Emilio Casanova, PhD

Medical University of Vienna
Center for Physiology and Pharmacology
Institute of Physiology
Währinger Str. 13a
1090 Vienna, Austria

Phone: +43 1 40160-31341
Fax: +43 1 40160-931300
E-Mail: emilio.casanova@meduniwien.ac.at
» Website

Research interests

Our research goal is to unravel the contribution of key cellular signaling pathways to tumorigenesis, with especial emphasis in lung cancer. To this aim, we make use of genetically modified mouse models (conditional knock-outs, knock-ins, BAC-based transgenic, etc.) mimicking human tumorigenesis. In addition, we complement our studies in the mouse autochthonous tumors by performing gene gain and loss-of-function experiments (e.g. lentiviral overexpression and/or CRISPR/Cas9-induced knock-outs) in human cancer cell lines and xenograft mouse models and by analyzing human tumor biopsies.

Current research topics:

• Role of EGFR/ERBB in KRAS driven lung adenocarcinomas.
• Inflammation and NFkB driven lung cancer
• Development of preclinical models of immunotherapy in lung cancer

Advertised project

Evaluating resistance mechanisms to afatinib in KRAS-driven lung adenocarcinoma (AC). The mutually exclusive KRAS and EGFR mutations account for approximately 50% of the somatic alterations found in lung AC^1,2. While patients harboring EGFR-mutated lung AC benefit from targeted therapy based on EGFR inhibitors, the generation of KRAS inhibitors remained elusive³. Recently, we (Moll et al. Sci Transl Med, in press) and others (Kruspig et al. Sci Transl Med, in press) have shown that pan-ErbB inhibitors, such as afatinib, impair KRAS driven lung AC, opening the possibility for the targeted treatment of KRAS mutated tumors. In view of the clinical experiences with targeted therapies, we hypothesize that KRAS driven lung AC patients will eventually develop resistance to afatinib therapy. Therefore, we propose to identify and analyze resistance mechanisms by establishing preclinical models of afatinib resistance. Resistant lung AC cell lines will be obtained by in vitro selection and treatment of mice xenografted with GFP-expressing cells (with WB and GS). Parental and resistant cell lines obtained in vitro and by sorting eGFP-positive cells derived from resistant xenografts will be subjected to exome sequencing and RNAseq analysis. Relevance of altered mechanisms in resistance and collateral sensitivity will be validated by mutagenesis by CRISPR/Cas9 and drug screening using the PLACEBO library (Center for Molecular Medicine, CeMM). By identifying pathways responsible for resistance we expect to target de novo tumor vulnerabilities associated with resistance to afatinib inhibition in KRAS driven lung AC.

Reference

1. Imielinski, M.; Berger, A. H.; Hammerman, P. S.; Hernandez, B.; Pugh, T. J.; Hodis, E.; Cho, J.; Suh, J.; Capelletti, M.; Sivachenko, A.; et al. Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing. Cell 2012, 150 (6), 1107–1120. doi.org/10.1016/j.cell.2012.08.029.
2. Roberts, P. J.; Stinchcombe, T. E. KRAS Mutation: Should We Test for It, and Does It Matter? J. Clin. Oncol. 2013, 31 (8), 1112–1121. doi.org/10.1200/JCO.2012.43.0454.
3. Langer, C. J. Roles of EGFR and KRAS Mutations in the Treatment Of Patients With Non–Small-Cell Lung Cancer. Pharm. Ther. 2011, 36 (5), 263–279.