My lab focuses on identifying new ways of treating disease driven by Ras proteins. These diseases include pancreatic cancer, more than 90% of which driven by K-Ras, colorectal cancer (50% K-Ras) and lung cancer (25% K-Ras), as well as the hereditary syndrome Neurofibromatosis Type 1 which affects 1 in 3500 people worldwide, and gives rise to multiple tumors, learning disabilities and many other serious clinical problems.
We have recently made progress in the following areas:
-We have discovered that the K-Ras proteins promotes stem-cell properties in cancer cells, enabling them to establish metastatic tumors with high efficiency, and making them drug resistant. We have identified the molecular basis of these effects and are testing therapeutic agents that interfere with them, in preclinical cancer models.
-We have identified small molecules that binds irreversibly to K-Ras and prevent prenylation. We are working on solving the crystal structure of the K-Ras protein complexed with this molecules, and hope that this could provide a new and safe way of blo9cking K-Ras function.
- We have developed a collection of highly potent and specific siRNAs that target K-Ras, and the components of the pathways K-Ras controls (MAPK, PI kinase, etc). These potent siRNAs can be used in combinations to kill K-Ras cancers effectively. In collaboration with Dr Mark Davis (Caltech) we have been able deliver these siRNAs efficiently in vivo, resulting in tumor destruction in preclinical models.
-We have made major progress in understanding the mechanism underlying the disease Neurofibromatosis Type 1(NF1). The gene responsible for this disease encodes a protein that negatively regulates Ras: loss of this gene in affected individuals results in hyperactivation of Ras, just as mutation in Ras locks the Ras protein in its hyperactive state. Recently we discovered that the NF1 protein depends on another protein, SPRED1, which is mutated in another familial syndrome called Legius Syndrome. This connection provides new insights into the basis of NF1 disease and also human cancers in which the NF1 gene is loss sporadically. We are developing new therapeutic strategies based on these insights.
-We have developed a system of analyzing individual Ras mutations that cause cancer. Clinical data show that cancers caused by different mutations in K-Ras, such as G12C, G12D, Q61L, and so on, have different outcomes and may signal to different downstream pathways. We have expressed these mutants in the background of “Ras-less” cells, ie cells lacking N-Ras, H-Ras or K-Ras. Each clones is now driven by a single, mutant isoform, thus allowing us to examine the roles of these proteins in isolation. This will allow us to tailor therapies for individual mutant cancers in the future.
Young, A., Lyons, J., Miller, A.L., Phan, V.T., Alarcon, I.R., McCormick, F. 2009. Ras signaling and therapies. Adv Cancer Res 102:1-17.
Harris, T. J., & McCormick, F. 2010. The molecular pathology of cancer. Nat Rev Clin Oncol 7:251-265.
Gysin, S., Salt, M., Young, A., and McCormick, F. 2011. Therapeutic strategies for targeting ras proteins. Genes & Cancer 2:359-372.
Stowe IB, Mercado EL, Stowe TR, Bell EL, Oses-Prieto JA, Hernández H, Burlingame AL, McCormick F. 2012. A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. Genes Dev 26:1421-6.
Young A, Lou D, McCormick F. 2013. Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling. Cancer Discov 3:112-23.
Holderfield, M., Merritt, H., Chan, J., Wallroth, M., Tandeske, L., Zhai, H., Tellew, J., Hardy, S., Hekmat-Nejad, M., Stuart, D.D., McCormick, F., Nagel, T.E. 2013. RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. Cancer Cell 23:594-602.
Nan, X., Collisson, E.A., Lewis, S., Huang, J., Tamguney, T.M., Liphardt, J.T., McCormick, F., Gray, J.W., Chu, S. 2013. Single-molecule superresolution imaging allows quantitative analysis of RAF multimer formation and signaling. Proc Natl Acad Sci USA 110:18519-24.
Salt, M.B., Bandyopadhyay, S., McCormick, F. 2014. Epithelial-to-Mesenchymal Transition Rewires the Molecular Path to PI3K-Dependent Proliferation. Cancer Discov 4:186-99.
Stephen, A.G., Esposito, D., Bagni, R.K., McCormick, F. Dragging Ras Back in the Ring. Cancer Cell 25:272-281.
Holderfield, M., Lorenzana, E., Weisburd, B., Lomovasky, L., Boussemart, L., Lacroix, L., Tomasic, G., Favre, M., Vagner, S., Robert, C., Ghoddusi, M., Daniel, D., Pryer, N., McCormick, F., Stuart, D. Vemurafenib Cooperates with HPV to Promote Initiation of Cutaneous Tumors. Cancer Res 74:2238-45