Objective Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells(Turk et al.,Cancer Res, 2009. 69(21));- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).I propose a comprehensive series of studies that will address thefollowing critical questions:- First, what is the scope of MDR-selective compounds?- Second, what is their mechanism of action?- Third, what is the optimal therapeutic modality?Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care. Fields of science medical and health sciencesclinical medicineoncologymedical and health sciencesbasic medicinepharmacology and pharmacydrug resistancemultidrug resistance Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-SG-LS7 - Applied life sciences, biotechnology and bioengineering: agricultural, animal, fishery, forestry/food sciences; biotechnology, chemical biology, genetic engineering, synthetic biology, industrial biosciences; environmental biotechnology. Call for proposal ERC-2010-StG_20091118 See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Host institution HUN-REN TERMESZETTUDOMANYI KUTATOKOZPONT EU contribution € 1 499 640,00 Address MAGYAR TUDOSOK KORUTJA 2 1117 Budapest Hungary See on map Region Közép-Magyarország Budapest Budapest Activity type Other Administrative Contact Pál Székács (Mr.) Principal investigator Gergely Szakacs (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all HUN-REN TERMESZETTUDOMANYI KUTATOKOZPONT Hungary EU contribution € 1 499 640,00 Address MAGYAR TUDOSOK KORUTJA 2 1117 Budapest See on map Region Közép-Magyarország Budapest Budapest Activity type Other Administrative Contact Pál Székács (Mr.) Principal investigator Gergely Szakacs (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data