Unlocking a secret of the anti-cancer gene p53

The gene p53 has long been a target of intense research in the oncology community because in its unaltered form it suppresses cancer. Mutations in p53 are known to promote the formation of several types of cancer, but researchers have struggled to figure out how this process works—and how to stop it.

Now a team at the University of Wisconsin-Madison has discovered an enzyme that acts as a key regulator of the p53 protein. They believe the finding, reported in the journal Nature Cell Biology, will inspire new ideas for targeting p53 with drugs.

The enzyme is called PIPK1-alpha, and it kicks into action when cells become stressed. The enzyme produces a lipid “messenger” that causes mutant p53 to link up with heat shock proteins and promote the development of aggressive cancers, according to a statement.

The researchers were surprised by the finding because PIPK1-alpha mostly exists in cell membranes, but mutant p53 does most of its damage in the cell center. Still, they showed that if they disrupted the enzyme pathway, they could prevent mutant p53 from accumulating and damaging cells.

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The intense research interest in p53 has translated into some significant investments in efforts to commercialize therapies that target the gene. PMV Pharma, one of 2017’s Fierce 15 companies, has raised more than $100 million in venture capital to develop small molecule drugs designed to restore mutant p53’s normal functioning without damaging healthy tissue.

Meanwhile, academic researchers continue to discover nuances of p53 that may be targetable in the future. A Stanford team, for example, found a mutated form of the gene that strengthens its ability to combat pancreatic tumors. And researchers at the University of Chicago studied cells from elephants, which have significantly more copies of the p53 gene than humans do, and found that it activates another gene, LIF6, which kills cancer precursor cells.

The University of Wisconsin researchers are now searching for a kinase enzyme that can inhibit PIPK1-alpha. "Although p53 is one of the most commonly mutated genes in cancer, we still do not have any drugs that specifically target p53," said co-author Vincent Cryns, M.D., professor of medicine at the University of Wisconsin, in the statement. "Our discovery of this new molecular complex points to several different ways to target p53 for destruction, including blocking the kinase or other molecules that bind to p53."