Principal Investigator

Prof. Dr. med. Jens Siveke

Bridge Institute for Experimental Tumor Therapy
University Hospital Essen

Prof. Dr. Jens Siveke
 

Participating Senior Scientist

Dr. Marija Trajkovic-Arsic

Dr. Marija Trajkovic-Arsic
 

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Summary

Despite decades of active research, pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers without effective chemo- or targeted therapies. Radiation therapy (RT) has recently shown promising effects in resectable PDAC yet faces heterogenic responses and resistance. Radioresistance development involves metabolic reprogramming of tumors, however, how radiation interferes with tumor and stromal cellular states and metabolism and what may be effective combinatory treatment strategies to suppress resistance is not well understood. This project aims to investigate the potential of radiation therapy as a modulator of interactions among cancer cells and the tumor microenvironment with an emphasis on cancer-associated fibroblasts (CAF).

We will use comprehensive mouse (syngeneic xenografts and genetically engineered mice) as well as human PDAC models (PDAC patient derived primary cells and tissue explants) to investigate (i) tumor and stroma cell interactions in the context of RT; (ii) how this interaction provides radioprotective/sensitizing features to the cancer cells and CAFs; and (iii) explore metabolically driven strategies to achieve better radiosensitivity.
 

Publications

Cheung PF, Yang J, Fang R, Borgers A, Krengel K, Stoffel A, Althoff K, Yip CW, Siu EHL, Ng LWC, Lang KS, Cham LB, Engel DR, Soun C, Cima I, Scheffler B, Striefler JK, Sinn M, Bahra M, Pelzer U, Oettle H, Markus P, Smeets EMM, Aarntzen E, Savvatakis K, Liffers ST, Lueong SS, Neander C, Bazarna A, Zhang X, Paschen A, Crawford HC, Chan AWH, Cheung ST, Siveke JT. Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression. Nat Commun. 2022;13(1):156.

Sun N, Trajkovic-Arsic M, Li F, Wu Y, Munch C, Kunzke T, Feuchtinger A, Steiger K, Schlitter AM, Weichert W, Esposito I, Siveke JT, Walch A. Native glycan fragments detected by MALDI mass spectrometry imaging are independent prognostic factors in pancreatic ductal adenocarcinoma. EJNMMI Res. 2021;11(1):120.

Rosery V, Reis H, Savvatakis K, Kowall B, Stuschke M, Paul A, Dechene A, Yang J, Zhao B, Borgers A, Kasper S, Schuler M, Cheung PF, Siveke JT. Antitumor immune response is associated with favorable survival in GEP-NEN G3. Endocr Relat Cancer. 2021;28(10):683-93.

Kunzmann V, Siveke JT, Algul H, Goekkurt E, Siegler G, Martens U, Waldschmidt D, Pelzer U, Fuchs M, Kullmann F, Boeck S, Ettrich TJ, Held S, Keller R, Klein I, Germer CT, Stein H, Friess H, Bahra M, Jakobs R, Hartlapp I, Heinemann V, German Pancreatic Cancer Working G, investigators N. Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2021;6(2):128-38.

Heid I, Karakaya S, Münch C, Lueong SS, Winkelkotte AM, Liffers ST, Godfrey L, Cheung PF, Savvatakis K, Topping GJ, Englert F, Kritzner L, Grashei M, Kunzke T, Sun N, Walch A, Tannapfel A, Viebahn R, Wolters H, Uhl W, Vangala D, Smeets EMM, Aarntzen EHJG, Rauh D, Hoheisel JD, Hellerschmied D, Hahn SA, Schilling F, Braren R, Trajkovic-Arsic M, Siveke JT. Functional metabolic phenotyping of human pancreatic ductal adenocarcinoma. bioRxiv. 2021:2021.07.23.452145.

Altmann A, Haberkorn U, Siveke J. The Latest Developments in Imaging of Fibroblast Activation Protein. J Nucl Med. 2021;62(2):160-7.

Weisner J, Landel I, Reintjes C, Uhlenbrock N, Trajkovic-Arsic M, Dienstbier N, Hardick J, Ladigan S, Lindemann M, Smith S, Quambusch L, Scheinpflug R, Depta L, Gontla R, Unger A, Muller H, Baumann M, Schultz-Fademrecht C, Gunther G, Maghnouj A, Muller MP, Pohl M, Teschendorf C, Wolters H, Viebahn R, Tannapfel A, Uhl W, Hengstler JG, Hahn SA, Siveke JT, Rauh D. Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib in KRAS-Mutant Pancreatic and Colorectal Cancer. Cancer Res. 2019;79(9):2367-78.

Delfino P, Neander C, Filippini D, D’Agosto SL, Vicentini C, Fiorini E, Lupo F, Fiorini C, Rusev B, Temgue Tane GD, De Sanctis F, Simbolo M, Ugel S, Bronte V, Fassan M, Lawlor RT, Boschi F, Barbi S, Scarpa A, Cheung PF, Siveke JT, Corbo V. MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages. bioRxiv. 2019:759779.

Cheung PF, Neff F, Neander C, Bazarna A, Savvatakis K, Liffers ST, Althoff K, Lee CL, Moding EJ, Kirsch DG, Saur D, Bazhin AV, Trajkovic-Arsic M, Heikenwalder MF, Siveke JT. by Dual Genetic Targeting. Cancer Res. 2018;78(17):4997-5010.

Trajkovic-Arsic M, Heid I, Steiger K, Gupta A, Fingerle A, Worner C, Teichmann N, Sengkwawoh-Lueong S, Wenzel P, Beer AJ, Esposito I, Braren R, Siveke JT. Apparent Diffusion Coefficient (ADC) predicts therapy response in pancreatic ductal adenocarcinoma. Sci Rep. 2017;7(1):17038.

Heid I, Steiger K, Trajkovic-Arsic M, Settles M, Esswein MR, Erkan M, Kleeff J, Jager C, Friess H, Haller B, Steingotter A, Schmid RM, Schwaiger M, Rummeny EJ, Esposito I, Siveke JT, Braren RF. Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer. Clin Cancer Res. 2017;23(6):1461-70.

Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sanchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noel PB, Braren R, Erkan M, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Hessmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J, Siveke JT. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med. 2015;21(10):1163-71.