Biomarkers for toxicity from and response to pre-operative radiochemotherapy: clinical, pharmacogenomic, and functional analyses

• Applicant: Privatdozent Dr. Hendrik A. Wolff, since 4/2012
• Subject Area: General and Visceral Surgery
• Term: from 2007 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 33996666

Subproject 6 focuses on the acquisition, documentation, and prediction of treatment-related toxicity. We aim to assess whether the benefit/risk ratio can be improved by intensifying the induction chemoradiotherapy. To provide treatment homogeneity, we will monitor the quality of radiation therapy using an intensive schedule of dose distribution calculations and physical measurements. In addition, we aim to measure the serum concentrations of fluorouracil (5-FU), its metabolites, and oxaliplatin during the application of chemotherapy, which will further allow us perform functional pharmacogenomic analyses. Also, concentrations of the active 5- FU metabolites FdUMP and FUTP will be analyzed in leucocytes. Likewise, intracellular oxaliplatin accumulation will be measured to investigate genetic variability in membrane transport. Radiation and probably chemoradiotherapy act through DNA damage induction and signaling activation. Therefore, for biodosimetry as well as a surrogate marker for DNA repair capacity, spontaneous and induced DNA damage will be analyzed by chromosome aberrations. The transforming growth factor-beta (TGF-beta) pathway and the signaling of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) have been identified as co-regulators of radiation effects. Therefore, in selected genes of these pathways and in 5-FU metabolism, single nucleotide polymorphisms (SNPs) will be determined. The selection will be performed according to described or bioinformatics-deduced functionality. Functional relevance of these SNPs will be elucidated by molecular biological approaches in tissues and cell cultures. That includes growth receptor internalization, its interactions with the TGF-beta pathway, and molecular effects of the combined 5-FU/oxaliplatin chemoradiotherapy.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 179: Biological Basis of Individual Tumour Response in Patients with Rectal Cancer
• Participating Persons: Professor Dr. Jürgen Brockmöller; Privatdozent Dr. Markus Schirmer
• Ehemaliger Antragsteller: Professor Dr. Hans Christiansen, until 4/2012