Perspectives p53 and cancer management

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Over the past 15 years, many attempts have been made to translate basic knowledge of p53 protein structure and function into advances in cancer management and therapy (Table 16.2) (Seemann et al., 2004). It is not over-pessimistic to state that many of these attempts have been unsuccessful in delivering clear and ready-to-use clinical solutions. This lack of success is due to many factors, but the most important is, in my view, the widespread tendency to underestimate the complexity of the biological processes in which p53 is involved. For example, all experimental evidence points to TP53 gene status as a major determinant of cancer cell response to cytotoxic therapies (Fridman and Lowe, 2003). Since wild-type p53 is a key effector of apoptosis under conditions of DNA damage, it is widely expected that cancer cells that retain wildtype TP53 allele are more sensitive to therapy than those containing mutant allele. This prediction holds true in many experimental systems. With real-life cancer, however, the TP53 gene status is not a satisfying discriminator nor predictor of tumor response to treatment. This may be due to the fact that tumors with wild-type TP53 alleles may have acquired other genetic alterations as an adaptation to the presence of wild-type p53. Another important confounding factor is that all

Table 16.2. Experimental therapy using p53 as a target

Agent (1)


Target (2)



Lipophilic compound, mechanism of action

Cells with Mut p53

Reactivation of Mut p53,




Redox-activation of reactive thiols; enhances


Chemo protective effects in

p53 binding to DNA

normal cells


Peptide binding to p53 core domain

Mut p53

Reactivation of Mut p53,



''Adaptor'' binding to p53 core domain;

Mut p53


stabilizes p53 into wt form


Single chain antibody to C-terminal domain

Wt and Mut p53

Activation of DNA-binding

of p53


Single chain antibody to mut p53

Mut p53

Activation of transactivation


Adenovirus expressing wtp53 for gene

Cells with loss of p53

Restoration of wtp53 function in



cancer cells


ElB-deficient adenovirus that replicates only

p53-deficient cells

Specific killing of cells that have

in p53-deficient cells

lost p53 function

(2): Mut p53: mutant p53 protein; wtp53: wild-type p53 protein.

(2): Mut p53: mutant p53 protein; wtp53: wild-type p53 protein.

mutant p53 proteins are not functionally equivalent. Under close examination, p53 mutants differ from each other by the degree of retention of wild-type properties, their dominant-negative effects, and their gain-of-function characteristics. More subtle classifications than ''yes'' or ''no'' for mutation are needed to fully exploit knowledge of TP53 status for tumor prognosis (Martin et al., 2002).

Detection of TP53 mutation can be an aid in cancer diagnosis or prognosis, as recently shown in breast cancer (Olivier etal., 2006). Several methods are now available, including in particular DNA chip-based methods, which resequence TP53 with speed, sensitivity, cost and accuracy compatible with clinical use (Tonisson et al., 2002; Wikman et al., 2000). The detection of mutant TP53 in a borderline, pre-neoplastic or cancer-predisposing lesion, should be seen as an indication that this lesion has high potential for evolution towards neoplasia, justifying more aggressive therapeutic approaches. Detection of mutant TP53 can also be performed on histologically normal tumor margins as an additional test to evaluate the invasive capacity of a primary cancer. Mutations are sometimes detectable in surrogate specimens, such as DNA isolated from plasma or from exfoliated cells in subjects with suspicion of cancer but no identified, localized lesion. Finding of a mutation in such surrogate specimens should be taken as a justification for more intensive investigation in order to identify a primary lesion.

With respect to therapy itself, gene therapy aimed at reintroducing a wild-type TP53 allele into cancer cells has shown only limited success (Seemann et al., 2004). In addition to the difficulty of introducing the corrector gene into a sufficient number of target cells, it seems that cancer cells are extremely competent at eliminating the transgene. After all, they have already done it for their endogenous TP53 alleles. Among other gene therapy approaches, one of the most impressive is the one developed by ONYX, based on the use of cytolytic viruses selectively replicating in TP53-deficient cells (McCormick, 2003). However, perhaps the most promising approach is the development of small lipophilic compounds or peptides that cross membranes and restore the activity of mutant p53 proteins. The compound PRIMA-1, isolated by K. Wiman and collaborators in a screen of an NCI drug library, has shown remarkable potential to kill cancer cells which specifically express a mutant p53, but not their counterparts without p53 or expressing wild-type p53 (Bykov et al., 2002a; Bykov et al., 2002b). This compound has moderate toxicity in animal tests and may represent a model for developing drugs targeting p53 for human therapy. It will take years before such drugs are fully validated for clinical applications. It should be stressed, however, that there are pathological contexts in which simple drugs of low toxicity targeting mutant p53 may have a huge public health impact. In hepatocellular carcinomas that arise in subtropical areas of Asia and Africa, over half of the patients have a unique mutation in TP53 at codon 249 as the result of mutagenesis by aflatoxins, a group of mycotoxins that are frequent contaminants of the diet in these areas (Szymanska et al., 2004). There is currently no affordable therapy for these cancers in low-resource countries and the death toll of hepatocel-lular carcinomas is in the range of several hundreds of thousands per year. In such a bleak context, a small, simple drug against mutant p53 may make a world of difference and pave the way for extending this type of therapy to cancers where the TP53 mutation pattern is more complex and heterogenous.


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