Vol 7. Issue 14 / April 30, 2007

Cancer-Specific Mutations May Offer Path to Treatments

By Mark Schrope

Three years ago, Scripps Research Professor Peter Vogt was astonished to read a paper that identified three cancer-specific mutations in the gene known as PIK3CA. He was surprised, because his laboratory had been studying the role played by the same gene, along with the enzyme whose production it codes, in causing cancer in chickens. Until the paper was published, though, the team had no idea of the gene's significance in humans.

"We immediately took up the challenge of these cancer-specific mutations," says Vogt,  head of the Division of Oncovirology in the Department of Molecular and Experimental Medicine. In short order he and his team were able to show that each of the three mutations identified was in fact capable of inducing the onset of cancer. Later research by the group, published recently in the online edition of the Proceedings of the National Academy of Sciences, has led to some remarkable discoveries about related mutations in the same gene, broadening understanding of how the mutations cause cancerous cell proliferation. Collectively, the work has revealed a tantalizing potential pathway for cancer-specific drug treatments.

PIK3CA codes for the production of an enzyme called PI3 kinase, which, in its normal state, plays a variety of critical roles in cell signaling, regulating such aspects of cell growth as glucose metabolism and cell survival. PIK3CA mutations are found in about 30 percent of cancer cases, and are especially common in colon, breast, and endometrial cancers.

The three mutations first identified in PIK3CA are by far the most common, making up some 80 percent of the gene's mutations, but more than 80 additional mutations have also been discovered, and the Vogt team's recent work focused on 15 of these.

At the outset, the researchers fully expected that the rare mutations would not be oncogenic (causing the creation of tumors). Instead, they found that 14 of these15 mutations examined could in fact induce cancer, though not quite as strongly as the three more common mutations. "That was a complete surprise," says Vogt, "and it gave us a terrific tool for looking at all these mutations and their relation to the functioning of the protein."

A possible conclusion based on the pervasive oncogenicity discovered was that the gene simply has a propensity to turn oncogenic in response to almost any mutation. To test this idea, the group made random mutations to the gene, none of which proved capable of causing cancer.

In hopes of discovering why the rare mutations cause cancer, the Vogt lab worked with Marc Elsliger, from Scripps Research Professor Ian Wilson's lab, to develop a 3-D map of the PI3 kinase and its mutations. This effort revealed that the rare oncogenic mutations produce changes clustered at various positions, but always on the surface of the protein. The three common mutations also induce surface changes on the protein.

Marco Gymnopoulos, lead author of the recent PNAS paper from the Vogt lab, says that, based on this discovery, there exist several molecular mechanisms that can lead to a gain of function in PI3K. These include enhanced affinity for the plasma membrane of the cell where PI3K is active, altered interaction with regulatory proteins, and structural changes that enhance the function of the catalytic domain of the protein.

This new understanding of the common and rare mutations and their effects opens a promising new path for the discovery of potential new cancer treatments. One possibility would be to identify small molecules that specifically target the mutations to prevent increased cell division. The most obvious initial focus would be drugs that target the three most common mutations to block their impacts.

Treatments aimed at the rare mutations might also be possible, but this would be a more daunting prospect because there would be so many potential targets, and because far fewer cancer cases involve these mutations. Gymnopoulos says the main benefit of the discoveries regarding the rare mutations may instead take another form.

"The rare mutations are very important, because they tell us how this whole signaling cascade functions," says Gymnopoulos. Understanding the various mechanisms involved may well lead to broader understanding of interactions between the protein and cells, he says, and, hence, broader treatments. For instance, the work could illuminate a method for blocking the interaction between the enzyme in a variety of mutated forms and other cells, preventing the cancerous increase in cell division.

Treatments that address the PIK3CA mutations would be especially attractive, according to Vogt. Because the mutations are cancer-specific, treatments targeting their impacts could conceivably have no impact on the protein's regular functioning, or on healthy cells. Also, it is typically much easier to block an increase in function, such as that induced by the PIK3CA mutations, than it is to restore function reduced by mutations.

The Vogt team is awaiting word on a proposal for funding from the National Cancer Institute to begin screening for drugs that target the mutations, and is also in discussions with pharmaceutical companies interested in pursuing potential treatments based on the team's research.

The article, "Rare cancer-specific mutations in PIK3CA show gain of function," by Marco Gymnopoulos, Marc-André Elsliger, and Peter K. Vogt, is available on the Proceedings of the National Academy of Sciences web site. See http://www.pnas.org/cgi/content/abstract/104/13/5569.


Send comments to: mikaono[at]scripps.edu






Ribbon and molecular surface representation of p110, showing the locations of gain-of-function mutations on the homology model. Click for image details.
















"We immediately took up the challenge of these cancer-specific mutations."

—Peter Vogt