 My name is Stuart Aaronson, I'm working at Mount Sinai School of Medicine, and I have been working in the area of cancer biology for a good number of years. We've worked on a variety of pathways that are important in cancer, and over the last two or three years, became interested in a pathway that is now more and more being studied in this disease, and that's a pathway called the hippo inhibitory pathway. It was first identified in the fly, and has been studied in mammalian cells by a number of very good workers, and we decided to really investigate this pathway in cancer, first of all because there was good evidence already that the pathway was inactivated. So this is an inhibitory pathway that in tumor cells is lost, and what happens in response to that is that transcription factors, a pair of transcription factors, one that binds DNA called TEAD, or TEED, and another co-transcription factors called YAP, YAP, or TAS, T-A-Z, interact to activate a variety of target genes that can contribute both to cell proliferation, to cell motility, and in other reports to cell survival, all of which are important in cells acquiring tumor-genic properties. In its normal situation, this inhibitory pathway apparently is very important in what we call contact inhibition of cell division, that is when cells come into contact, they get signals through this pathway to stop dividing. When the pathway is lost, that signal is also lost, and cells continue to grow in a rather simplistic way of explaining things. Because of the fact that we like to explore pathways that are still amenable to new discoveries, we decided to look for molecules that might be inhibitory to this up-regulated transcription. And in a paper that's titled, Angiomotent Stabilization by Tank-Rays Inhibitors, antagonizes constitutive, TED-dependent transcription and proliferation of human tumor cells with hippo-pathway core component mutations. That's a long title, but it explains the work. And basically through a screen of small molecules, we identified an inhibitor of tank raises called Zav XAV939 that had an ability to inhibit this up-regulated transcription. The paper shows that this was really specific to the effects of this inhibitor on this activated transcription, and that it has a profound effect in inhibiting the growth of tumor cells with lesions in hippo-pathway core components. And I hope that the paper shows nicely that this is really the case. And the mechanism by which the Tank-Rays Inhibitor works is by inhibiting the targeted degradation of a regulatory molecule in this pathway called Angiomotent. Normally, Tank-Rays stimulate the degradation of some molecules like this one called Angiomotent through targeting it for proteasome mediated degradation. By inhibition of the Tank-Rays, the level of this protein goes up and the inhibitory pathway is reconstituted and therefore the transcription of this TED-YAP type of transcription goes down. And that is enough to inhibit the growth in a specific manner of tumor cells that have lesions in this pathway with respect to these core pathway components. The work is important, we hope, in identifying a new kind of molecule that is inhibitory to the pathway. Another group has also reported similar findings with respect to the mechanism. And the data that we show indicates that there can be not only sensitivity to the drug, but also resistance to it based on the inability of the Tank-Rays Inhibitor to durably and at high level increase the level of Angiomotent. So we have both mechanisms by which to inhibit this cancer pathway, but also a means to use a biomarker, namely Angiomotent protein level to determine whether or not the inhibitor is likely to be effective. Hopefully in some period of time other inhibitors of this nature or this inhibitor itself can be used to eventually target tumors that have disruption of this inhibitory pathway and therefore have proliferation and growth due to this oncogenic pathway. The work of this nature can't be done by one person, but it's really the work in fact of particularly two members of our lab, Albino, Troilo, and Erika Benson, both of whom contributed incredibly important findings to this study and were helped in that by work by Davide Esposito in particular and in the collaboration that we had with Dr. Prem Reddy, who had a small molecule library that we were able to use in our screen for Tank-Rays, actually for hippo pathway deregulation inhibitors. And so with that I will close.