Dissecting the phenomenon of multidrug resistance transporter overexpression in a murine model of head and neck squamous cell carcinoma.

• Applicant: Professor Dr. Dirk Theile
• Subject Area: Otolaryngology, Phoniatrics and Audiology ; Pharmacology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260326226

Overexpression of ATP-binding cassette (ABC-) transporters such as P-glycoprotein (Pgp) causes multidrug resistance (MDR) in vitro and has been associated with clinical unresponsiveness to chemotherapy in several cancer entities. So far, it is unclear whether acquired chemotherapy resistance of head and neck squamous cell carcinoma (HNSCC) through overexpression of ABC-transporters is caused by progression of the tumor disease or by treatment with cytostatics. Such iatrogenic chemotherapy resistance can in turn be caused by transcriptional induction of MDR genes or by Darwinian selection of pre-existing drug resistant sub-clones. Using state-of-the-art mouse models, these fundamental questions will be addressed by the applicant. One of the two murine MDR1 genes will be substituted with luciferase gene by homologous recombination using RU486-inducible Cre recombinase under tissue specific keratin promoter (mdr1a.flox/K5.Cre*PR1 mice). In consequence, luminescence in the oral cavity is a surrogate for MDR1 transcript expression. Carcinogenesis in the oral cavity will subsequently be caused by exposure of the epithelia to 4-nitroquinoline 1-epoxide (4-NQE). Luminescence, murine Pgp expression, tumor volume, and Ki-67 staining index at end of observation period will be recorded during carcinogenesis and treatments with docetaxel, paclitaxel, or placebo. To compare this 4-NQE model to carcinogenesis mediated by mutant K-ras protein, mdr1a.flox/K5.Cre*PR1 mice will also be mated with LSL-K-rasG12D mice leading to progeny with oral cavity specific malign lesions after Cre activation by RU486.Taken together, the results will clarify whether there are differences between HNSCC etiologies (K-ras mutation vs carcinogenic toxins) or drugs (docetaxel vs paclitaxel) and scrutinize the mechanism of iatrogenic overexpression of ABC-transporters (transcriptional induction vs selection).

• DFG Programme: Research Fellowships
• International Connection: USA
• Hosts: Professorin Susan Kane, Ph.D.; Professor Timothy Synold, Ph.D.