Polyoma Virus Genes Reveal New Insights into Cancer Signaling
Thirteen million individuals in the United States have a history of cancer, and nearly 600,000 of them will die of the disease in 2014. These numbers underscore the continuing burden of the disease on the population and on individual lives, 40 years after the signature of the National Cancer Act that improved funding for cancer research.
Despite breakthroughs, such as the use of imatinib to treat chronic myelogenous leukemia or that of Herceptin in early breast cancer, first-generation targeted therapies have not always met survival expectations. For example, while progress was made in locoregional squamous cell carcinoma of the head and neck by the monoclonal anti-EGFR antibody cetuximab with 19.7 months of overall survival, the clinical management of many other cancers, and that of advanced cancers in general, remains challenging: in HER2-positive metastatic breast cancer, the recently approved monoclonal anti-HER2 antibody trastuzumab conjugated to the microtubule inhibitor emtansine achieves a more modest 5.8 months of overall survival benefit. A deeper understanding of the pathways that contribute to cancer is needed to further improve therapeutic strategies.
The Schaffhausen laboratory studies mechanisms of transformation to seek targets that may offer novel therapeutic opportunities. One of the experimental models used in the laboratory is the middle tumor (MT) oncogene, the main driver of transformation by murine polyomavirus, a DNA tumor virus that causes tumors in many tissues and organs. MT alters a variety of signaling pathways. For example, we understand that MT transforms in part by recruiting kinase enzymes that add phosphate groups to three specific tyrosine residues in its C-terminal domain. In turn, these modified amino acids activate several intracellular signaling pathways, such as the phosphatidylinositol-3 kinase (PI3K) pathway, that promote cellular survival and proliferation. The importance of tyrosine phosphorylation and PI3K were made apparent by studying MT neoplastic transformation. Inhibitors of both tyrosine kinase activity and PI3K are now being used in patients.
Cecile Rouleau, a Biochemistry graduate student in the Schaffhausen laboratory, developed a new inducible model of MT expression to characterize the functions of MT important for transformation. At one level, her work aims to understand a particular transformation-defective MT mutant that fails to activate downstream of PI3K despite doing everything MT is known to do to activate the enzyme. This suggests that there is an as yet unappreciated aspect to PI3K signaling. Proteomic analysis of wild type and mutant MT complexes identified a novel candidate effector of PI3K/Akt signaling currently undergoing validation study. The proteomic experiments have borne fruit beyond the characterization of the Akt-defective mutant, identifying previously unrecognized binding partners of MT, among which the serine/threonine protein phosphatase PP4. Current efforts are focusing on assessing the significance of these novel molecular interactions to transformation.