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Title: Pre-clinical and clinical evaluation of the heat shock protein 90 (HSP90) inhibitor 17-allylamino, 17-demethoxygeldanamycin (17-AAG)
Author: Banerji, Udai
ISNI:       0000 0001 2439 9093
Awarding Body: Institute of Cancer Research (University Of London)
Current Institution: Institute of Cancer Research
Date of Award: 2005
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17 allylarnino, 17-demethoxygeldanamycin (17-AAG) is a heat shock protein inhibitor (HSP90) that is the first of its class to go into phase I clinical trials. This thesis describes pre-clinical and clinical studies with 17-AAG directed towards rational development of the drug. The first section describes the development and validation of pharmacodynamic (PD) markers. A molecular signature of inhibition of HSP90, i. e. depletion of client proteins c-RAF-1, CDK4 and induction of the co-chaperone heat shock protein 70 (HSP70), was validated in human cancer cell lines and human peripheral blood leukocytes (PBLs) in vitro. The pharmacokinetic (PK) - PID relationship was established in tumour and PBLs in two human ovarian tumour xenograft models. The second section of the thesis describes the phase I clinical trial of 17-AAG. The highest dose reached was 450 mg/m2/wk, and dose limiting toxicities of diarrhoea and hepatotoxicity were seen in 2/9 of patients at this dose. It was possible to demonstrate potentially therapeutic plasma levels and PID changes in PBLs and tumour tissue at the dose level of 450 mg/m2/wk, which was the recommendedd ose for phase 11tr ials. The third section of the thesis addresses the combination of 17-AAG and platinum compounds. The effects of the combination were studied in vitro and in vivo and will provide the pre-clinical validation for a combination phase I trial in the future. The fourth section discusses the study of 17-AAG in malignant melanoma prompted by the indication of clinical activity in the phase I clinical Mal. c-DNA microarrays were used to study gene expression changes in response to 17-AAG in two melanoma cell lines (SKMEL-2 and SKMEL-5). The changes in gene expression were used to try and identify new PID markers and understand factors influencing sensitivity of malignant melanoma cells to 17-AAG.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available