p53-Targeting Cancer Therapies

  • Posted on May 19, 2015 by pharmaadmin in Oncology

p53 is known to play a critical role in a broad range of functions—DNA repair, cell cycle arrest, senescence, and apoptosis—to conserve gene stability, thus suppressing tumor development. Millions of cancer patients have defects in p53 signaling, possessing either a mutant p53 or an inactive wild type p53 that has lost its antitumor activity. Efforts to develop novel molecules that could activate or restore p53 signaling have now been emerging. In this post, we highlight the major advances and challenges in p53-targeted antitumor therapies.

Protein levels of p53 within cells are tightly controlled: When cells sense stress signals, p53 can accumulate and transcriptionally regulate genes to control cell cycle and cell death. By contrast, p53 levels are kept low in healthy cells by its negative regulator, the E3 ubiquitin-protein ligase MDM2, which binds to p53, targeting it for ubiquitylation and subsequent degradation. p53 regulates MDM2 transcriptionally, thus creating a feedback loop. MDM4 is a structural homologue of MDM2 and also acts as a negative regulator of p53 through a manner similar to MDM2.

Studies with mouse models clearly demonstrate that p53 restoration contributes to the regression of existing tumors. These data indicate that wild type p53 reactivation is a valid therapeutic target and that inhibiting MDM2/MDM4 activity is a viable strategy for cancer therapy. Currently, p53-targeting therapeutics include 1) molecules that disrupt the interaction between MDM2/MDM4 and p53; 2) antisense molecules that target the expression of MDM2; 3) inhibitors that suppress MDM2 E3 ubiquitin ligase activity; and 4) agents that induce nucleolar stress.

Targeting p53-MDM2 interaction

By disrupting the interaction between p53 and MDM2, the wild-type p53 activator RG7112 (Roche) has recently completed its phase I clinical trial in acute myeloid leukemia patients. Although RG7112 treatment generally correlated with increased p53 levels and decreased proliferation, the clinical results revealed that this MDM2 antagonist has a relatively narrow therapeutic window. That is, up to the maximum tolerated dose is required to obtain clinical benefits, which are accompanied by a few serious adverse events. The limitations of RG7712 come from the fact that it activates wild type p53 in all types of cells, both cancer and normal cells.

Activation of nucleolar stress

Blocking ribosome RNA (rRNA) biogenesis that triggers nucleolar stress has emerged as a new direction of p53-targeting cancer therapy. In fact, many approved chemotherapies have been shown to impede various stages of rRNA biogenesis, although in a nonselective manner.

Based on the fact that hyperactivation of Pol I transcription is accompanied by increased levels of rRNA biogenesis distinctively occurring in cancer cells, the working theory of an rRNA biogenesis inhibitor is as follows: The selective molecule blocks rRNA synthesis by inhibiting Pol I transcription, resulting in excessive accumulation of free ribosomal proteins and subsequent nucleolar stress in cancer cells, which ultimately induces p53 as a means of promoting apoptosis and cell death. Importantly, such a process would not be triggered in normal cells.

Although it is still in the preclinical stage, the potent activator of nucleolar stress, CX5461, has shown promising results in that it selectively inhibits rRNA biogenesis when employed in human leukemia and lymphoma cell lines and in the acute myeloid leukemia animal model.

Other p53-targeting novel molecules

Aside from the above molecular entities, a plethora of novel molecules have been developed that can potentially block the interactions of p53-MDM2 and/or p53-MDM4 or reactivate mutant p53. For example, a stapled p53-based peptide—containing a hydrocarbon linkage, thus conferring protease resistance and promoting cellar uptake—has shown that it selectively prevents MDM4-p53 binding, enabling p53 activation and tumor growth suppression.

Regarding reactivating mutant p53, a chaperone-like mechanism has been implemented to generate novel molecules. By binding the unfolded or distorted mutant p53, these chaperone peptides shift mutant p53 proteins to a more native state, resulting in mutant p53 regaining the DNA-binding property of wild-type p53. These emerging new approaches bring with them the exciting prospect of cancer therapies; nevertheless, the efficacy and safety of these new entities need to be tested and scrutinized in clinical trials.

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Categories: Oncology

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