PRIMA-1 as a cancer therapy restoring mutant p53: a review

BioscienceHorizons Volume 8 2015  10.1093/biohorizons/hzv006 Review article PRIMA-1 as a cancer therapy restoring mutant p53: a review Emily J. Lewis* University of Exeter Medical School, Exeter, Devon EX1 2LU, England *Corresponding author: St Luke’s Campus, Magdalen road, Exeter, Devon EX1 2LU, England. Email: With a continuing increase in the prevalence of cancer, there is an increasing pressure to produce novel cancer therapies. The production of targeted cancer therapies could lead to the replacement of conventional cancer chemotherapy and, consequently, the minimization of the associated distressing side effects. This review addresses the process of restoring a mutant tumour suppressor protein, p53, in the apoptosis pathway as a potential therapeutic target for cancer therapy. Current literature highlights the small molecule PRIMA-1 as a particularly promising novel cancer therapy; however, there are currently many potential therapies being investigated; CP-31398 is another small molecule with potential anti-cancer effects. PRIMA-1 acts to restore the mutant p53 by modifying thiol groups in the core domains of the protein. Its success is well documented, with many studies in different cancer models proving its effectiveness. This, however, is not unanimous, with some questions being raised about its efficacy and other aspects such as possible resistance mechanisms as well as potentially harmful degradation products. This said, PRIMA-1 has entered Stage II clinical trials and with more data collected on in vivo models and potential complications of the drug, it could ultimately provide an alternative to conventional cancer chemotherapy. This could therefore help to prevent cancer patients suffering the displeasing side effects with which it is associated. Key words: cancer therapy, targeted therapy, PRIMA-1, p53 Submitted on 24 September 2014; accepted on 7 September 2015 Introduction There are >200 types of cancer that caused an estimated 12.7 million new cases in 2008 (Cancer Research UK, 2014). With this, cancer incidence rates have increased by 33% in the UK since the 1970s (Cancer Research UK, 2014), and this is set to increase with an ageing population. As a result, the pressure for the discovery of novel treatments is ever increasing. Current chemotherapy methods, among other advances, have led to a 2-fold increase in the survival rates in the UK in the last 40 years meaning that half of the people diagnosed with cancer now survive for at least 5 years after diagnosis (Cancer Research UK, 2014). With this said, chemotherapy has long been associated with side effects that can dramatically reduce the quality of life of cancer patients, due to the lack of specificity of chemotherapy causing other dividing cells to be affected. Carelle et al. (2002) documented these with the most distressing side effects including the loss of hair, weight gain and loss of sexual feeling. To try and minimize the side effects associated with current chemotherapy methods, researchers are now exploring the use of drug targeting for the development of novel therapies. Targeted cancer therapies use specific molecules involved in the development of the tumour as targets to halt its proliferation (National Cancer Institute, 2014b). Success in this field has resulted from the use of both therapeutic antibodies and small molecules acting on a range of targets to effectively prevent the proliferation of tumours while aiming to lower the toxicity of the drugs (Wu, Chang and Huang, 2006). This review will look at some of these developing methods focusing on targeting the absence of sufficient apoptosis, one of the hallmarks of cancer, (see Fig. 1) (Hanahan and Weinberg, 2011) with a reduction in tumour © The Author 2015. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1 Supervisor: Emma Taylor, University of Exeter Medical School, Exeter, Devon EX1 2LU, England. Review article Bioscience Horizons • Volume 8 2015 size considered evidence of a regression of malignant cells. The apoptosis pathway is modified in a number of ways in cancerous cells, but this review will centre on the protein p53. The location of p53 in the apoptosis pathway has been highlighted in Fig. 2. p53 is involved in many physiological process but is mainly categorized as a tumour suppressor. It is involved in cell fate by integrating various forms of cell signalling mechanisms, including but not limited to nutrient, cytokine and hormone levels. The underlying mechanisms remain unclear; however, it is thought that the TP53 gene can encode different isoforms that modulate the activity of p53, either promoting cell survival or death, depending on cell context and external stresses by differentially regulating gene transcription (Surget et al., 2013). It is normally kept at low levels through ubiquitation and proteasomal degradation in the cell but becomes up-regulated by stress signals, often induced by DNA damage (Selivanova et al., 1999). Once activated it leads to a pathway of downstream effects including physiological functions and the induction of apoptosis which halts cancer progression (Martinez, 2010). In cancerous cells, p53 is often mutated and so this pathway does not proceed, which can result in uncontrolled cell proliferation of cells with damaged DNA that may include mutations in oncogenes or tumour suppressor genes. Subsequently, this may lead to the formation of a tumour. Hollstein et al. (1991) estimated that up to 50% of human cancers have a mutation in p53, and this is therefore a promising target for novel cancer therapies without causing the death of healthy cells as seen with traditional chemotherapy. So far there have been three main methods for targeting p53 in cancerous cells. The first technique is to reactivate the apoptosis pathway by modifying mutant p53; the second is to reintroduce the p53 protein by an exogenous 2 mechanism and finally inhibiting mdm2, which is in itself an inhibitor of p53. Shchors et al. (2013) used a genetically engineered mouse model that pharmacologically restores p53 function. They were able to activate and deactivate cancerous effects that established the mechanism of reactivation of the tumour suppressor. This literature review will explore the restoration of the mutated protein to its wild-type form as a novel target for cancer therapy to supplement or even replace conventional chemotherapy methods that have undesirable side effects. PRIMA-1 mechanism of action There have been a number of clinical trials on drugs targeted at restoring mutant p53 proteins in cancerous cells. The most promising thus far is PRIMA-1, which is a small molecule therapy that entered its second phase of clinic (...truncated)