Manipulating the p53 pathway for cancer treatment

Roxburgh, Patricia (2013) Manipulating the p53 pathway for cancer treatment. PhD thesis, University of Glasgow.

Abstract

p53 is a tumour suppressor that is dysfunctional in most cancers. In some cancers, mutation of the TP53 gene results in expression of a mutant protein or loss of p53 expression, while in others wild-type p53 is retained but there is a defect in the mechanisms that allow for the activation of p53, including, but not limited to, upregulation of p53’s negative regulators (MDM2 and MDMX). Restoration of wild-type p53 function can lead to tumour regression and is therefore an attractive anti-cancer therapy. Several small molecule compounds that activate wild-type p53 have been described, and in this study the functions of two new compounds that stabilise p53 are described. While these drugs may be useful to activate p53-dependent apoptosis or senescence in wild-type p53 tumours, an alternative approach that depends on the use of transient p53 activation to protect normal cells while leaving p53 null or mutant tumour cells vulnerable to cytotoxic drugs is also explored. Finally, the identification of pharmacodynamic biomarkers for p53 stabilisation is described.
In chapter 3 a new class of MDM2 inhibitor (MPD compounds) is described. The compounds are capable of stabilising and activating p53 in cells by inhibiting the E3 ligase activity of MDM2 in a mechanism that involves compound binding to the RING-tail of MDM2. Although the MPD compounds have limitations in terms of solubility and potency they have demonstrated a new method of achieving MDM2 inhibition and support design of further RING-tail binding compounds with more favourable chemical properties.
In chapter 4 the function of a dual inhibitor of MDM2 and MDMX has been explored (HLI373). This compound is shown to activate p53 in cells and in vivo by interfering with ribosomal biogenesis, causing ribosomal stress and inhibiting MDM2. In addition it is capable of reducing MDMX expression at the promoter level by a mechanism that requires intact MDM2-p53 binding. Further work is required to fully define the mechanism of action of this compound and demonstrate its anticancer activity in xenograft and transgenic mouse models.
In chapter 5 a chemoprotective approach for p53 activation, which might be applied to situations where tumours express mutant p53, is explored in cell lines. Low-dose actinomycin D treatment can activate p53 without occult DNA damage via the ribosomal stress pathway, thereby protecting wild-type p53 expressing cells from the cytotoxic effects of paclitaxel. Low-dose actinomycin D may therefore be used to limit chemotherapy-induced toxicity to normal cells while targeting a mutant p53 expressing tumour.
In chapter 6 the potential for developing pharmacodynamic biomarkers for MDM2 inhibition in serum, peripheral blood mononuclear cells and hair follicles taken from patients prior to and following chemotherapy was examined. Measurement of serum MIC-1 level showed most promise, although further evaluation of this marker is needed before it could be used as a pharmacodynamic endpoint in a clinical study.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: p53, cancer, mdm2, mdmx, treatment, biomarkers
• Subjects: Q Science > QH Natural history > QH301 Biology; R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research
• Supervisor's Name: Vousden, Prof. K.
• Date of Award: 2013
• Depositing User: Dr Patricia Roxburgh
• Unique ID: glathesis:2013-4576
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 09 Oct 2013 10:48
• Last Modified: 09 Oct 2013 11:46
• URI: https://theses.gla.ac.uk/id/eprint/4576