Abstract:
Alternative splicing is known to occur in more than 94% if genes in humans. Cancers express specific splice isoforms, or the normal ratios of isoforms are disrupted. While some of these events may be just a silent by-product of the cancer progression, many of them have functional significance and indeed, manipulation of their expression or splicing ratios is beneficial to the disease phenotype. Abnormal alternative splicing is therefore a new area where therapeutic interventions may be designed.
While there are several approaches to manipulate alternative splicing in cancer, the strategy that we use is to screen for small molecules that can switch splicing from detrimental isoforms characteristic to cancer progression to their normal counterparts and therefore rescue phenotype and inhibit tumor growth.
We present here examples from two repositioning screens using splicing sensitive-reporters designed to reproduce aberrant splicing of two genes in prostate cancer – VEGF-A, involved in angiogenesis and FGFR2 – involved in epithelial-mesenchymal transitions. We show that the compounds found to correct this aberrant splicing can reverse aggressive cancer cell properties in vitro and to slow tumor growth in nude mice xenografts when administered systemically.
In conclusion, we show that knowledge on the molecular mechanisms that connect alternative splicing and various cancer properties may be used as a platform for drug development.
Biography:
"Sebastian studied medicine at “Iuliu Hatieganu” Medical School, Cluj-Napoca, Romania and trained as a junior doctor in Nephrology and Dialysis before moving to the USA where he obtained a Ph.D. from the University of Nebraska-Lincoln in 2004. This was followed by postdoctoral training at Duke University Medical Center (North Carolina, USA) where he became interested in studying the connections between alternative splicing and cancer. In 2008 he moved to the University of Bristol where he continued to study alternative splicing in vivo, with a focus towards the importance of several genes splice isoforms (e.g VEGF, FGFR2) in cancer as well as kidney diseases and development of splice-based therapeutics. In 2012 he was appointed Independent Research Fellow and Principal Investigator and developed his own research group in Bristol before moving to the University of Exeter Medical School in 2017.
My research interests include the study of alternative splicing in vivo, coordinated regulation of alternative splicing in physiology and disease as well as manipulation of splice isoforms choice for therapeutic goals. Alternative splicing is the main process that decides the diversity of proteins in our bodies. It is estimated that more than 90% of genes are alternatively spliced in humans and therefore this process affects all cellular properties. The function of the majority of splicing isoforms is not characterized yet. Numerous splicing isoforms have been associated with disease progression in recent years and there is much interest in understanding their contribution to pathogenesis and how this can be reversed"
