eprintid: 1477184 rev_number: 37 eprint_status: archive userid: 608 dir: disk0/01/47/71/84 datestamp: 2016-05-13 12:52:46 lastmod: 2020-02-13 03:18:50 status_changed: 2016-05-13 12:52:46 type: thesis metadata_visibility: show creators_name: Zainal, HB title: Targeting the epidermal growth factor receptor (EGFR) pathway for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) ispublished: unpub divisions: UCL divisions: A01 divisions: B02 divisions: C10 divisions: D17 divisions: G93 divisions: C09 divisions: D13 divisions: G24 keywords: ADPKD, EGFR, ErbB2 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. date: 2016-03-28 date_type: published oa_status: green full_text_type: other thesis_class: doctoral_open language: eng thesis_view: UCL_Thesis primo: open primo_central: open_green verified: verified_manual elements_id: 1121048 lyricists_name: Norman, Jill lyricists_name: Standing, Joseph lyricists_name: Wilson, Patricia lyricists_name: Zainal, Hadzliana lyricists_id: JTNOR32 lyricists_id: STAND26 lyricists_id: PDWIL35 lyricists_id: HZAIN35 actors_name: Zainal, Hadzliana actors_id: HZAIN35 actors_role: owner full_text_status: public pagerange: 1-203 pages: 203 event_title: University College London institution: UCL (University College London) department: Nephrology thesis_type: Doctoral editors_name: Norman, J editors_name: Standing, J editors_name: Wilson, P citation: 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). Green open access document_url: https://discovery-pp.ucl.ac.uk/id/eprint/1477184/1/Targeting%20the%20epidermal%20growth%20factor%20receptor%20%28EGFR%29%20pathway%20for%20the%20treatment%20of%20Autosomal%20Dominant%20Polycystic%20Kidney%20Disease%20%28ADPKD%29.pdf