Editors' ChoiceCancer

Sticky business

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Science Translational Medicine  17 Feb 2016:
Vol. 8, Issue 326, pp. 326ec26
DOI: 10.1126/scitranslmed.aaf3847

Mutations within the TP53 tumor suppressor gene are the most common acquired cancer-driving genetic changes. Some cancer-associated TP53 mutations create sticky patches on the surface of TP53 protein molecules, resulting in accumulation of nonfunctional protein aggregates. Rescuing the TP53 response to kill cancer cells by reactivating their own security checkpoints remains a Holy Grail of precision oncology.

Small-molecule TP53 activators have not yet produced the much-needed breakthrough in cancer therapy. Therefore, in their recent work, Soragni et al. took a different approach to resuscitating the ailing tumor suppressor. The investigators designed a peptide predicted to cover the sticky patch on the surface of the mutant TP53 proteins with the ultimate goal of breaking apart the aggregates of misfolded TP53 that accumulate in cancer cells. Immunofluorescence microscopy clearly showed that the ReACp53 peptide freely entered malignant cells and dissolved the mutant TP53 conglomerates. The liberated TP53 molecules were then able to execute their antitumor function. Thus, the ReACp53 peptide reactivated the cascade of TP53-dependent genes and triggered death in cultured TP53-mutant cancer cells without affecting cells with normal TP53. Most important, administration of the ReACp53 peptide dramatically slowed down the growth of human ovarian cancers transplanted into immunodeficient mice without causing any major side effects.

Future clinical tests in oncology patients will determine the safety and efficacy of this exciting strategy in treatment of human malignancies. In this study, the investigators tested their freshly developed drug in preclinical models of ovarian cancer, but the same strategy should work against other tumors addicted to the disrupted TP53 signaling network. At this point, the TP53-reactivating peptide appears promising as a potential targeted drug against cancers harboring selected TP53 mutations.

A. Soragni et al., A designed inhibitor of p53 aggregation rescues p53 tumor suppression in ovarian carcinomas. Cancer Cell 29, 90–103 (2016). [Abstract]

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