Zainal, HB;
(2016)
Targeting the epidermal growth factor receptor (EGFR) pathway for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD).
Doctoral thesis , UCL (University College London).
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Targeting the epidermal growth factor receptor (EGFR) pathway for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD).pdf Download (6MB) | Preview |
Abstract
Kidney enlargement and cyst formation is the hallmark presentation of Autosomal Dominant Polycystic Kidney Disease (ADPKD). To date, only one treatment has been approved in Europe and the UK for a small subset of patients to slow down cyst growth. EGFR(ErbB1)/ErbB2 complexes, which are not expressed in normal adult kidney tubules, have been found to be highly expressed on the apical membrane of epithelium lining the cysts. Studies have shown that EGFR(ErbB1) and ErbB2 inhibitors significantly reduce cyst expansion and reverse the ADPKD phenotype in vitro and in vivo. This project is aimed at determining whether the tyrosine kinase inhibitors (TKIs) - lapatinib, gefitinib or CP-724,714 for targeting EGFR(ErbB1) and/or ErbB2 may be an effective retardation therapy for ADPKD. C57/BL6 Pkd1null+/- mice that faithfully mimic human ADPKD were used in the pharmacokinetic and efficacy studies. TKIs administered on day 1 through gavage and subsequent doses in drinking water for 1, 2, 4 weeks or 3 months, were monitored at high (IC50) and low (IC10) doses to evaluate their pharmacokinetic parameters, plasma/kidney drug disposition and relative efficacies. Groups of 6-month-old mice were used to model early-stage, mild disease and 9-month-old mice were used to model mid-stage, moderate disease. Plasma drug levels 1, 2, 4 and 6 hours post-gavage, terminal plasma and kidney drug concentrations, immunoblotting and histochemical analysis of phospho-extracellular regulated kinase (p-ERK) relative to total ERK, the downstream target of EGFR(ErbB) family receptor proliferative pathways were monitored. CP-724,714 and gefitinib are more effective than lapatinib as determined by reductions in kidney/body weight ratio, kidney size, cyst numbers and ERK activation. Simulations of best dose and duration parameters suggest that 8-20-fold lower than standard TKI doses successfully supressed the EGFR(ErbB) pathway long-term and potentially effective at reducing cyst proliferation.
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