The behavior of a particular signaling network in a living individual is often significantly different when compared to a cell culture model system due to the presence of multiple cell types and therefore multiple stimuli. Developments in Molecular Imaging over the last decade have yielded tools wherein signaling cascades as well as individual enzymatic reactions within the cascade can be imaged in living subjects.
It is also becoming generally accepted that most human disease including cancer, originates from alterations in signaling. Malfunctioning of signaling cascades may not be the result of defects in a single enzyme, but the combined effects of multiple malfunctioning complexes. An understanding of how individual components function within the context of the entire system under a variety of situations is critical for our understanding of why interactions between aberrant signaling pathways often result in pathophysiology. The ability to quantitatively and in real-time monitor signaling pathways in mice that are genetically engineered to develop disease processes (e.g. cancer) and in addition have “on-board” reporters for key signaling events in a tissue specific manner, will for the first time enable the development of therapies that target a signaling cascade rather than a single signaling molecule. The ability of tumor cells to adapt to targeted inhibition of a single kinase attests to the need to enhance our understanding of entire signaling cascades and their regulation (or dysregulation) in a living subject and using this knowledge to target pathways rather than single enzymes.
To this end my research program has undertaken the development of Genetically Engineered Mouse Models which develop cancer at specific sites and have the ability to activate the expression of specific reporter genes in a cancer cell specific manner. Mouse models that develop Glioblastoma Multiforme, Pancreatic Cancer and Ovarian Cancer are being developed by conditionally altering specific signaling events in a tissue specific manner. Simultaneously, these mice have been engineered so that key signaling cascades (Apoptosis, Akt, MEK and c-Met) for each disease can be quantitatively and non-invasively monitored in real time.
XIAP as a ubiquitin ligase in cellular signaling. Galbán S, Duckett CS. Cell Death Differ. 2010 Jan;17(1):54-60. Epub.
Two distinct signalling cascades target the NF-kappaB regulatory factor c-IAP1 for degradation.Csomos RA, Wright CW, Galbán S, Oetjen KA, Duckett CS. Biochem J. 2009 Apr 28;420(1):83-91.
Caspases and IAPs: a dance of death ensures cell survival. Galbán S, Brady GF, Duckett CS. Mol Cell. 2008 Nov 21;32(4):462-3.
Cytoprotective effects of IAPs revealed by a small molecule antagonist. Galbán S, Hwang C, Rumble JM, Oetjen KA, Wright CW, Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris SJ, Duckett CS. Biochem J. 2009 Feb 1;417(3):765-71.