Ahmed-Ebbiary, Amro
(2014)
Developing novel therapeutic strategies for targeting
the p53 pathway in renal cell carcinoma.
PhD thesis, University of Liverpool.
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Abstract
Renal cell carcinoma (RCC) is a notoriously difficult cancer to treat. RCC has an unpredictable course, is radio- and chemo-resistant and survival in response to treatment with current therapies for the metastatic disease is generally very poor. This underscores the necessity for novel therapeutics for this condition. The tumour suppressor p53 is rarely mutated in RCC and up-regulation of p53 and its negative regulator, MDM2, has recently been shown to be an independent prognostic indicator for patients with poor outcome. The function of p53 in RCC cells in culture appears to be partially intact and is regulated by MDM2. Rescue of p53 from the inhibitory effects of MDM2 using inhibitors of the p53-MDM2 interaction results in cell cycle arrest or senescence, not apoptosis, three cell fates that p53 can induce depending on the tissue or tumour type. Because of the potentially deleterious effects of senescent cells on the tissue microenvironment, it was decided that apoptosis would be the preferable cell fate for the therapeutic reactivation of p53 in RCC cells. To that end, the MDM2 inhibitor Nutlin-3 was combined with the Bcl-2 family inhibitor ABT-737. This combination of drugs synergistically inhibited the proliferation of RCC cells harbouring wild type p53 but not in cells harbouring mutant p53. This synergistic inhibition of proliferation was shown to be p53-dependent and was confirmed to be inducing apoptosis, but only in RCC cells that had high levels of p53 protein. The synergistic inhibition of proliferation was not recapitulated when an inhibitor of MDM2 ubiquitin ligase activity was combined with ABT-737. The combination of Nutlin-3 and ABT-737 induced pro-apoptotic Puma and Noxa in RCC cells and the apoptosis was shown to be substantially Bax-dependent. This study suggests that the combination of Nutlin-3 and ABT-737 should be considered as a candidate for pre-clinical development in the treatment of RCC.
| Item Type: | Thesis (PhD) |
|---|---|
| Additional Information: | Date: 2014-06 (completed) |
| Divisions: | Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 07 Aug 2014 10:51 |
| Last Modified: | 17 Dec 2022 01:14 |
| DOI: | 10.17638/00018973 |
| Supervisors: |
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| URI: | https://livrepository.liverpool.ac.uk/id/eprint/18973 |
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