KFO 210:  Genetics of Drug Resistance in Cancer

• Subject Area: Medicine
• Term: from 2008 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 59021035

Cancer is a major threat to human society in industrialised countries. Only 50 percent of all cancers can be cured by local therapies such as surgery or radiation therapy. Current evidence supports the growing importance of systemic therapies even in cancers, which were curatively operated on (so-called adjuvant therapies). However, only a minority of patients' cancer is diagnosed at an advanced stage where systemic therapies (i.e. chemotherapy and immunotherapy) are not expected to cure the patients, but primarily to prolong life or treat symptoms. Only a minority of cancers can be cured in an advanced stage by chemotherapy. In addition, in recurrent cancers response to systemic chemotherapy is mainly poor.
As a consequence, resistance to systemic therapy is one of the major problems in medical oncology. Most programmes to influence primary or secondary resistance to chemotherapy have failed and not entered clinical practice. Therefore, this proposal heads for a detailed molecular understanding of resistance. To discover new candidate genes, we will take advantage of functional RNA interference based shRNA libraries, which have been established in our groups.
Drugs such as platinum, cytarabine as well as doxorubicine will be used to uncover novel genes and pathways responsible for resistance in leukemia, lung and pancreatic cancer.
We will also use sophisticated cell sorting techniques to address the question of in vivo resistance in leukemias. In addition, we will work on already established resistance genes such as NFAT and p73. We believe that this approach will lead to a better understanding of molecular pathways of resistance in cancer and enable the development of new drugs influencing these pathways.

• DFG Programme: Clinical Research Units

Projects

• A synthetic lethal screen to identify novel targets for therapy in acute myeloid leukemia (Applicant Neubauer, Andreas )
• Exploring cancer therapies based on p53-reactivating drugs using shRNA barcode screening (Applicant Wanzel, Michael )
• Functional genomic analysis of sorafenib resistance in human FLT3-ITD-positive AML (Applicant Burchert, Andreas )
• Genome-wide analysis of the CUX1 transcriptional network mediating resistance to apoptosis in pancreatic cancer (Applicant Michl, Patrick )
• GSK-3beta regulated NFATc1 transcription complexes in pancreatic carcinogenesis and drug resistance (Applicant Burchert, Andreas )
• Head of Clinical Research Group (Applicant Burchert, Andreas )
• Modulation of the p19Arf-pü53 tumor suppressor response to overcome persistence in CML (Applicant Burchert, Andreas )
• Molecular mechanisms of cancer resistance against anti-angiogenic therapy (Applicant Acker, Till )
• Role of p73 for drug resistance (Applicant Stiewe, Thorsten )
• Signaling in persisting leukemic stem cells in acute myeloid leukemia (Applicant Brendel, Cornelia )
• Systematic shRNA and siRNA screens to investigate drug resistance in human leukemia (Applicant Eilers, Martin )
• Systematic shRNA and siRNA screens to investigate drug resistance in human leukemia (Applicant Krause, Michael )

• Leader: Professor Dr. Andreas Burchert
• Spokesperson: Professor Dr. Andreas Neubauer