The growth of solid tumours beyond a threshold size (~1 mm dia) requires angiogenesis, the development of new blood vessels. This has focussed attention on anti-angiogenic agents for the treatment of cancers and particularly to inhibit the growth of secondary tumours (metastases).
We showed some years ago that combretastatin-4P (CA-4P), a tubulin-binding compound that disrupts neovasculature, not only retards primary tumour growth but is a potent inhibitor of metastasis in mouse models. Subsequently we have used targetted gene therapy focused on the transforming growth factor beta signalling pathway that generally inhibits the proliferative activity of all mitogenic stimuli for endothelial cells in vitro. We hypothesise that shifting the balance of TGFb signalling to the anti-proliferative ALK5 receptor pathway by blocking signalling through the competing pro-proliferative ALK1 pathway would antagonise all the alternative pro-angiogenic pathways that are enhanced as a response to agents that block specific pathways.
We have compared adenoviral (Ad) delivery of a kinase–defective (KD) ALK1 to inhibit ALK1 signalling with Ad-thymidine kinase (TK) regulated by the Tie2 promoter (Tie2-TK). Tie2 is expressed mainly in proliferating endothelial cells: TK activates the pro-drug gancyclovir (GCV) to give targetted endothelial cell killing. In vitro both Ad-ALK1-KD and Ad-Tie2-TK completely inhibit endothelial cell growth in the presence of endothelial mitogens.
In mouse models we have shown that either Ad-ALK1-KD or Ad-Tie2-TK with GCV inhibit the growth of carcinoma and melanoma tumours with no evidence of toxicity due to repeated viral treatment. These studies are continuing with a variety of virally-delivered genes. In a complementary study we are investigating the possibility that a range of different tumour types may express PEG3 and whether the PEG3 promoter may be used to drive the expression of fluorescent and luminescent reporters to enhance tumour detection in vivo.
I am not able to offer Ph.D. or post-doctoral positions.
2. Hesketh, R. (2012). A great adventure: from quantitative metabolism to the revelation of Chinese science. The Biochemical Journal, Issue 1, 1-4.
3. Oklu, R., Habito, R., Mayr, M., Deipolyi, A.R., Albadawi, H., Hesketh, R., Walker, T.G., Linskey, K.R., Long, C.A., Wicky, S., Stoughton, J. and Watkins, M.T. (2012). Pathogenesis of Varicose Veins. Journal of Vascular and Interventional Radiology 23, 33-39.
4. Scollen, S., Luccarini, C., Baynes, C., Driver, K., Humphreys, M.K., Garcia-Closas, M., Jonine, F., Lissowska, J., Pharoah, P. D., Easton, D.F., Hesketh, R., Metcalfe, J.C. and Dunning, A. M. (2011). TGF-beta Signaling Pathway and Breast Cancer Susceptibility. Cancer Epidemiology Biomarkers & Prevention 20, 1112-1119.
5. Oklu, R., Walker, T.G., Wicky, S. and Hesketh, R. (2010). Angiogenesis and Current Antiangiogenic Strategies for the Treatment of Cancer. Journal of Vascular and Interventional Radiology 21, 1791-1805.
6. Scollen, S., Dunning, A., Bradshaw, A., Hesketh, R. and Metcalfe, J.C. (2008). Association of gene variants in the TGF-beta signalling pathways with invasive breast cancer risk. Breast Cancer Research 10, S25-S26.
Robin Hesketh (2012). “Betrayed by Nature: The War on Cancer” Macmillan. ISBN 978-0-230-33848-7.
Robin Hesketh (2013). “Introduction to Cancer Biology” Cambridge University Press. ISBN-13: 9781107013988.