The research of Dr. Lewis Cantley, newly appointed Director of the Cancer Center of Weill Cornell Medical College and NewYork-Presbyterian Hospital, is focused on understanding the biochemical pathways that regulate normal mammalian cell growth and the defects that cause cell transformation. Dr. Cantley, whose early work was on the structure and mechanism of enzymes that transport small molecules across cell membranes, pioneered the application of fluorescence resonance energy transfer (FRET) for studying such processes.
In the mid 1980s, Dr. Cantley conducted research on biochemical mechanisms of cellular responses to hormones and growth factors that led to the discovery of the phosphoinositide 3-kinase (PI3K) signaling pathway. Dr. Cantley and his colleagues at Tufts University School of Medicine identified PI3K as an enzyme that co-purified with a variety of oncoproteins. Subsequent research from their laboratory and other laboratories showed that PI3K activation is critical for oncogene-mediated cell transformation, as well as for insulin-dependent stimulation of glucose uptake and metabolism, with the subsequent revelation that lipid products of PI3K directly activate the AKT/PKB protein kinase to provide a cell survival signal. This discovery, as well as subsequent discoveries from other laboratories that human cancers frequently have activating mutations in PI3K genes and/or inactivating mutations in the PTEN gene (encoding a phosphatase that degrades PI3K lipid products), stimulated pharmaceutical companies to develop PI3K pathway inhibitors for cancer therapy.
At Harvard Medical School, Dr. Cantley’s laboratory has been utilizing mouse models, genetically engineered with mutations in the PI3K pathway, to investigate opportunities for therapeutic intervention in diseases that result from defects in the PI3K pathway. Recent studies from this laboratory have revealed that growth factors, through activation of PI3K and other signaling pathways, cause major changes in cellular metabolism that are critical for the growth of cancer cells. Of particular interest, cancer cells invariably utilize an embryonic form of pyruvate kinase (PKM2) to channel glucose metabolites for optimal cell growth. Ongoing studies are defining how oncogene transformation of cells alters the flux of metabolites such as glucose and glutamine and how these changes enhance cell growth and cell survival. In 2009, Dr. Cantley received one of only five grants from Stand Up 2 Cancer, a highprofile initiative created to bring new cancer treatments to patients in a faster time frame. The $15 million, three-year grant funded a team of researchers under Dr. Cantley’s leadership to investigate the role of PI3K in the development of breast, ovarian, and endometrial cancers.
Dr. Cantley has also pursued major research on the structural basis for specificity in protein/protein interactions in signal transduction cascades that control cell growth and survival. In particular, Dr. Cantley and his research team focused on the mechanism by which protein phosphorylation can control the assembly of signaling complexes. This technique was subsequently modified to determine optimal substrates for protein kinases. A novel oriented peptide library technique was developed to determine optimal phosphopeptides for binding to various protein domains. The identification of optimal peptides has facilitated the determination of the structure of protein-peptide complexes and explained how specificity in signaling is maintained. These studies led to a bioinformatics approach (Scansite) for predicting sites of protein phosphorylation and protein interaction from primary sequences.