Project-ID: LS15-003
Project start: 01. December 2016
Runtime: 36 months / ongoing
Funding amount: € 292.110,00

Brief summary

Many diseases of the brain (e.g. brain tumors, Alzheimer’s disease) cannot be adequately treated despite the availability of drugs which target disease-relevant molecular mechanisms in the brain. One important reason for this is the inability of available drugs to penetrate the blood-brain barrier (BBB) and to achieve therapeutically effective concentrations inside the brain. A significant obstacle to brain delivery of small drug molecules is often the combined action of the multidrug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). These two transporters are located in the luminal membrane of brain capillary endothelial cells forming the BBB, where they efflux their substrates back into the blood stream. A promising strategy to increase brain distribution of drugs targeted to the brain without affecting plasma concentrations is the concomitant administration of efflux transporter inhibitors. As P-gp and BCRP have been shown to functionally compensate each other, it is essential to employ dual P-gp/BCRP inhibitors to improve brain delivery of dual P-gp/BCRP substrate drugs. Despite the fact that some potent inhibitors of P-gp/BCRP have been described (e.g. elacridar, tariquidar) use of these non-marketed drugs in humans is restricted due to safety concerns and limited or no availability for clinical use. An alternative to the use of these experimental P-gp/BCRP inhibitors would be the use of marketed drugs for which it is known that they can inhibit P-gp and BCRP. This requires drugs which are safe enough so that they can be dosed at higher than therapeutic doses to achieve high enough plasma concentrations for inhibition of both P-gp and BCRP at the BBB. The aim of this project is to identify drugs from the therapeutic class of tyrosine kinase inhibitors (e.g. regorafenib, lapatinib, erlotinib, nilotinib) which can achieve inhibition of both P-gp and BCRP at the BBB at clinically feasible plasma concentrations. We will use two radiolabelled anticancer drugs and model P-gp/BCRP substrates (erlotinib and topotecan) to study i) in vitro transporter inhibition in cell lines which express human P-gp and BCRP and ii) in vivo transporter inhibition at the BBB of rats by means of positron emission tomography (PET) imaging. The availability of a marketed and safe P-gp/BCRP inhibitor will enable a use in humans to boost brain distribution of drugs targeted to the brain and thereby significantly improve treatment of brain diseases.

Keywords:
oncology, neurology