Drugging the undrugged: targeting the transcription factor activity in vascular development and diseases
Associate Professor Mathias Francois
Group Leader, IMB
The University of Queensland
Classic genetic approaches have established that SOX18 transcription factor (TF) plays a central role to instruct the genetic program that promotes arterio-venous specification and lymphangiogenesis during vertebrate development. Genetic ablation of this TF in adult prevent aberrant angio- and lymphangiogenesis that occur during solid cancer metastasis, establishing a proof of concept that SOX18 is a potential molecular target. We have developed a molecular strategy to disrupt pharmaceutically SOX18 activity using small molecule inhibitors to halt blood vascular development in vivo in pre-clinical model of cancers. Further, we have identified a FDA approved drug that can be repurposed to target SOX18 and improve the management of specific vascular disorders. Our discovery provides a basis for innovative pharmacological manipulation of TFs function, challenges the prevailing dogma that TFs are not suitable drug targets and open up new avenues in drug discovery.
Mat Francois was rewarded with a PhD in Molecular Pathophysiology (Paris VI) in June 2004. In 2005, under a NHMRC & INSERM Fellowship, he moved to the Koopman Laboratory (The University of Queensland, IMB) to study the role of SOX transcription factors in lymphatic vessel development in mammals. The major discovery of his post-doctoral work is how SOX18 protein instructs the embryonic origin of lymphatic vessels.
The Francois lab was set up at IMB in 2012 and its strategic approach to research is based on a highly multi-disciplinary approach that encompasses developmental biology, chemical biology, and pathophysiological model systems complemented by biophysics and genomics methods. The research program is designed at identifying novel therapeutic strategies to target the pathological vasculature via the pharmacological manipulation of transcription factor activity. The laboratory has now established the proof of principle that transcription factors are viable molecular target using small molecule inhibitors in the context of solid cancer metastasis.