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)

Principle

Target (2)

Effect

PRIMA-1

Lipophilic compound, mechanism of action

Cells with Mut p53

Reactivation of Mut p53,

unknown

apoptosis

WR1065

Redox-activation of reactive thiols; enhances

Wtp53

Chemo protective effects in

p53 binding to DNA

normal cells

CDB3

Peptide binding to p53 core domain

Mut p53

Reactivation of Mut p53,

apoptosis

CP-31398

''Adaptor'' binding to p53 core domain;

Mut p53

Apoptosis

stabilizes p53 into wt form

ScFV421

Single chain antibody to C-terminal domain

Wt and Mut p53

Activation of DNA-binding

of p53

ScFVME1

Single chain antibody to mut p53

Mut p53

Activation of transactivation

Adp53

Adenovirus expressing wtp53 for gene

Cells with loss of p53

Restoration of wtp53 function in

therapy

function

cancer cells

ONYX-15

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.

REFERENCES

Bardos, J.I. and Ashcroft, M. (2004). Hypoxia-inducible factor-1 and oncogenic signalling. Bioessays, 26, 262-9.

Beckman, G., Birgander, R., Sjalander, A. et al. (1994). Is p53 polymorphism maintained by natural selection? Hum Hered, 44, 266-70. Bergamaschi, D., Gasco, M. and Hiller, L. (2003). p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell, 3, 387-402.

Blandino, G. and Dobbelstein, M. (2004). p73 and p63: why do we still need them? Cell Cycle, 3, 886-94.

Bykov, V.J., Issaeva, N., Selivanova, G. and Wiman, K. G. (2002a). Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the National Cancer Institute database. Carcinogenesis, 23, 2011-18.

Bykov, V. J., Issaeva, N., Shilov, A. et al. (2002b). Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med, 8, 282-8.

Chaturvedi, V., Qin, J.Z., Stennett, L., Choubey, D. and Nickoloff, B.J. (2004). Resistance to UV-induced apo-ptosis in human keratinocytes during accelerated senescence is associated with functional inactivation of p53. J Cell Physiol, 198, 100-9.

Cho, Y., Gorina, S., Jeffrey, P. D. and Pavletich, N. P. (1994). Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations see comments. Science, 265, 346-55.

Courtois, S., de Fromentel, C. C. and Hainaut, P. (2004). p53 protein variants: structural and functional similarities with p63 and p73 isoforms. Oncogene, 23, 631-8.

Courtois, S., Verhaegh, G., North, S. et al. (2002). DeltaN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. Oncogene, 21, 6722-8.

de Vries, A., Flores, E.R., Miranda, B. et al. (2002). Targeted point mutations of p53 lead to dominantnegative inhibition of wild-type p53 function. Proc Natl Acad Sci USA, 99, 2948-53.

Dumble, M.L., Donehower, L.A. and Lu, X. (2003). Generation and characterization of p53 mutant mice. Methods Mol Biol, 234, 29-49.

Fridman, J. S. and Lowe, S. W. (2003). Control of apoptosis by p53. Oncogene, 22, 9030-40.

Ghosh, A., Stewart, D. and Matlashewski, G. (2004). Regulation of human p53 activity and cell localization by alternative splicing. Mol Cell Biol, 24, 7987-97.

Gronroos, E., Terentiev, A. A., Punga, T. and Ericsson, J. (2004). YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc Natl AcadSci USA, 101, 12165-70.

Guimaraes, D. P. and Hainaut, P. (2002). TP53: a key gene in human cancer. Biochimie, 84, 83-93.

Hainaut, P. and Hollstein, M. (2000). p53 and human cancer: the first ten thousand mutations. Adv Cancer Res, 77, 81-137.

Hanahan, D. and Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57-70.

Hussain, S. P., Amstad, P., Raja, K. et al. (2000). Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res, 60, 3333-7.

Hussain, S.P., Amstad, P., Raja, K. et al. (2001). Mutability of p53 hotspot codons to benzo(a)pyrene diol epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lung. Cancer Res, 61, 6350-5.

Kastan, M.B., Lim, D.S., Kim, S.T. and Yang, D. (2001). ATM - a key determinant of multiple cellular responses to irradiation. Acta Oncol, 40, 686-8.

Koster, M.I. and Roop, D.R. (2004). Transgenic mouse models provide new insights into the role of p63 in epidermal development. Cell Cycle, 3, 411-13.

Linke, S. P., Clarkin, K.C. and Wahl, G. M. (1997). p53 mediates permanent arrest over multiple cell cycles in response to gamma-irradiation. Cancer Res, 57, 1171-9.

