A New Approach To Cancer Therapy

An estimated 50% of human cancers contain nonfunctional mutant p53 tumor suppressor, which renders them insensitive to anticancer agents (e.g., cisplatin) whose therapeutic efficacy depends on their ability to activate this apoptotic pathway. The current paper describes a novel approach to utilizing this pathway that should prove effective against a broad range of cancers.

A p53-related protein, p73, has been found to be important for chemosensitivity in tumor cells, and unlike p53, it is rarely mutated. Normally, gene activation by p73 is blocked by iASPP, an inhibitor to the apoptosis stimulating protein of p53. The authors of this paper describe the preparation of a 37 amino acid peptide related to p53 that is capable of binding with iASPP and thereby derepressing p73 activity. This active peptide was first created by truncating the p53 protein and testing for the induction of apoptosis. The 37AA peptide neither transactivates p53 target genes nor alters the cell cycle in causing cell death. The peptide was active against several types of cancer cells and specifically for oncogene-transformed cells. The mechanism of action is not fully elucidated, but 37AA is associated with the nucleus, binds with iASPP, which causes this inhibitor to migrate to the cytoplasm, and appears to derepress members of the p53 family, notably p73. This was substantiated in p73 knock down variants, created via RNA interference. In these cell cultures, 37AA failed to induce apoptosis.

An animal model, created by implanting LoVo cells in athymic mice, demonstrated that 37AA also induces cell death in vivo. Intravenous administration of a 37AA expression plasmid via dendrimer nanoparticles resulted in tumor regression, as did treatment with wild-type p53. Moreover, the in vivo activity of 37AA resembled that observed in cell culture: It was independent of endogenous p53, but dependent on expression of p73 and sensitive to inhibition by iASPP.

The findings point to a new approach to designing anticancer therapies – by altering iASPP function. At this juncture, however, the dendrimer delivery system needs improvement, as only 25% of the tumor cells expressed the transgene after each administration.

Message posted by: Keith Markey