Development of Anti-Angiogenic Oligosaccharides
Lead Research Organisation:
University of Manchester
Department Name: Medical and Human Sciences
Abstract
Tumour growth is critically dependent on the formation of new blood vessels, which provide oxygen and nutrients to the tumour. Clinical trials have demonstrated that drugs, which inhibit blood vessel formation, can improve the outcome of patients with several different types of cancer.
We have developed a new drug for the treatment of ovarian cancer that works by blocking blood vessel formation inside the tumour. The drug blocks three of the critical growth factors (like hormones) that drive blood vessel formation in ovarian cancer. The drug emerged from a novel chemistry research programme that allows us to make custom-designed oligosaccharides (complex sugar molecules) that block growth factors from generating new blood vessels in a cancer.
In the laboratory the oligosaccharides block blood vessel formation in several different types of experiments. In this research project we will continue our research on these new molecules by testing several different oligosaccharides in experiments that will test the safety and effectiveness of the drugs. At the end of this grant we will have identified the lead molecule and will be ready to move the drug towards clinical trials.
We have developed a new drug for the treatment of ovarian cancer that works by blocking blood vessel formation inside the tumour. The drug blocks three of the critical growth factors (like hormones) that drive blood vessel formation in ovarian cancer. The drug emerged from a novel chemistry research programme that allows us to make custom-designed oligosaccharides (complex sugar molecules) that block growth factors from generating new blood vessels in a cancer.
In the laboratory the oligosaccharides block blood vessel formation in several different types of experiments. In this research project we will continue our research on these new molecules by testing several different oligosaccharides in experiments that will test the safety and effectiveness of the drugs. At the end of this grant we will have identified the lead molecule and will be ready to move the drug towards clinical trials.
Technical Summary
Randomized trials have demonstrated that anti-angiogenic VEGF inhibitors improve survival in several malignancies. However, the benefit is of limited duration and the drugs can be toxic. Thus there is a clear need to develop new anti-angiogenic agents.
Heparan sulfate (HS), a linear disaccharide polymer, is essential for the biological activity of most angiogenic cytokines. In an MRC Milstein grant-funded project we have evaluated a series of defined HS oligosaccharides synthesised using novel and scalable chemistry. A lead molecule has been identified that significantly inhibits the activity of a number of angiogenic targets to reduce endothelial tube formation, migration and proliferation in vitro. Previous data demonstrated anti-angiogenic activity with structurally related compounds, in vivo.
In this application the molecule will progress through defined developmental milestones to generate a lead candidate that has the required potency and suitable ADMET characteristics to support progression into late stage pre-clinical development and phase I clinical trial evaluation.
Heparan sulfate (HS), a linear disaccharide polymer, is essential for the biological activity of most angiogenic cytokines. In an MRC Milstein grant-funded project we have evaluated a series of defined HS oligosaccharides synthesised using novel and scalable chemistry. A lead molecule has been identified that significantly inhibits the activity of a number of angiogenic targets to reduce endothelial tube formation, migration and proliferation in vitro. Previous data demonstrated anti-angiogenic activity with structurally related compounds, in vivo.
In this application the molecule will progress through defined developmental milestones to generate a lead candidate that has the required potency and suitable ADMET characteristics to support progression into late stage pre-clinical development and phase I clinical trial evaluation.
