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Exploiting the endocannabinoid system in chronic lymphocytic leukaemia


Project Description

Endocannabinoids, such as anandamide and 2-arachidonoyl glycerol, are endogenous cannabinoids produced in mammalian tissues that are anti-proliferative, anti-metastatic and pro-apoptotic in lymphoma and leukaemia. Endocannabinoids act via G protein-coupled receptors, such as cannabinoid receptor-1 (CB1), -2 (CB2) and GPR55. We have shown that the expression of CB2-receptors is up regulated in patients with aggressive chronic lymphocytic leukaemia (a common adult leukaemia in the UK, which is characterized by the accumulation of apoptosis resistant CD5+ B-cells) and activation of CB2 induces apoptosis of the malignant B-cells (Insel et al., 2018).

CB2 agonists, by selectively killing these malignant B-cells, thus provide a rational therapeutic approach for chronic lymphocytic leukaemia, however the use of cannabinoid-based drugs is hampered due to off-target side effects. Recent advances in drug discovery have seen the development of novel CB2-targeted drugs that could exploit the body’s own endocannabinoid system (Gado et al., 2019), namely positive allosteric modulators (PAM). PAMs, which work with the endogenous agonist of a receptor, have exciting potential clinical utility since they have increased selectivity and efficacy and therefore CB2-PAMs could enhance the CB2-pro-apoptotic effects of endocannabinoids. This studentship, which will provide the successful candidate with a unique training opportunity that combines molecular biology, pharmacology, drug discovery and the unique access to patient samples. The project will investigate the level of circulating endocannabinoids in patients with chronic lymphocytic leukaemia and the expression of CB receptors to determine if this can predict the severity of the disease. Furthermore, the pro-apoptotic effects and mechanism of action of novel CB2 PAMs, alone and in combination with endocannabinoids and novel CB2 agonists will be investigated in cell stabling overexpression the CB receptors and primary malignant B-cells. Such research will provide details regarding the mechanism of action of novel selective CB2 agonists and positive allosteric modulators. We believe exploiting the body’s endocannabinoid system has the potential to uncover the next generation of therapeutic agents for chronic lymphocytic leukaemia and other leukaemia and lymphomas.

APPLICATION PROCEDURE:
Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.

Further information on Cancer research at Aberdeen can be found here: https://www.abdn.ac.uk/smmsn/research/cancerabdn-1022.php

Funding Notes

This project is part of a competition funded by the School of Medicine, Medical Sciences and Nutrition for a 4 year PhD programme. Full funding is available to UK/EU candidates only. Overseas candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £15,680 per annum).

Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Merit/Commendation/Distinction at Masters level.

References

1. Insel et al., (2018), GPCRomics: GPCR Expression in Cancer Cells and Tumors Identifies New, Potential Biomarkers and Therapeutic Targets. Front Pharmacol, 22;9:431

2. Gado et al., (2019), Identification of the First Synthetic Allosteric Modulator of the CB2 Receptors and Evidence of Its Efficacy for Neuropathic Pain Relief. J Med Chem, 62:276-287

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