p53 as a target for anti-cancer drug development

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Abstract

Loss of p53 function compromises genetic homeostasis in cells exhibiting deregulated DNA replication and/or DNA damage, and prevents normal cytotoxic responses to cancer therapies. Genetic and pharmacological approaches are being developed with the ultimate goal of restoring or controlling p53 functions in cancer patients. Progress has recently been made in the clinical use of replication-deficient virus carrying wt-TP53 (Ad5CMV-p53) and/or cancer-selective oncolytic adenoviruses (ONYX-015). These strategies demonstrated clinical activity as monotherapy and were synergistic with traditional chemotherapy agents in the treatment of some types of cancer. In addition, pharmacological methods are under development to either stimulate wild-type p53 protein function, or induce p53 mutant proteins to resume wild-type functions. These methods are based on small chemicals (CP-31388, PRIMA-1), peptides (CDB3) or single-chain Fv antibody fragments corresponding to defined p53 domains. Here, we discuss the mechanisms underlying these approaches and their perspectives for cancer therapy.

Introduction

It is now widely acknowledged that normal cells respond to DNA damage and inappropriate growth signals, such as oncogenic activation, by inducing genetically encoded programs that eliminate inappropriately proliferating cells from the cell cycle, thus protecting multicellular organisms from cancer development. Consequently, in an early phase of tumor development, oncogene-driven hyperproliferation must be associated with evasion of anti-proliferative and cell-death mechanisms that normally limit clonal expansion of somatic cells. In support of this hypothesis, it has been recently shown that precursor lesions of human cancers commonly express markers of a p53-dependent DNA damage response, indicating that early tumorigenesis (before malignant conversion and genomic instability) activates a p53-dependent response that delays or prevents cancer progression [1], [2]. Activation of this checkpoint may be due to deregulated DNA replication, including abnormalities in pre-replication complex maturation and stalled or collapsed replication forks, followed by the generation of double-strand breaks. Mutations compromising this checkpoint might thus allow, early in tumorigenesis, cell proliferation, survival, increased genomic instability and tumor progression.

p53, the most frequently mutated gene in human malignancies [3], is found inactivated in approximately 50% of tumors of any location and histological type (generally, point mutations of one allele and deletion of the other allele). This transcription factor is considered as the “guardian of the genome”. Present in an inactive form in normal cells, p53 becomes fully functional when activated in response to cell stress (either oncogenic or genotoxic stress). p53 activation leads to the upregulation of various target genes responsible for cell cycle arrest or apoptotic cell death, depending on the cellular environment.

Due to its crucial tumor suppressor activity, TP53 thus appears to be an appealing target for gene therapy or pharmacological intervention in cancer treatment. In this review, we highlight the current knowledge concerning the different strategies to restore wild-type p53 function and thereby either reverting the malignant phenotype or enhancing drug sensitivity.

Section snippets

TP53 structure and function

The human TP53 gene spans 20 kb on chromosome band 17p13.1. The gene is composed of 11 exons, the first of which is non-coding [4]. Its promoter does not contain a TATA box but harbors a number of consensus binding sites for common transcription factors, such as Sp1, NF-kappaB or c-Jun. Despite these potential sites for transcriptional regulation, the expression of TP53 is constitutive and ubiquitous, most of the protein regulation taking place at the post-translational level.

The p53 protein is

TP53 mutations

Somatic TP53 mutations have been described in almost all types of cancers with a variable prevalence depending on the type of cancer. In cancers of the upper aero-digestive tract (oral, esophageal or bronchial cancers), TP53 is mutant in up to 75% of the cases of invasive cancers, particularly in smokers who are exposed to mutagens, and the mutation is often detectable in early, pre-neoplastic lesions. In cancers of the lower digestive tract, such as colon cancer, TP53 mutations are less common

Targeting TP53 for cancer therapy

Current, experimental approaches that target p53 for cancer treatment include attempts to activate p53 (Table 1) as well as to inactivate p53. These strategies aim to induce apoptosis or to prevent the destruction of normal cells by cytotoxic therapies. On the other hand, in certain cell types, activation of p53 by therapeutic agents may induce cell cycle arrest (and DNA repair) rather than apoptosis, thus resulting in a form of protection of cancer cells against the effects of therapy. Thus,

Gene therapy to restore p53 function

As function of TP53 is lost in many cancers, it seems reasonable to try to restore p53 function by replacing the mutant gene with a functional wild-type copy. It is believed that restoring of TP53 function in tumor cells may block tumor development and may sensitize cells to cytotoxic killing, thus improving therapeutic response. One of the most popular approaches to achieve TP53 restoration is the use of gene therapy. The primary requirement to treat cancer with TP53-gene therapy is the

Killing p53-deficient cells with modified adenoviruses

The use of E1B-defective adenoviruses represents an extremely promising approach to take advantage of TP53 status as a basis for cancer therapy. This approach is essentially different from “replacement” gene therapy. Indeed, it does not involve transfer of a TP53 gene into cells, but requires the introduction of genetically modified viruses that will take advantage of dysfunctional p53 in cancer cells to selectively kill them.

DNA tumor viruses, such as adenoviruses infect quiescent cells and

Pharmacological modulation of p53 protein functions

Conceivably, modulation of wt-p53 can exert different, if not opposite, effects depending on the target cells and the clinical context. In tumor cells with wt-TP53 gene, increasing the activity of p53 may help to increase the response to therapy and to eliminate these cells. In contrast, in non-tumor cells, it is possible that increasing p53 protein function may activate a physiological, “guardian-of-the-genome” effect that contributes to the protection against the toxic effects of cancer

Use of vaccinia vectors

Several studies have reported success in using viral vectors derived from the vaccinia virus as candidates for delivering TP53 gene for therapy. Timiryasova et al. have analyzed the effect of local injection of a recombinant p53-expressing vaccinia vector in nude mice bearing implanted glioma cells [111], [112]. Injection of the viral vector induced a major oncolytic effect, probably due to p53-mediated cell apoptosis. This effect was increased when injection was accompanied by radiotherapy

Perspectives and future challenges

Given their central role in the control of life and death of cells exposed to DNA-damage, TP53 and the p53 protein are attractive targets for therapeutic approaches that may be added to current protocols. A first approach is to restore or increase p53 function in cancer cells. These cells would then become more susceptible to killing by radio- or chemotherapy. This is the aim of most current TP53-based gene therapy approaches. In this sense, the use of replication-deficient virus carrying wt-

Reviewers

Hervé Bonnefoi, Professor, Département de Gynécologie et d’Obstétrique, Unité d’Oncogynécologie Médicale, Hôpitaux Universitaires de Genève, Boulevard de la Cluse 30, CH-1211 Genève 14, Switzerland.

Jack A. Roth, M.D., F.A.C.S., The University of Texas MD Anderson Cancer Center, Professor and Chairman, Bud Johnson Clinical, Distinguished Chair, Department of Thoracic & Cardiovascular Surgery, Professor of Molecular & Cellular Oncology, Director, W.M. Keck Center for Cancer Gene Therapy, 1515

Benjamin P. Bouchet is a Doctor of Pharmacy from the Claude Bernard University of Lyon, France. He is a Ph.D. student at the INSERM 590 unit located at the Léon Bérard Center, Cancer Institute, Lyon. His work is supported by the Fondation pour la Recherche Médicale.

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    Benjamin P. Bouchet is a Doctor of Pharmacy from the Claude Bernard University of Lyon, France. He is a Ph.D. student at the INSERM 590 unit located at the Léon Bérard Center, Cancer Institute, Lyon. His work is supported by the Fondation pour la Recherche Médicale.

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