Project 8
Comprehensive assessment of the impact of deregulated signal transduction on the radiotherapy response of non-small cell lung cancer
Principal Investigator
Prof. Dr. med. Martin Schuler
Dept. of Medical Oncology,
West German Cancer Center
Essen University Hospital
Summary
Radiotherapy is an important modality in curative and palliative treatment of patients with non-small cell lung cancer (NSCLC). Although the current development of innovative pharmacotherapies for NSCLC is tailored to tumor-specific molecular aberrations, radiotherapy still does not take advantage of disease heterogeneity. We hypothesize that aberrant signal transduction pathways modulate the outcome of radiotherapy for NSCLC and thus provide potential targets for optimized combined modality treatments. To this end we will devise ge-netically modified NSCLC lines, which form tumors that conditionally express or activate transgenes in mice before, in cojunction with or following irradiation (IR). This will enable a systematic assessment of the impact of selected signal transduction mediators (RAF, MEK, AKT), regulators of cell cycle, senescence and apoptosis (p21/WAF1, RASSF1A), and oncogenes (MYC, HRAS, HPV16-E6/E7, Ad5-E1A) on the growth and survival of NSCLC tumors in vitro and in vivo. These studies will form the basis for definition of suitable targets for further preclinical development and validation of "personalized" chemoradiotherapy protocols for NSCLC.
Selected Publications
Petry IB, Fieber E, Schmidt M, Gehrmann M, Gebhard S, Hermes M, Schormann W, Selinski S, Freis E, Schwender H, Brulport M, Ickstadt K, Rahnenführer J, Maccoux L, West J, Kölbl H, Schuler M, Hengstler JG: ERBB2 induces an anti-apoptotic expression pattern of Bcl-2 family members in node negative breast cancer. Clin Cancer Res. 2010;16:451-60.
Thaler S, Hähnel PS, Schad A, Dammann R, Schuler M. RASSF1A mediates p21Cip1/Waf1-dependent cell cycle arrest and senescence through modulation of the Raf- MEF-ERK pathway and inhibition of Akt. Cancer Res 2009;69:1748-1757.
Hoffarth S, Zitzer A, Wiewrodt R, Hähnel PS, Beyer V, Kreft A, Biesterfeld S, Schuler M. pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer. Cell Death Differ. 2008;15:161-70.
Hähnel PS, Thaler S, Antunes E, Huber C, Theobald M, Schuler M. Targeting AKT signaling sensitizes cancer to cellular immunotherapy. Cancer Res 2008;68:3899-3906.
Wesarg E, Hoffarth S, Wiewrodt R, Kröll M, Biesterfeld S, Huber C, Schuler M. Targeting BCL-2 family proteins to overcome drug resistance in non-small-cell lung cancer. Int J Cancer 2007;121:2387-94.
Chipuk JE, Maurer U, Green DR, Schuler M. Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Cancer Cell 2003;4:371-81.