Lomazzi, M., Moroni, M. C., Jensen, M. R., Frittoli, E. and Helin, K. (2002). Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry. Nat Genet, 31, 190-4.

Marin, M.C., Jost, C.A., Brooks, L.A. et al. (2000). A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat Genet, 25, 47-54.

Martin, A. C., Facchiano, A. M., Cuff, A. L. et al. (2002). Integrating mutation data and structural analysis of the TP53 tumor-suppressor protein. Hum Mutat, 19, 149-64.

Massion, P. P., Taflan, P. M., Jamshedur Rahman, S. M. et al. (2003). Significance of p63 amplification and overexpression in lung cancer development and prognosis. Cancer Res, 63, 7113-21.

May, P. and May, E. (1999). Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene, 18, 7621-36.

McCormick, F. (2003). Cancer-specific viruses and the development of 0NYX-015. Cancer Biol Ther, 2, S157-S160.

McLure, K.G. and Lee, P.W. (1998). How p53 binds DNA as a tetramer. EMBO J, 17, 3342-50.

Moll, U.M. and Petrenko, O. (2003). The MDM2-p53 interaction. Mol Cancer Res, 1, 1001-8.

Montes, d.O.L., Wagner, D.S. and Lozano, G. (1995). Rescue of early embryonic lethality in Mdm2-deficient mice by deletion of p53. Nature, 378, 203-6.

Moore, L., Venkatachalam, S., Vogel, H. et al. (2003). Cooperativity of p19ARF, Mdm2, and p53 in murine tumorigenesis. Oncogene, 22, 7831-7.

Murray-Zmijewski, F., Lane, D. P and Bourdon, J. C. (2006). p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ, 13, 962-72.

Olivier, M., Eeles, R., Hollstein, M. et al. (2002). The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat, 19, 607-14.

Olivier, M., Hussain, S. P., Caron, d. F., Hainaut, P. and Harris, C. C. (2004). TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci Publ, 247-70.

Olivier, M., Langerod, A., Carrieri, P. et al. (2006). The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res, 15, 1157-67.

Pfeifer, G. P., Denissenko, M. F., Olivier, M. et al. (2002). Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene, 21, 7435-51.

Pluquet, O. and Hainaut, P. (2001). Genotoxic and non-genotoxic pathways of p53 induction. Cancer Lett, 174, 1-15.

Schreiber, M., Kolbus, A., Piu, F. et al. (1999). Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev, 13, 607-19.

Seemann, S., Maurici, D., Olivier, M., Caron de Fromentel, C. and Hainaut, P. (2004). The tumor suppressor gene TP53: implications for cancer management and therapy. Crit Rev Clin Lab Sci, 41, 551-83.

Szymanska, K., Lesi, O.A., Kirk, G.D. et al. (2004). Ser-249TP53 mutation in tumour and plasma DNA of hepatocellular carcinoma patients from a high incidence area in the Gambia, West Africa. Int J Cancer, 110, 374-9.

Taniere, P., Martel-Planche, G., Saurin, J.C. et al. (2001). TP53 mutations, amplification of P63 and expression of cell cycle proteins in squamous cell carcinoma of the oesophagus from a low incidence area in Western Europe. Br J Cancer, 85, 721-6.

Tonisson, N., Zernant, J., Kurg, A. et al. (2002). Evaluating the arrayed primer extension resequencing assay of

TP53 tumor suppressor gene. Proc Natl Acad Sci USA, 99, 5503-8.

Venot, C., Maratrat, M., Dureuil, C. et al. (1998). The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression. EMBO J, 17, 4668-79.

Wang, L., Wu, Q., Qiu, P. et al. (2001). Analyses of p53 target genes in the human genome by bioinformatic and microarray approaches. J Biol Chem, 276, 43604-10.

Wiederschain, D., Kawai, H., Gu, J., Shilatifard, A. and Yuan, Z. M. (2003). Molecular basis of p53 functional inactivation by the leukemic protein MLL-ELL. Mol Cell Biol, 23, 4230-46.

Wikman, F.P., Lu, M.L., Thykjaer, T. et al. (2000). Evaluation of the performance of a p53 sequencing microarray chip using 140 previously sequenced bladder tumor samples. Clin Chem, 46, 1555-61.

Wilson, J.W., Pritchard, D.M., Hickman, J.A. and Potten, C.S. (1998). Radiation-induced p53 and p21WAF-1/ CIP1 expression in the murine intestinal epithelium: apoptosis and cell cycle arrest. Am J Pathol, 153, 899-909.

Yang, A. and McKeon, F. (2000). P63 and P73: P53 mimics, menaces and more. Nat Rev Mol Cell Biol, 1, 199-207.

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