Lewis C. Cantley, MD
William Bosworth Castle Professor of Medicine at Harvard Medical School, and Director of the Cancer Center at Beth Israel Deaconess Hospital, Boston, MA
2009-2010 BCRF Project
Co-investigator:
Charles L. Sawyers, MD, Memorial Sloan-Kettering Cancer Center, New York, NY
Mutations in components of the PI3K pathway are among the most common across all cancers including breast cancer. It is crucial to annotate tumors for PIK3CA status as well as other members of the pathway in order to know their prognostic impact (i.e, do they define distinct subgroups with different outcome regardless of therapy?) as well as their correlation with response to PI3K pathway inhibitors. P53 mutations have been carefully studied in breast cancer, and are common, but their association with PIK3CA status is unknown. It will be important to know if they impact response to PI3K inhibitors. PTEN mutations are less common in breast cancer, but loss of protein expression is found in basal-like ("triple negative") breast cancers. The association of the gene INPP4B (which the Cantley group has recently shown can act as a tumor suppressor of PI3K signaling, analogous to PTEN) with breast cancer is less well studied but early data indicate loss of heterozygosity in basal-like breast cancer. Drs. Cantley and Sawyers will conduct the p53, PTEN and INPP4B sequencing analysis for mutations using the same DNAs previously characterized for PIK3CA status. They will also assess the copy number status of all three genes and will assess PTEN protein expression by immunohistochemistry.
Mid-Year Progress Report:
The purpose of this research is to identify mutations or deletions of genes that occur frequently in human breast cancers and to determine which investigational drugs are most potent at suppressing growth of breast cancer cell lines that have these same mutations. In addition the researchers will determine whether the drugs that are most effective in suppressing growth of the cell lines also suppress growth of tumors in genetically engineered laboratory models that have the same mutations as those found in human breast cancers. Their preliminary results show that a gene called INPP4B is frequently deleted in basal-like (triple-negative) breast cancers and that PI3K inhibitors that are currently in clinical trials inhibit growth of cancer cells in which INPP4B expression is impaired. These results suggest that PI3K inhibitors now in phase 1 clinical trials may be useful in treating basal-like breast cancers, such as those with BRCA1 mutations and INPP4B deletions.
Bio:
Throughout his career, Dr. Cantley has been interested in the biochemical mechanisms by which growth factors and hormones control cell growth and cell metabolism and the defects in these control mechanisms that lead to diseases such as diabetes, immune disorders and cancers. In the course of this work, Dr. Cantley discovered a cell growth pathway involving the enzyme Phosphoinositide 3-Kinase (PI3K). This pathway is now known to be the most frequently mutated pathway in human cancers. His discoveries have led to the development of drugs to target this pathway for treating cancers.
In recognition of his contributions to the understanding of human diseases, Dr. Cantley was elected to the American Academy of Arts and Sciences (1999) and the National Academy of Sciences (2001). He has received numerous awards, including the ASBMB Avanti Award for Lipid Research (1998), the Heinrich Weiland Preis for Lipid Research (2000), the Caledonian Prize from the Royal Society of Edinburgh (2002) and the American Association of Cancer Research/Pezcoller Award for Cancer Research (2005).
