Skip to content
Open menu Close menu

Role of hypoxia in promotion of higher grade glioblastoma

Summary of Project:

Glioblastomas are categorized into four grades. Grade I is essentially benign and slow growing, and most amenable to treatment. Grade II tumors are larger and invade surrounding tissue. The two lower grade gliomas show little necrosis and vascular proliferation. Grade III gliomas are malignant and demonstrate foci of high vascular proliferation with a defined necrotic core that expands rapidly in grade IV to afford a highly malignant, heterogeneous and invasive cancer (glioblastoma multiforme or GBM).

Progression to higher grade gliomas is irreversible, and at grades III and IV, treatment options for the disease are very limited. As a result, median survival rate for patients suffering from grade IV glioma is below 15 months. Understanding the mechanisms by which glioma progresses from lower grades 1 and 2 to higher grades 3 and 4 is important in order to devise new and more efficient therapeutic interventions, and to identify biomarkers for disease progression, so existing therapeutic interventions can be more appropriately applied.
Of particular interest to us is the chemotactic formyl peptide receptor-1 (FPR-1), which is activated by short chain N-formylated peptides (e.g. fMLF) and annexin A1. Interestingly, in cancer cell lines, much of the pathophysiological effects of the activation of FPR-1 appear to be directly relevant for the differences observed between lower and higher grade gliomas.

Hypothesis

We have hypothesised that the progression from lower to higher grade gliomas is associated with the development of a hypoxic, necrotic core in the tumour as it expands., Lack of nutrients and oxygen (hypoxia) within the expanding tumour drives necrosis. Hypoxia also drives the expression of FPR-1, whilst necrosis results in the release of chemotactic peptide agonists for FPR-1. The combination of these two events enables cells to acquire a more invasive, malignant and death-resistant phenotype, which is characteristic of higher grade glioma.

Objectives of PhD study:

  1. We will detect proteins of interest using immunohistochemistry on frozen or paraffin embedded tissue. Proteins of interest include FPR-1 and Annexin A1, as well as Ki67 (as a marker of proliferation), MMP-9 and EGFR (markers of malignancy), pimonidazole, HIF-1α, CAIX, LDH-5, and GLUT-1. GFAP will be used to identify glial cells. We will assess the correlation between FPR-1 expression and these key markers for hypoxia, necrosis and tumour expansion.
  2. Multicellular spheroids of glioma cells with diameters between 200-800 microns are prepared in our lab; we will expand on this work and compare the expression of the same proteins in the spheroid cores, thus establishing the validity of the spheroids without a hypoxic core and with hypoxic core as in vitro models for low and high grade glioblastomas respectively.
  3. Antagonists from our FPR-1 antagonist program will be evaluated in an iterative process in such models.


Relevance and context:

Our group is very active in the discovery of new cancer agents. Specifically, we have been engaged in the study of potent FPR-1 antagonists, as a new treatment for glioblastoma.

This project will provide further evidence in support of our disease hypothesis; therefore, this project strongly supports 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:

 

Applicants will need to have their own funding or external sponsorship. A bench fee is required 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. 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.
  2. Vinader, V.; Afarinkia, K. “The Emerging Role of CXC Chemokines and Their Receptors in Cancer” (2012) Future Med. Chem., 7, 853-867,
  3. Vinader, V.; Afarinkia, K. “A Beginner’s Guide to Chemokines” (2012) Future Med. Chem., 7, 845-852.
  4. 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.
  5. 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.
  6. 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.
  7. 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,
  8. W.Y., Ho, L.H. “Targeting cancer stem cells for treatment of glioblastoma multiforme” (2013) Cell Transplant, 22(4):731-739.
  9. 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.
  10. 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.
  11. 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.

Supervisors:

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

See the PhD (School of Pharmacy and Medical Sciences) course page to find out more about studying at the University of Bradford, including fees, how to apply, facilities, and the support available to you.