For the General Public 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. The lab then applies the new knowledge to the identification of small chemical inhibitor compounds and of novel biological molecules with the goal of developing these into targeted cancer therapies. For Scientists Background and History Cancer is a disease initiated by genetic changes that affect both growth and metabolism. We now have a wealth of basic information on the cancer cell and its unique properties. New therapeutic targets have been defined: growth-promoting oncogenes that acquire a gain of function in cancer and growth-attenuating tumor suppressors that suffer a loss of function in cancer. Much of the excitement in cancer research today comes from the opportunities to translate basic science into clinical applications. The dramatic therapeutic effect of Gleevec/Imatinib in chronic myelogenous leukemia and in other cancers has shown that targeted therapy, inhibiting the activity of an oncogene, can lead to spectacular 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 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 (Toyoshima and Vogt 1969, Duesberg and Vogt 1970, Vogt 1971a, Vogt 1971b, Stehelin et al. 1976, Duesberg et al. 1977, Bohmann et al. 1987). Current Research Current activities in our lab focus on basic genetic and molecular mechanisms of oncogenesis. But increasing efforts are also devoted to applied and translational problems. This work is stimulated and supported by collaborations with world class chemists at the institute. Collaborations between the lab and pharmaceutical and biotech companies are also ongoing. PI 3-kinase: viral oncogene and cancer target PI 3-kinase is a lipid kinase with oncogenic potential. An avian retrovirus discovered in our lab carries a homolog of the catalytic subunit of PI 3-kinase as its oncogene (Chang et al. 1997). This virus causes aggressive tumors in chickens. PI 3-kinase also plays an important role in human cancer. The alpha isoform of PI 3-kinase is mutated in many tumors. The mutations increase enzymatic activity, deregulate PI 3-kinase signaling and make the protein oncogenic (Kang et al. 2005). The mutant proteins are ideal cancer targets: they occur only in tumor tissue, and because they are enzymes and show increased function, they could be readily controlled by small molecular inhibitors. Mutant-specific drugs would leave the life-sustaining activities of the wild-type PI 3-kinase untouched. Besides the hot spot mutations, other mutations occur in cancer tissue. These are rare and map over most of the PI 3-kinase gene. Virtually all of them show oncogenic activity, although their signaling and enzymatic activities are not always elevated (Gymnopoulos et al. 2007). The excitement about PI 3-kinase and cancer has focused mainly on the alpha isoform, because of the gain-of-function mutations in that enzyme. There are, however, three other isoforms, beta, gamma and delta, that belong to class I PI 3-kinase. Surprisingly, the wild-type forms of these non-alpha isoforms can induce oncogenic transformation in cell culture when they are overexpressed (Kang et al. 2006). In human cancer, the non-alpha isoforms are not mutated, but there is recurrent overexpression in certain tumor types. Therefore non-alpha isoforms of PI 3-kinase probably also play important roles in human cancer. This background information defines several currently active projects. These include determining the molecular mechanisms for the gain of function in mutant PI 3-kinase exploring functions of down- and upstream components of PI 3-kinase signaling in oncogenicity explaining the oncogenic activity of the wild-type non-alpha isoforms of PI 3-kinase finding novel cellular regulators of PI 3-kinase activity Small molecule inhibitors of oncoproteins Synthetic organic chemistry is strongly represented at The Scripps Research Institute. A wealth of non-redundant libraries of chemical compounds is available for testing and for screening. We take advantage of these unique resources to obtain inhibitors of oncoproteins. Current projects include the following: identify and characterize inhibitors of PI 3-kinase with the goal of achieving isoform- and mutant-specificity identify small molecule inhibitors of components of PI 3-kinase signaling: PDK1, AKT, TOR extend screening for inhibitors to additional oncoproteins: ALK, FOX-M1 Controlling protein-protein interactions All cellular activities depend on specific protein interactions. These would be prime targets for intervention were it not for the fact that the interacting surfaces are large and often shallow. There are usually no obvious docking sites for small molecules in these surfaces. Yet some protein-protein interactions have been interrupted by small molecules. Compounds referred to as Nutlins inhibit the interaction of the p53 protein with its regulator MDM2. In collaboration with Dale Boger’s and Kim Janda’s labs in the Department of Chemistry at The Scripps Research Institute, we have identified small molecules that interfere with the dimerization of the Myc and Max proteins (Berg et al. 2002, Xu et al. 2006). This dimerization is essential for the oncogenic activity of the Myc protein. Boger has and coworkers have generated a large library of compounds targeted to protein-protein interaction surfaces. This library is being used in the following studies: identify improved inhibitors of the Myc-Max interaction identify inhibitors of interactions in the PI 3-kinase pathway: RAS/p110 and Rheb/FKBP38 Stabilizers of protein-protein interactions are also of interest. We have identified a stabilizer of the Max homodimer. This stabilizer reduces the availability of Max for other interactions and hence down-regulates the Myc transcriptional network. The current studies on stabilizers include: characterization of the stabilizer of the Max homodimer identification of stabilizers for the TOR/FKBP38 interaction. TOR is an important target of the PI 3-kinase pathway and is inhibited by binding to the FKBP38 protein. Control of oncogenes with small non-coding RNAs Small, non-coding RNAs can recruit protein complexes that either transiently or permanently silence gene expression. In collaboration with Kevin Morris in the Department of Molecular and Experimental Medicine at TSRI, we are taking advantage of new mechanistic insights to target human oncogenes with small, non-coding RNAs and will determine the effects of transient and long-term gene silencing on the oncogenic phenotype of the cancer cell. induce long term transcriptional gene silencing of oncogenes. Among the oncogenes that are being targeted are PIK3CA, the gene coding for the catalytic subunit of PI 3-kinase, AKT and MYC. Others will follow. Target posttranscriptional gene silencing to cancer-specific mutants of oncogenes, beginning with the hot spot mutations in the alpha isoform of PI 3-kinase.