Targeting the p53 signaling pathway in cancer therapy - the promises, challenges and perils

Abstract

Introduction: Research over the past three decades has identified p53 as a multi-functional transcription factor. p53 influences myriad, highly diverse cellular processes, and represents one of the most important and extensively studied tumor suppressors. Activated by various stresses, p53 blocks cancer progression by provoking transient or permanent growth arrest, by enabling DNA repair, or by advancing cellular death programs. This anti-cancer activity profile, together with genomic and mutational analyses documenting inactivation of p53 in more than 50% of human cancers, motivated drug development efforts to (re-) activate p53 in established tumors.

Areas covered: The complexities of p53 signaling in cancer are summarized, including current strategies and challenges to restore p53's tumor suppressive function in established tumors, to inactivate p53 inhibitors, and to restore wild type function of p53 mutant proteins.

Expert opinion: p53 represents an attractive target for the development of anti-cancer therapies. Whether p53 is 'druggable', however, remains an area of active research and discussion, as p53 has pro-survival functions and chronic p53 activation accelerates aging, which may compromise the long-term homeostasis of an organism. The complex biology and dual functions of p53 in cancer prevention and age-related cellular responses pose significant challenges to the development of p53-targeting cancer therapies.

Figure 1. p53 is a tetrameric transcription factor with nuclear, transactivating, and cytoplasmic, apoptogenic functions at the level of mitochondrial membranes

Activated by a wide variety of different tresses, including oncogene activation (sensed by p14^Arf), telomere dysfunction, and DNA damage, p53 transcriptionally induces a broad spectrum of genes implicated in apoptosis, cell cycle progression, DNA repair, autophagy, metabolism, antioxidant signaling, angiogenesis, and fertility. In addition, p53 interacts with Bcl-2 family proteins, and mitochondrial membranes to induce mitochondrial outer membrane permeabilization (MOMP), to trigger cytochrome c release and subsequent caspase activation. Importantly, p53 is regulated by the E3 ubiquitin ligases Mdm2, and Mdm4. Importantly, cytoplasmic and nuclear functions of p53 are intertwined, as Mdm2, a p53 transcriptional target, promotes mitochondrial localization of of p53 through mono-ubiquitination [190], and p53-induced PUMA can release Bax and/or p53 from inhibitory Bax/Bcl-x_L and p53/Bcl-x_L complexes, to trigger MOMP.

Figure 2. Therapeutics targeting the p53-signaling pathway

Depicted are the five classes of p53-targeting therapeutics, i.e., genetherapeutic agents to delivery p53 via adenoviral transduction into p53-deficient cancer cells; anti-sense oligonucleotides targeting Mdm2; small molecules targeting wild-type p53 (i.e., compounds that liberate p53 from a inhibitory p53:Mdm24 complexes); small molecules targeting mutant p53 to restore its native conformation, and transactivational activity; and vaccination approaches (i.e., p53-SLP, a mixture of overlapping p53 peptides representing amino acids 70 to 248 used in conjunction with montanide, a water in oil emulsions as adjuvant; INGN-225, a vaccine utilizing p53-peptide transfected dendritic cells; and ALT-801, an interleukin-2-T cell receptor fusion protein directed against MHC-presented p53 peptides). RITA, reactivation of p53 and induction of tumor cell apoptosis; PRIMA, p53 reactivation and induction of massive apoptosis-1; MIRA-3, mutant p53 reactivation and induction of rapid apoptosis; STIMA, SH group targeting and induction of massive apoptosis; RETRA, reactivation of transcriptional reporter activity.