Cancer is caused by increased activity of growth-promoting genes and decreased activity of growth-inhibitory genes. These genes produce proteins that can be targeted by specific drugs. Our lab works on the molecular mechanisms of the cancer-specific changes in the regulation of cell growth and proliferation. We then apply the new knowledge to the identification of small chemical inhibitor compounds and of novel biological molecules with the goal of developing these into cancer therapies.

Cancer is a disease initiated by genetic changes that affect cell proliferation and metabolism. We now have a wealth of basic information on the cancer cell and its unique properties. New therapeutic targets have been defined. These include oncogenes that promote cell proliferation and survival and tumor suppressor genes that attenuate cell growth and proliferation. In cancer, oncoproteins, the products of oncogenes, show a gain of function, and tumor suppressor proteins suffer a loss of function. Much of the excitement in cancer research today comes from the opportunities to translate these basic insights into clinical applications. Inhibiting the activity of an oncoprotein can lead to clinical success.

Research in our lab originated in the study of cancer-inducing retroviruses in animals and in cell culture. Tumor virology has laid much of the foundation for our understanding of cancer. Early milestones were the discovery of the first retroviral oncogenes, genes that are responsible for the tumor-inducing activity of a virus. All retroviral oncogenes have been acquired from the genome of the host cell, and as cellular genes they encode important growth-regulatory factors in the cell, including protein and lipid kinases, transcription factors and adaptor proteins. We have participated in several of these pioneering discoveries.

Current activities in our lab focus on basic genetic and molecular mechanisms of oncogenesis and on novel translational approaches. Our work deals predominantly with two oncoproteins, PI 3-kinase and MYC.

PI 3-kinase is a lipid kinase with oncogenic potential as became evident when we discovered an avian retrovirus that carries a homolog of the cellular gene encoding the catalytic subunit of PI 3-kinase as its oncogene. This virus causes aggressive tumors in chickens. Class I PI 3-kinase encompasses four distinct isoforms with non-redundant functions. The alpha isoform of PI 3-kinase is mutated in many human tumors, and most mutations map to two hotspots in the gene. These mutations increase enzymatic activity, deregulate PI 3-kinase signaling and make the protein oncogenic. The non-alpha isoforms of PI 3-kinase are usually not mutated in cancer, but they have a native oncogenic potential that becomes apparent when the wild-type protein is overexpressed.

PI 3-kinase has been a promising cancer target for more than 15 years, but despite intensive efforts by industry and academia no breakthrough drug has emerged. Several fundamental problems have contributed to this impasse. PI 3-kinase activity is essential for normal cells, and broad interference with this activity results in significant therapeutic side effects. Isoform-specific or mutant-specific targeting of chemical inhibition is essential. Notably, the four FDA-approved PI 3-kinase inhibitors in clinical use are isoform-selective or isoform-specific. Our knowledge of PI 3-kinase isoforms is incomplete. We need a better understanding of isoform-specific PI 3-kinase activities and their context-dependent connectivity as well as their contribution to specific human cancers. Chemical control of PI 3-kinase activity must also take into account the fact that cancer-specific gain of function in PI 3-kinase profoundly reshapes the cellular transcriptome. Many of these transcriptional changes have no known link to the PI 3-kinase network, and inhibition of PI 3-kinase activity can only partially restore transcriptional normalcy. These questions on isoforms and transcriptional signatures define several current projects in the lab.

The ideal PI 3-kinase drug would be one that is specific for the cancer-mutated protein. To facilitate achieving this goal, we are working on more complete structural information of PI 3-kinase and its mutants. On the forefront of chemistry, we are employing DNA-encoded libraries to identify PI 3-kinase mutant-specific small molecule ligands.