overcome intrinsic or acquired resistance against TRAIL and TRAIL-R agonists. In this review, we summarize the status quo of clinical studies involving TRAIL-R agonists for the treatment of pancreatic cancer and critically discuss the suitability of utilizing the TRAIL-TRAIL-R system for successful treatment. View Full-Text
Keywords: TRAIL; pancreatic adenocarcinoma; TRAIL-R agonists TRAIL; pancreatic adenocarcinoma; TRAIL-R agonists

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Kretz, A.-L.; Von Karstedt, S.; Hillenbrand, A.; Henne-Bruns, D.; Knippschild, U.; Trauzold, A.; Lemke, J. Should We Keep Walking along the Trail for Pancreatic Cancer Treatment? Revisiting TNF-Related Apoptosis-Inducing Ligand for Anticancer Therapy. Cancers 2018, 10, 77.

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