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.

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.

Publications

10 25 50

 
Description bevacizumab in ovarian cancer for NICE
Geographic Reach North America 
Policy Influence Type Participation in a national consultation
 
Title synthetic heparan sulphate oligosaccharides 
Description We have made families of structurally defined heparan sulphate oligosaccharides 
Type Of Material Biological samples 
Provided To Others? No  
Impact Our data suggest that there may be much greater structural specificity in the HS-growth factor relationship than has been suspected before. 
 
Description Development of Oligosaccharides as Anti-Angiogenic Agents 
Organisation University of Manchester
Department School of Chemistry Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been the PI on all grants emerging from the collaboration between Cancer Studies and Organic Chemistry. The ideas and drive emerged from my post-doctoral work in angiogenesis and the critical contribution of heparan sulfate to this phenotype. Dr. Gardiner's group developed the chemistry and synthesised the oligosaccharides and we subsequently evaluated the compounds in vitro.
Collaborator Contribution We are translating the field of heparan sulfate proteoglycans towards human ovarian cancer angiogenesis. The oligosaccharide programme forms one work stream of the overall programme.
Impact We have elucidated and patented the first inexpensive and scalable synthesis of L-iduronate, a saccharide that is essential for heparan sulfate structure. We have then progressed the chemistry so that we can generate using scalable chemistry, oligosaccharide species containing 12 residues bearing spatially defined sulfate residues. This resulted in the second patent published in July 2009. The first patent has been published this year in Org Lett (Pubmed 19764712). The patents are: Production of L-Iduronate containing polysaccharides, Int. publication: WO 2006/129075 A1: 2006-12-07 Jayson G, Gardiner J, Hansen S Synthesis route for multioligomeric heparan sulfate molecules, PCT Application : PCT/ GB2009/ 000300, 2009-02-04 Jayson G, Gardiner J, Hansen S
Start Year 2006
 
Description In vivo evaluation of oligosaccharides as anti-angiogenic agents 
Organisation Cancer Research UK
Department Cancer Research UK London Research Institute (LRI)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We developed and evaluated the oligosaccharides using the chemistry described above. We have now established a collaboration with Dr. Holger Gerhardt (Inst. Cancer Research, London) who has some novel models of angiogenesis allowing us to evaluate the molecules in vivo.
Collaborator Contribution Egle Avizienyte, Graham Rushton and Claire Cole- Contributed towards the in vivo experiments.
Impact The collaboration has only been established in November 2009. It is too early for an output
Start Year 2009
 
Description Structural studies of GAG-protein interactions and development of GAG-nanoparticle/vesicle constructs 
Organisation University of Manchester
Department School of Chemistry Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Providing biological input and facility for assays.
Collaborator Contribution The synthetic work developed during the MRC funding has facilitated enabling BBSRC-funded studentships and an EPSRC-funded studentships in Chemistry looking at structure for other forms of discrete structural studies (e.g. by spectroscopy and single molecule studies), and the new chemistry methods developed are now being applied to synthesis of conjugates for protein and lipid-synthetic constructs which have several applications. This funding has thus lead to significant future potential in new areas of GAG-syntehtic chemical biological and preclinical, and pteotnial for translational, developments.
Impact To date include din outputs under main grant but outputs are expected once studentships progress to publication
Start Year 2012
 
Description biosensor evaluation of HS oligosaccharides 
Organisation European Institute of Oncology (IEO)
Country Italy 
Sector Charity/Non Profit 
PI Contribution We have generated the oligosaccharides and evaluated them in vitro and in vivo
Collaborator Contribution Professor Marco Presta is measuring the KD and on/off rates of oligosaccharides with respect to angiogenic cytokines Professor Marco Presta is measuring the KD and on/off rates of oligosaccharides with respect to angiogenic cytokines
Impact The data will contribute to our MRC DPFS output
Start Year 2011
 
Description biosensor evaluation of HS oligosaccharides 
Organisation European Institute of Oncology (IEO)
Country Italy 
Sector Charity/Non Profit 
PI Contribution We have generated the oligosaccharides and evaluated them in vitro and in vivo
Collaborator Contribution Professor Marco Presta is measuring the KD and on/off rates of oligosaccharides with respect to angiogenic cytokines Professor Marco Presta is measuring the KD and on/off rates of oligosaccharides with respect to angiogenic cytokines
Impact The data will contribute to our MRC DPFS output
Start Year 2011
 
Title synthesis of iduronate and longer HS oligosaccharides 
Description we have developed and patented (i) the complete scalable synthesis of iduronate and (ii) the complete synthesis of heparan sulphate oligosaccharides. this is 2 patents 
IP Reference US2009137792 
Protection Patent granted
Year Protection Granted 2009
Licensed Yes
Impact Cancer Research Technology (linked with CRUK) are managing the IP on behalf of the University of Manchester and MRC. They are outlicensing the IP to pharmaceutical companies
 
Title HS oligosaccharides 
Description HS oligosaccharides. we are modifying the structures to improve activity and in so doing have discovered much greater structural specificity than previously suspected 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2011
Development Status Under active development/distribution
Impact as above. the identification of structure-function relationships will generate a platform upon which a new generation of drugs based on the inhibition of the HS-GF relationship. 
 
Description patient group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact i regularly talk to patient groups or interested lay members or relatives

I am now medical patron of the cancer charity "Chai Cancer Care" in Manchester
Year(s) Of Engagement Activity 2010,2011
 
Description school lectures 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I talk every year at different schools. The students can contact me about medicine after that.

advise students on medical school entry and meet and talk with prospective med students
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010