Cancers are lethal diseases in desperate need of new therapeutic approaches: despite dramatic advances in the use of conventional chemo and radiotherapy and the growth of more “targeted” drugs, many cancers are still incurable. The principal problem is that we have no systematic or informed way of predicting which, out of the legion of aberrant processes in pancreatic cancer cells, is the best to target with drugs or where, within that process the most effective molecular targets lie. To address this problem, we employ a novel class of genetically engineered mouse (GEM) in which individual oncogenes and/or tumour suppressor genes may be systemically toggled off and on, reversibly and at will, in vivo. In this way we can identify the most effective therapeutic targets irrespective of contemporary (and ephemeral) prejudices as to their “druggability”.
This approach is well illustrated by two such GEMs: one mouse that models pharmacological inhibition of Myc, a core component of the replicative machinery of all tumour and normal cells and a downstream conduit for many (perhaps all) oncogenic growth signals, and a second mouse that models pharmacological restoration of the p53 tumour suppressor, which is functionally inactivated in most human cancers. Since it is the endogenous oncogene or tumour suppressor that is toggled in such GEMs, they may be easily applied to any existing or new preclinical mouse cancer model. Using these two GEMs, we have directly ascertained the therapeutic impact, efficacy and side effects of Myc inhibition and p53 restoration - establishing both mechanism of action and therapeutic index.
More generally, our laboratory is developing a suite of “switchable genetic” technologies that allow the reversible systemic or tissue-specific toggling on and off of any target gene in adult mice. In this way we will overcome the great shortcoming of classical, germ-line (knock-out and transgenic) genetics, which is severely limited in its ability to define gene function in vertebrates due to embryonic lethality, developmental compensation and adaptive functional degeneracy, all of which obscure the roles played by genes in adult tissues that would normally have developed in the presence of that gene. We also employ the range of cell and molecular biology technologies to address the roles played by key oncogenic signaling pathways (E2F/Rb, Ras, Myc, HIF1a) in the genesis and progression of cancers.
Lab members: Deborah Breiner, Debbie Burkhart, Megan Bywater, Lucia Correia, Molly Craxton, Ivonne Gamper, Adam Guterres, Stephanie Hall, Tim Humpton, Roderik Kortlever, Peter Kreuzaler, Trevor Littlewood, Dan Lu, Frank McCaughan, Fiona McDuff, Luca Pellegrinet, Alexandra Perfetto, Ana Rebocho, Nick Salisbury, Nicole Sodir, Claire Walker, Cathy Wilson, Houjiang Zhou
1. Finch, A.J., Soucek, L., Junttila, M.R., Swigart, L.B., and Evan, G.I. (2009). Acute overexpression of Myc in intestinal epithelium recapitulates some but not all the changes elicited by Wnt/beta-catenin pathway activation. Mol Cell Biol 29, 5306-5315.
2. Garcia, D., Warr, M.R., Martins, C.P., Brown Swigart, L., Passegue, E., and Evan, G.I. (2011). Validation of MdmX as a therapeutic target for reactivating p53 in tumors. Genes Dev 25, 1746-1757.
3. Junttila, M.R., Karnezis, A.N., Garcia, D., Madriles, F., Kortlever, R.M., Rostker, F., Brown Swigart, L., Pham, D.M., Seo, Y., Evan, G.I., et al. (2010). Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 468, 567-571.
4. Murphy, D.J., Junttila, M.R., Pouyet, L., Karnezis, A., Shchors, K., Bui, D.A., Brown-Swigart, L., Johnson, L., and Evan, G.I. (2008). Distinct thresholds govern Myc's biological output in vivo. Cancer Cell 14, 447-457.
5. Sodir, N.M., Swigart, L.B., Karnezis, A.N., Hanahan, D., Evan, G.I., and Soucek, L. (2011). Endogenous Myc maintains the tumor microenvironment. Genes Dev 25, 907-916.
6. Soucek, L., Whitfield, J., Martins, C.P., Finch, A.J., Murphy, D.J., Sodir, N.M., Karnezis, A.N., Swigart, L.B., Nasi, S., and Evan, G.I. (2008). Modelling Myc inhibition as a cancer therapy. Nature 455, 679-683.