Novel engineered TRAIL-based chimeric protein strongly inhibits tumor growth and bypasses TRAIL resistance |
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Authors: | Piotr Rozga Damian Kloska Sebastian Pawlak Malgorzata Teska-Kaminska Marlena Galazka Katarzyna Bukato Anna Pieczykolan Albert Jaworski Anna Molga-Kaczmarska Aleksandra Kopacz Bogna Badyra Neli Kachamakova-Trojanowska Olga Zolnierkiewicz Marta Targosz-Korecka Katarzyna Poleszak Michal Szymanik Bartlomiej Zerek Jerzy Pieczykolan Alicja Jozkowicz Anna Grochot-Przeczek |
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Institution: | 1. Department of Drug Discovery, Adamed Pharma S.A. Pienkow, Czosnow, Poland;2. Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland;3. Department of Physics of Nanostructures and Nanotechnology, Institute of Physics, Jagiellonian University, Krakow, Poland |
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Abstract: | Targeting of the TRAIL-DR4/5 pathway was proposed as a promising approach for specific induction of apoptosis in cancer cells. Clinical trials, however, showed inadequate efficiency of TRAIL as a monotherapy. It is a widely held view that the application of multifunctional molecules or combination therapy may lead to substantial improvement. Here, we demonstrate the effectiveness and safety of a novel chimeric protein, AD-O51.4, which is a TRAIL equipped with positively charged VEGFA-derived effector peptides. The study was performed in multiple cancer cell line- and patient-derived xenografts. A pharmacokinetic profile was established in monkeys. AD-O51.4 strongly inhibits tumor growth, even leading to complete long-term tumor remission. Neither mice nor monkeys treated with AD-O51.4 demonstrate symptoms of drug toxicity. AD-O51.4 exhibits a satisfactory half-life in plasma and accumulates preferentially in tumors. The cellular mechanism of AD-O51.4 activity involves both cytotoxic effects in tumor cells and antiangiogenic effects on the endothelium. The presence of DRs in cancer cells is crucial for AD-O51.4-driven apoptosis execution. The TRAIL component of the fusion molecule serves as an apoptosis inducer and a cellular anchor for the effector peptides in TRAIL-sensitive and TRAIL-resistant cancer cells, respectively. The FADD-dependent pathway, however, seems to be not indispensable in death signal transduction; thus, AD-O51.4 is capable of bypassing the refractoriness of TRAIL. AD-O51.4-driven cell death, which exceeds TRAIL activity, is achieved due to the N-terminally fused polypeptide, containing VEGFA-derived effector peptides. The high anticancer efficiency of AD-O51.4 combined with its safety has led to the entry of AD-O51.4 into toxicological studies. |
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Keywords: | TRAIL apoptosis chimeric protein anticancer therapy antiangiogenic therapy |
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