Abo Donia, Mohammed Najim Abed ORCID: 0000-0002-2253-4420 (2018) Evaluation of drug combinations to sensitize ovarian cancer cells to chemotherapy. Doctoral thesis, Keele University.

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Abstract

Ovarian cancer is a complex disease characterized by low incidence, accounting for about 4% of cancer diagnoses in women, but with rapid progression and higher mortality rate than any other gynecological malignancy. Approximately 70 % of the cases are diagnosed late in the course of the disease due to unawareness of subtle symptoms and failure of screening methods for detecting the disease at early-stage. Although most patients respond well to standard treatment, which involves surgery followed by platinum/taxane combination therapy, relapse seems unavoidable and the majority of patients presented with chemoresistant disease, which is considered as the main obstacle to successful treatment. Reduced susceptibility to apoptosis is one of the major causes for the development of resistance to chemotherapy, one cause of it is overexpression of pro-survival members of Bcl-2 family. Advances in understanding of the molecular mechanisms of the involvement of pro-survival proteins in the emergence of resistance to chemotherapy has made them attractive targets for the development of new therapies to treat ovarian cancer. BH3 mimetics are agents that antagonize the apoptosis inhibitors of Bcl-2 family, and have been shown to potentiate the activity of carboplatin against a panel of ovarian cancer cell lines. However, in clinical trials, agents that antagonize Bcl-XL were associated with life-threatening thrombocytopenia. To avoid this venetoclax was developed to selectively inhibit Bcl-2 and avoid inhibition of Bcl-XL. Unfortunately, Bcl-XL appears to be more frequently deregulated than Bcl-2 in ovarian cancer. In this study, the ability of venetoclax, and the Bcl-XL selective compound WEHI-539, to potentiate the activity of carboplatin were assessed in ovarian cancer cell lines.

In addition to the genes encoding the Bcl-2 family of proteins, a number of other genes have shown to be overexpressed in drug resistant ovarian cancer. These are potential targets for the development of new therapeutic agents to overcome drug resistance. Work from our group previously reported an RNAi screen to assess whether knockdown of some of these genes increases the sensitivity to carboplatin or paclitaxel. In the present study, some of these hits were validated and branched-chain amino acid dehydrogenase kinase emerged as a potential new target for developing chemosensitizing agents.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Lisa Bailey
Date Deposited: 16 Mar 2018 15:48
Last Modified: 30 Jul 2018 14:32
URI: http://eprints.keele.ac.uk/id/eprint/4591

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