p53-based cancer therapy

Abstract

Inactivation of p53 functions is an almost universal feature of human cancer cells. This has spurred a tremendous effort to develop p53 based cancer therapies. Gene therapy using wild-type p53, delivered by adenovirus vectors, is now in widespread use in China. Other biologic approaches include the development of oncolytic viruses designed to replicate and kill only p53 defective cells and also the development of siRNA and antisense RNA's that activate p53 by inhibiting the function of the negative regulators Mdm2, MdmX, and HPV E6. The altered processing of p53 that occurs in tumor cells can elicit T-cell and B-cell responses to p53 that could be effective in eliminating cancer cells and p53 based vaccines are now in clinical trial. A number of small molecules that directly or indirectly activate the p53 response have also reached the clinic, of which the most advanced are the p53 mdm2 interaction inhibitors. Increased understanding of the p53 response is also allowing the development of powerful drug combinations that may increase the selectivity and safety of chemotherapy, by selective protection of normal cells and tissues.

Figure 1.

Design considerations of a superactive p53 for gene therapy. The p53 protein can be modified to be more potent and effective in gene therapy. At the amino terminus the F19A mutant makes p53 resistant to Mdm2 mediated degradation. Other mutations in this region may enhance its activity as a transcription factor. In the DNA binding domain the 121 F mutation makes the protein better at inducing apoptosis rather than growth arrest.

Figure 2.

Targets for small molecules to activate the p53 response. Small molecules that can activate the p53 response include those that block interaction with Mdm2 or MdmX, as shown above, Inhibit proteins that deacetylate p53 such as the sirtuins, Kinase inhibitors such as Roscovitine, molecules that block deubiquitinating enzymes and molecules that mobilize ribosomal proteins.

Figure 3.

Peptide and small molecule interactions with mdm. The structures of MDM2 bound to wild-type p53 (center, pdb id 1YCR), high affinity peptides (top and bottom left pdb ids: 1T4F, 3EQY) and nutlin (bottom right, pdb id 1RV1). The image shows the highly dynamic nature of the MDM2 surface that can assimilate a diversity of compounds. (We thank Dr Verma of the BII Singapore, for producing Fig. 3.)

Figure 4.

The principle of cyclcotherapy to exploit p53 mutation in tumor cells. Cyclotherapy can selectively kill p53 mutant tumor cells. Exposure to a nongenotoxic p53 activating coumpound induces a reversible cell cycle arrest in normal cells but not p53 mutant tumor cells which continue to divide in the presence of the drug. Subsequent treatment with an anti-S phase or antimitotic drug then kills the tumor cells but not the normal cells. Following drug removal; only the normal cells survive and can divide.