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FPR-1 antagonists, a novel treatment for glioma

Summary of Project:

Glioblastomas account for nearly half of the cases of brain tumours in the UK and have an invariably poor prognosis. Survival rates for glioblastoma have hardly improved in the past 40 years. One of the reasons for this lack of success is the high heterogeneity of glioma tumours. Therapeutics that target specific signaling pathways can rapidly become ineffective, as other drivers of tumour expansion and malignancy take over. As a result, in spite of an initially encouraging response, many patients develop resistance to their treatment. An example of this is bevacizumab (avastin), which is highly effective in halting the progression of the disease for a few months, albeit this does not translate to improving overall survival. After treatment with bevacizumab, as is the case with other treatments, including radiotherapy, the initial remission of the disease is followed by recurrence in a more aggressive, resistant form. A potential solution to this problem is to target upstream events which contemporaneously drive different hallmarks of the disease.

In this project, we will explore the potential of small molecule antagonists of chemotactic receptor FPR-1 (formyl peptide receptor type 1), a member of highly druggable GPCR-7TM cell surface receptor family, as a new multifaceted treatment for glioma. Activation of FPR-1 by its ligands, annexin A1 (ANXA1) and short chain formylated peptides e.g. fMLF, has multiple roles in advancing glioma. In particular, FPR-1 is present in stem-like (CD133+) glioma tumour cells and plays an important role in vasculogenesis, a key feature of the advanced disease. Hence, targeting FPR-1 can provide the opportunity for an exciting clinical intervention that can significantly improve the outcome by restricting resistance and recurrence.

PhD Project objectives:

  1. To synthesise novel FPR-1 antagonists, with the aim to optimise their physicochemical properties while maintaining biological activity.
  2. To investigate the effect of the newly synthesised agents on the functional activity of the receptor with respect to calcium mobilisation, motility, invasion and processes associated with tumour progression.
  3. To investigate the potential of the compounds for brain penetration.

Compounds will be synthesised and tested for potency and permeability in an iterative fashion until a suitable compound is identified.

Relevance and context:

Our group is very active in the investigation of the role of chemotactic receptors in cancer, the discovery of new cancer agents targeting chemotactic receptors and development of methods for assessment of chemotactic response. This project builds on current results from our lab to deliver a new clinical agent against glioma, and provides further preclinical evidence in support of our disease hypothesis linking transition to higher grade gliomas to tumour necrosis. Therefore, this project strongly supports and extends existing lines of research currently within our group.

Cancer research and drug discovery is a research focus area in the Faculty of Life Sciences and an area of strength as evident with the activities of ICT. This project strengthens the research in ICT and faculty by contributing to the development of new agents, supporting an already established target and thus consolidating the pipeline of new agents from ICT.

Funding:

A bench fee applies to this project, in addition to the tuition fees.

Entry requirements:

At least 2i Honours degree in Chemistry, Pharmaceutical or Biomedical Sciences or equivalent. MSc with Merit preferred.

Key references

  1. Boer, J. C., van Marion, D.M., Joseph, J.V., Kliphuis, N.M., Timmer-Bosscha, H., van Strijp, J.A., de Vries, E.G., den Dunnen, W.F., Kruyt, F.A., Walenkamp, A.M. “Microenvironment involved in FPR1 expression by human glioblastomas” (2015) J. Neurooncol., 123(1):53-63.
  2. Cho, D.Y., Lin, S.Z., Yang, W.K., Lee, H.C., Hsu, D.M., Lin, H.L., Chen, C.C., Liu, C.L., Lee, [3]. W.Y., Ho, L.H. “Targeting cancer stem cells for treatment of glioblastoma multiforme” (2013) Cell Transplant, 22(4):731-739.
  3. Liu, M., Zhao, J., Chenn, K., Bian, X., Wang, C., Shi, Y., Wan,g J.M. “G protein-coupled receptor FPR1 as a pharmacologic target in inflammation and human glioblastoma” (2012), Int. Immunopharmacol., 14(3):283-288.
  4. Yang, Y., Yao, X., Ping, Y., Jiang, T., Liu, Q., Xu, S., Huang, J., Mou, H., Gong, W., Chen, K., Bian, X., Wang, J.M. “Annexin 1 released by necrotic human glioblastoma cells stimulates tumor cell growth through the formyl peptide receptor 1” (2011) Am. J. Pathol., 179(3):2674-2675.
  5. van Tellingen, O., Yetkin-Arik, B., de Gooijer, M.C., Wesseling, P., Wurdinger, T., de Vries, H.E. “Overcoming the blood-brain tumor barrier for effective glioblastoma treatment” (2015) Drug Resist. Updat., 19:1-12.
  6. Vinader, V.; Ahmet, D.S.; Ahmed M.S.; Patterson L.H.; Afarinkia, K. “Discovery and Computer Aided Potency Optimization of a Novel Class of Small Molecule CXCR4 Antagonists” (2013) PLoS ONE, 8(10), e78744.
  7. Vinader, V.; Afarinkia, K. “The Emerging Role of CXC Chemokines and Their Receptors in Cancer” (2012) Future Med. Chem., 7, 853-867,
  8. Vinader, V.; Afarinkia, K. “A Beginner’s Guide to Chemokines” (2012) Future Med. Chem., 7, 845-852.
  9. Vinader, V.; Al-Saraireh, Y.; Wiggins, H. L.; Rappoport, J. Z.; Shnyder, S. D.; Patterson L. H.; Afarinkia, K. “An Agarose Spot Chemotaxis Assay for Chemokine Receptor Antagonists”, (2011) J. Pharmacol. Toxicol. Methods, 64, 213-216.
  10. Ayuso, J. M.; Basheer, H. A.; Monge, R.; Sánchez-Álvarez, P.; Doblaré, M.; Shnyder, S. D.; Vinader, V.; Afarinkia, K.; Fernández, L. J.; Ignacio Ochoa “Study of the chemotactic responses of multicellular spheroids in a microfluidic device” (2015), PLoSONE, 10(10), e0139515.

Supervisors:

Title and name:
Dr Victoria Vinader
Position:
Lecturer in Drug Toxicology and Safety Pharmacology
Email address:
Telephone number :
Work+44 (0) 1274 233205
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Title and name:
Dr Kamyar Afarinkia
Position:
Senior Lecturer in Medicinal Chemistry
Email address:
Telephone number :
Work+44 (0)1274 235831
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Title and name:
Dr Steve Shnyder
Position:
Senior Lecturer in Tumour Biology
Email address:
Telephone number :
Work+44 (0)1274 235898
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