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Targeting the CXCR4-CB2 G-protein coupled receptor complex as a treatment for breast cancer

Project Description

Breast cancer is the most common cause of cancer in the UK, causing ~7% of cancer deaths.[1] It is classified into three subtypes: Luminal (oestrogen receptor positive (ER+) and/or progesterone receptor positive (PR+), HER2+ (amplification of the ERBB2 oncogene) and triple-negative (TN) (negative for ER, PR and ERBB2). HER2+ and TN breast cancer have the worst outcomes. A major hallmark of cancer cells, is their ability to migrate and generate metastases.[2] Current treatments include kinase inhibitors, angiogenesis inhibitors and hormone therapy. However, a key challenge for controlling this disease is to eradicate the metastatic capacity of cancer cells. Blocking dissemination is often hampered by the fact that cells that disseminate have different gene expression profiles from the primary tumour, thus to successfully treat these cells it is important to target the dissemination process itself.

To achieve this goal requires approaches that block specific activated pathways causing hyperproliferation, local dissemination and metastasis. This challenge is compounded by having to accomplish this with minimal effects to healthy cells. Two families of proteins that play key roles in dissemination and metastasis are the cannabinoid[3-5] and chemokine receptors [6], both members of the G-protein coupled receptor (GPCR) family. GPCRs are a superfamily of transmembrane proteins that interact with G-proteins and contain seven helices with interconnecting loops. Currently, >25% of drugs on the market target GPCRs, demonstrating their importance in medicine. It is now accepted that GPCRs can form ‘receptor heterodimers’.[7] This is when receptors of different gene families combine among themselves to generate new and unique biochemical/functional characteristics that are distinct from the single receptor. These heterodimers constitute an important and emerging area in GPCR drug discovery [8] with recent studies validating modulation of heterodimers as an effective therapeutic intervention. [9-11]

This project seeks to target a novel heterodimer between the cannabinoid and chemokine receptors, two major receptor families that impact tumour growth and metastasis in metastatic breast cancer; specifically, the CXCR4-CB2 complex. This approach takes advantage of blocking both proliferation and dissemination. The main challenge of targeting GPCRs for cancer therapies is their ubiquitous expression meaning simply targeting the individual receptors will lead to targeting both healthy and cancerous cells. To overcome this, we are targeting heterodimers that are ONLY formed in the tumour cells where the receptors are overexpressed.

When chemokine receptors form heterodimers it can result in an inhibition of signalling normally individually mediated by the receptors. It is proposed that CXCR4 signalling can be silenced through this physical heterodimeric association with CB2. [12] We will therefore design and synthesise bivalent molecules targeting this complex. These have the advantage over CXCR4 antagonists in that they will be selective for the cancer cell (as this is where the heterodimer is forming), therefore not inhibiting CXCR4 function in other cells including immune cells. Bivalent ligands consist of two pharmacophores, tethered together by a linker and are powerful tools to study heterodimers. [13,14] In general, bivalent ligands show increased affinity (thermodynamic advantage of cooperative binding and reduction in entropy) and selectivity for the receptor complex. [13,14]

In this proposal, bivalent ligands consisting of a CXCR4 antagonist connected via a linker to a CB2 inverse agonist will be synthesised. These chemical probes/tools will be used to understand when and where this complex exists in breast cancer.

Funding

Applicants wishing to apply for PhD funding through external scholarship providers are welcomed (see website for details of QMUL's international funding partners), as are those applicants who can self-fund.

Elgibility and Applying

Applicants must have an undergraduate degree in chemistry or pharmacy awarded with upper second class honours. 

Details of the application process can be found on this webpage.

References

  • http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer
  • D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell, 2001, 144, 646-674.
  • G. Velasco, C. Sánchez, M. Guzmán, Anticancer mechanisms of cannabinoids, Current Oncology, 2016, 23, S23-32.
  • R. Ramer, B. Hinz, Antitumorigenic targets of cannabinoids - current status and implications, Expert Opinion on Therapeutic Targets, 2016, 20, 1219-1235.
  • G. Velasco, C. Sánchez, M. Guzmán, Towards the use of cannabinoids as antitumour agents, Nature Reviews Cancer, 2012, 12, 436-444.
  • M. A. Mishan, N. Ahmadiankia, A. R. Bahrami, CXCR4 and CCR7: Two eligible targets in targeted cancer therapy, Cell Biology International, 2016, 40, 955-967.
  • S. Ferré, V. Casadó, L. A. Devi, M. Filizola, R. Jockers, M. J. Lohse, G. Milligan, J. P. Pin, X. Guitart, G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacological Reviews, 2014, 66, 413-434.
  • R. Franco, E. Martínez-Pinilla, A. Ricobaraza, P.J. McCormick, Challenges in the development of heteromer-GPCR-based drugs, Progress in Molecular Biology and Translational Science, 2013, 117, 143-162.
  • L. Pei, S. Li, M. Wang, M. Diwan, H. Anisman, P.J. Fletcher, J.N. Nobrega, F. Liu, Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects, Nature Medicine, 2010, 16, 1393-1395.
  • X. Viñals, E. Moreno, L. Lanfumey, A. Cordomí, A. Pastor, R. de La Torre, P. Gasperini, G. Navarro, L. Howell, L. Pardo, L., C. Lluís, E. I. Canela, P. J. McCormick, R. Maldonado, P. Robledo, Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors, PLoS Biology, 2015, 13, [e1002194].
  • M. L. Perreault, A. Hasbi, B. F. O'Dowd, S. R George, Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance, Neuropsychopharmacology. 2014, 39, 156-168.
  • C. J. Coke, K. A Scarlett, M. A. Chetram, K. J. Jones, B. J. Sandifer, A. S Davis, A. I. Marcus, C. V. Hinton, Simultaneous activation of induced heterodimerization between CXCR4 chemokine receptor and cannabinoid receptor 2 (CB2) reveals a mechanism for regulation of tumor progression, Journal of Biological Chemistry, 2016, 291, 9991-10005.
  • C. Hiller, J. Kühhorn, P. Gmeiner, A. Class, G-protein-coupled receptor (GPCR) dimers and bivalent ligands. Journal of Medicinal Chemistry, 2013, 56, 6542–6559.
  • J. Shonberg, P. J. Scammells, B. Capuano, Design strategies for bivalent ligands targeting GPCRs. ChemMedChem, 2011, 6, 963–974.

 

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