GRK 1739 - Research Projects
Project 8Identification of novel targets for rational chemoradiotherapy strategies in non-small-cell lung cancer
Prof. Dr. med. Martin Schuler
Dept. of Medical Oncology
West German Cancer Center
Essen University Hospital
Lung cancer is the leading cancer fatality worldwide, with non-small cell lung cancers (NSCLC) accounting for approximately 85% of all cases. Radiotherapy is an important modality in the curative and palliative treatment of patients with advanced NSCLC, and its efficacy is enhanced by simultaneous administration of radiosensitizing drugs. Current chemoradiotherapy protocols, however, still fall short in capitalizing on the recent progress in characterization of distinct NSCLC entities by genomic and additional biomarkers. Against this background, we set out to identify and validate novel targets for personalized chemoradiotherapy strategies in NSCLC.
Combining knowledge-based approaches and unbiased functional genomics screens using lentivirally expressed shRNA libraries in human NSCLC models we have nominated several putative modulators of the radiation response in NSCLC. We have initiated target validation in vitro and in xenograft models in vivo. Mechanistic studies deciphering the modes of radioresistance and potentially nominating additional targets are ongoing. Prevalence of expression and prognostic/predictive value of such preclinically validated resistance factors are studied in our institutional biobank including a large and well-characterized cohort of NSCLC patients treated with chemoradiotherapy.
Our studies provide a framework for preclinical development of novel personalized chemoradiotherapy strategies in lung cancer.
S. Kasper, H. Reis, S. Ziegler, S. Nothdurft, A. Mueller, M. Goetz, J. Phasue, S. Ting, S. Wieczorek, A. Even, K. Worm, M. Pogorzelski, M. Wiesweg, S. Breitenbücher, J. Meiler, A. Paul, T. Trarbach, K.W. Schmid, F. Breitenbuecher, M. Schuler: Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy. Oncotarget (2017) doi:10.18632/oncotarget.17438 [Epub ahead of print]
S.A. Wieczorek, F. Breitenbuecher, A. Soni, K. Paul-Konietzko, S. Ziegler, A. Sak, G. Iliakis, M. Schuler: Deregulated BCL-2 family proteins impact on repair of DNA double strand breaks and are targets to overcome radioresistance in lung cancer. J. Cancer Res. Clin. Oncol. (2017) doi: 10.1007/s00432-017-2427-1
H. Kalkavan, P. Sharma, S. Kasper, I. Helfrich, A.A. Pandyra, A. Gassa, I. Virchow, L. Flatz, T. Brandenburg, S. Namineni, M. Heikenwalder, B. Höchst, P.A. Knolle, G. Wollmann, D. von Laer, I. Drexler, J. Rathbun, P. Cannon, S. Scheu, J. Bauer, J. Chauhan, D. Häussinger, G. Willimsky, M. Löhning, D. Schadendorf, S. Brandau, M. Schuler*‡, P.A. Lang‡, K.S. Lang*‡: Spatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumor regression. (*corresponding authors, ‡shared senior authorship) Nat. Commun. 8:14447 (2017)
R.A. Okimoto, F. Breitenbuecher, V.R. Olivas, W. Wu, M. Hofree, S. Asthana, G. Hrustanovic, J. Flanagan, A. Tulpule, C.M. Blakely, H.J. Haringsma, A.D. Simmons, K. Gowen, J. Suh, V.A. Miller, S. Ali, M. Schuler, T.G. Bivona: Inactivation of the transcriptional repressor Capicua drives cancer metastasis. Nat. Genet. 49:87.96 (2017)
M. Wiesweg, W.E.E. Eberhardt, H. Reis, S. Ting, N. Savvidou, C. Skiba, T. Herold, D.C. Christoph, J. Meiler, K. Worm, S. Kasper, D. Theegarten, J. Hense, T. Hager, K. Darwiche, F. Oezkan, C. Aigner, S. Welter, H. Kühl, M. Stuschke, K.W. Schmid, M. Schuler: High prevalence of concomitant oncogene mutations in prospectively identified patients with ROS1-positive metastatic lung cancer. J. Thorac. Oncol. 12:54-64 (2016)
W.E.E. Eberhardt, C. Pöttgen, T. Gauler, G. Friedel, S. Veit, V. Heinrich, S. Welter, W. Budach, W. Spengler, M. Kimmich, B. Fischer, H. Schmidberger, D. De Ruysscher, C. Belka, S. Cordes, R. Hepp, D. Lütke-Brintrup, N. Lehmann, M. Schuler, K.-H. Jöckel, G. Stamatis, M. Stuschke: Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage III A (N2) and selected III B non-small-cell lung cancer following induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J. Clin. Oncol. 33:4194-4201 (2015)
J. George, J.S. Lim, S.J. Jang, Y. Cun, L. Ozretic, G. Kong, F. Leenders, X. Lu, L. Fernández-Cuesta, G. Bosco, C. Müller, I. Dahmen, N. Jahchan, K.-S. Park, D. Yang, A.N. Karnezis, D. Vaka, A. Torres, M.S. Wang, J.O. Korbel, R. Menon, S.-M. Chu, De. Kim, M. Wilkerson, N. Hayes, D. Engelmann, B. Pützer, I. Vlasic, D. Seidel, B. Pinther, P. Schaub, C. Becker, J. Altmüller, J. Yokota, T. Kohno, R. Iwakawa, K. Tsuta, M. Noguchi, T. Muley, H. Hoffmann, P.A. Schnabel, I. Petersen, Y. Chen, A. Soltermann, V. Tischler, C. Choi, Y.-H. Kim, P.P. Massion, Y. Zou, D. Jovanovic, M. Kontic, G.M. Wright, P.A. Russell, B. Solomon, I. Koch, L.A. Muscarella, A. la Torre, J.K. Field, M. Jakopovic, J. Knezevic, E. Castaños-Vélez, L. Roz, U. Pastorino, E. Thunnissen, J. Köhler, M. Schuler, J. Botling, M. Sandelin, M. Sanchez-Cespedes, H.B. Salvesen, V. Achter, U. Lang, M. Bogus, P.M. Schneider, T. Zander, S. Ansén, M. Hallek, J. Wolf, M. Vingron, Y. Yatabe, W.D. Travis, P. Nürnberg, C. Reinhardt, S. Perner, L. Heukamp, R. Büttner, S.A. Haas, E. Brambilla, M. Peifer, J. Sage, R.K. Thomas: Comprehensive genomic profiles of small cell lung cancer. Nature 524:47-53 (2015)