Science Watch® Interview With Lewis Cantley, Harvard Medical School

Science Watch Newsletter Interview: November/December 2010

Lewis Cantley It may seem like a particularly cruel injustice, but the fatter we are, and the more diabetic we become, the more likely we are to contract a host of human cancers as well. This is now well established by reams of epidemiological studies, but the attendant questions remain: What’s the biological mechanism? What’s the link between obesity , diabetes, and cancer?

The last decade has seen an explosion of research examining these questions and focusing ever more closely on the metabolism of cancer cells themselves—how the same hormones and enzymes that are disregulated in obesity and diabetes can promote the unfettered growth of malignant cells.

At the focal point of this convergence of chronic diseases is an enzyme known as phosphoinositide 3-kinase, or PI3K, discovered by the Harvard Medical School’s Lewis Cantley and his colleagues in the mid-1980s. The PI3K pathway is both the mechanism through which insulin regulates blood sugar and a major player in perhaps 80% of all human cancers.

Over the last decade alone, Cantley’s work on the PI3K pathway has placed him among the top 1% most-cited authors in three fields—Molecular Biology & Genetics, Biology & Biochemistry, and Clinical Medicine—according to Essential Science IndicatorsSM from Thomson Reuters.

Cantley was the first author on a 1991 Cell paper, "Oncogenes and signal transduction" (64[2]: 281-302, 1991), which has since been cited almost 2,800 times, while his 2002 review article in Science on PI3K—"The phosphoinositide 3-kinase pathway”—has garnered more than 1,600 citations, averaging 200 a year (in the table below).

Since 2000, he has authored three other articles that have each been cited over 500 times, along with more than 40 that have received over 100 citations each. More recently, three of his reports published in the last two years currently rank as Hot Papers, according to the latest bimonthly file.

Cantley, 61, graduated summa cum laude from West Virginia Wesleyan College in 1971 with a degree in chemistry. He received his Ph.D. in biophysical chemistry from Cornell University in 1975 and then spent three years as a post-doc at Harvard before joining the faculty as an assistant professor.

In 1985, he moved across town to the Tufts University School of Medicine to become a Professor of Physiology, and then returned in 1992 to Harvard Medical School, where he is now a Professor of Systems Biology. Since 2007, he has also been director of the Beth Israel Deaconess Cancer Center.

He is also the leader of a "dream team" of cancer researchers that received a $15 million grant from the Stand Up to Cancer Foundation to study the role of PI3K in women’s cancers.

Cantley spoke to from his office in Boston.

SW: How did you first discover PI3K, and what was it about this enzyme that first caught your interest?

I made the observation that an enzyme that phosphorylated a lipid was co-purifying with a variety of oncoproteins, which were encoded by both viral and human oncogenes. And this enzymatic activity correlated very well with the ability of those various oncogenes to transform cells in culture and cause tumors in mice. Around 1990, we discovered that the way insulin regulates glucose levels is by activating this PI3K enzyme.

So this was, in effect, insulin’s mechanism of action, how insulin works, and my lab has focused on that for the last 20 years. And it turns out to be far more important than we ever thought, because it’s this essential pathway through which cellular growth is maintained. The pathway allows glucose to be taken up into a cell to be diverted into either making ATP or, in the case of cancer cells, into making protein and DNA. If you look at insulin, it stimulates glucose uptake into both fat and muscle. In muscle, it diverts the glucose into making energy. In the fat cells, it diverts it into making lipid—triglycerides.

Selected Highly Cited Papers by Lewis Cantley and Colleagues, Published Since 2000

(Ranked by citations)
Rank Paper Citations
1 L.C. Cantley, et al., "The phosphoinositide 3-kinase pathway," Science, 296(5573): 1655-7, 2002. 1,618
2 B.D. Manning, L.C. Cantley, "AKT/PKB signaling: Navigating downstream," Cell, 129(7): 1261-74, 2007. 655
3 S.A. Beausoleil, et al., "Large-scale characterization of HeLa cell nuclear phosphoproteins," PNAS, 101(33): 12130-5, 2004. 550
4 J.A. Engleman, et al., "MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling," Science, 316(5827): 1039-43, 2007.  500
5 B.D. Manning, et al., "Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-Kinase/Akt pathway," Molecular Cell, 10(1): 151-62, 2002. 497
SOURCE: Thomson Reuters Web of Science®

As it happens, cancer cells work more like fat cells, and they revert to this type of metabolism, using PI3K to drive glucose uptake, but it diverts it not just into making fat but also protein and DNA. By having this pathway activated, cancer cells can use glucose to grow very rapidly.

SW: So PI3K is central to both diabetes and cancer?

Yes, and that fact is really quite striking. It turns out that PI3K is not one enzyme but multiple enzymes, and that there are multiple genes involved. Through the 1990s, we and others found that many retroviruses encoded oncogenes in this pathway.

SW: Was there a key discovery linking PI3K to common human cancers, and was that your work?

There were several and, no, they weren’t ours. In 1997, three different laboratories simultaneously isolated a tumor suppressor gene called PTEN that appeared to be the most frequently deleted gene in a whole host of advanced human cancers. This made a big splash at the time. Based on the sequence, this gene looked like a phosphatase, but it wasn’t clear what it dephosphorlyated.

In 1998, Jack Dixon, whose background in enzymology is similar to mine, discovered that this PTEN dephosphorylated the same lipid that PI3K makes. That put PI3K on everybody’s radar screen as something important in human cancer, since PTEN itself is lost in so many human cancers. That’s when oncologists started getting interested.

Then things got even more interesting. Victor Velculescu at Johns Hopkins decided that he would just start sequencing every exon of PI3K out of every colorectal tumor sample he could get, and he discovered that the PI3K enzyme itself is mutated in a very large fraction of cancers. At that point pharmaceutical companies doubled their efforts to develop drugs. [Incidentally, in the interest of full disclosure, perhaps I should add that I started a company, called Agios Pharmaceuticals, based on targeting enzymes involved in cancer-cell metabolism in order to develop cancer treatments.]

PI3K was a "druggable" target. If you lose a tumor suppressor like PTEN, there’s not much you can do to put it back. But if you have an oncogene activated, or if the tumor suppressor counteracts the effect of an endogenous enzyme, then targeting that enzyme makes sense. Currently there are 15 PI3K inhibitors in clinical trials, and the follow-up made it clear that this mutating of PI3K was happening in a lot of human cancers.

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