Universität zu Köln

Kretz, Anna-Laura, von Karstedt, Silvia, Hillenbrand, Andreas ORCID: 0000-0003-2896-4656, Henne-Bruns, Doris, Knippschild, Uwe, Trauzold, Anna and Lemke, Johannes ORCID: 0000-0003-2142-6097 (2018). Should We Keep Walking along the Trail for Pancreatic Cancer Treatment? Revisiting TNF-Related Apoptosis-Inducing Ligand for Anticancer Therapy. Cancers, 10 (3). BASEL: MDPI. ISSN 2072-6694

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kretz, Anna-Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED von Karstedt, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Hillenbrand, Andreas UNSPECIFIED orcid.org/0000-0003-2896-4656 UNSPECIFIED Henne-Bruns, Doris UNSPECIFIED UNSPECIFIED UNSPECIFIED Knippschild, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Trauzold, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Lemke, Johannes UNSPECIFIED orcid.org/0000-0003-2142-6097 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-193214
DOI:	10.3390/cancers10030077
Journal or Publication Title:	Cancers
Volume:	10
Number:	3
Date:	2018
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; DEATH RECEPTOR 5; CELL-SURFACE ANTIGEN; SUBEROYLANILIDE HYDROXAMIC ACID; HISTONE DEACETYLASE INHIBITOR; RECOMBINANT HUMAN APO2L/TRAIL; ANTI-DR5 MONOCLONAL-ANTIBODY; FADD-DEPENDENT APOPTOSIS; TARGETING DEATH; ANTITUMOR-ACTIVITY Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19321