Targeting AKT and DNA-PK as a therapeutic strategy in platinum resistant high grade serous ovarian cancer
File(s)
Author(s)
Rinne, Natasha
Type
Thesis
Abstract
High-grade serous ovarian cancer accounts for approximately 70% of Epithelial Ovarian Cancers. Despite being initially sensitive to platinum-based chemotherapy most women will relapse and become resistant to treatment. The PI3K/AKT/mTOR pathway, a key mediator in platinum resistance, is activated in approximately 70% of HGSOC cases and is responsible for promoting cell survival.
This study aimed to characterise the lead compound from novel PI3K/AKT/mTOR pathway inhibitors developed by the Imperial Drug Discovery Centre. MTL001, a dual AKT and DNAPK inhibitor, is a novel strategy for targeting platinum resistance in HGSOC. Through phenotypic evaluation and analysis in immortalised cell lines, primary models of HGSOC, and in vivo studies, the aim of this study was to provide a pre-clinical evaluation of MTL001.
Results from phenotypic experiments demonstrated that compared to single agent PI3K/AKT/mTOR inhibitors in development/clinical trials, treatment with MTL001 reduced HGSOC cell proliferation more effectively when combined with cisplatin. MTL001 worked more synergistically with cisplatin, and treatment with MTL001 induced the largest increase in apoptosis at lower concentrations.
A protein signature for MTL001 was established through time course experiments and proteomic RPPA analysis. Results indicate MTL001 is acting via the PI3K/AKT/mTOR kinase pathway through AKT either directly or indirectly via the action of DNAPK on AKT. When used in combination with cisplatin in 3D patient-derived organoid models, no antagonism between compounds was observed. Pharmacokinetic studies looking at elimination of the drug in tumour-free mice showed rapid clearance following single intraperitoneal or intravenous administration. Uptake of the drug into tumour was variable, and efficacy studies did not show a decrease in tumour volume for MTL001-HCL in combination with cisplatin or as a monotherapy.
By developing this novel strategy of dual AKT and DNA-PK inhibition for platinum resistant HGSOC patients, we aim to improve patient response to treatment and overall survival.
This study aimed to characterise the lead compound from novel PI3K/AKT/mTOR pathway inhibitors developed by the Imperial Drug Discovery Centre. MTL001, a dual AKT and DNAPK inhibitor, is a novel strategy for targeting platinum resistance in HGSOC. Through phenotypic evaluation and analysis in immortalised cell lines, primary models of HGSOC, and in vivo studies, the aim of this study was to provide a pre-clinical evaluation of MTL001.
Results from phenotypic experiments demonstrated that compared to single agent PI3K/AKT/mTOR inhibitors in development/clinical trials, treatment with MTL001 reduced HGSOC cell proliferation more effectively when combined with cisplatin. MTL001 worked more synergistically with cisplatin, and treatment with MTL001 induced the largest increase in apoptosis at lower concentrations.
A protein signature for MTL001 was established through time course experiments and proteomic RPPA analysis. Results indicate MTL001 is acting via the PI3K/AKT/mTOR kinase pathway through AKT either directly or indirectly via the action of DNAPK on AKT. When used in combination with cisplatin in 3D patient-derived organoid models, no antagonism between compounds was observed. Pharmacokinetic studies looking at elimination of the drug in tumour-free mice showed rapid clearance following single intraperitoneal or intravenous administration. Uptake of the drug into tumour was variable, and efficacy studies did not show a decrease in tumour volume for MTL001-HCL in combination with cisplatin or as a monotherapy.
By developing this novel strategy of dual AKT and DNA-PK inhibition for platinum resistant HGSOC patients, we aim to improve patient response to treatment and overall survival.
Version
Open Access
Date Issued
2023-04-27
Date Awarded
2024-06-01
Copyright Statement
Attribution-Non Commercial-No Derivatives 4.0 International Licence (CC BY-NC-ND)
Advisor
Cunnea, Paula
Fotopoulou, Christina
Sponsor
National Institute for Health Research (Great Britain)
Imperial College London
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)