Cancer and Inflammation

The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, smouldering inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

We are researching a particular class of receptors involved in inflammation called GPCRs, or G protein coupled receptors. GPCRs account for up 30% of the targets of drugs currently on the market and are of interest to Big pharma, academia and biotech. They are commonly referred to as 7TM proteins as they are composed of seven helices that span the membrane. They are implicated in many disease types, due to their widespread expression in a number of different cell types, particularly immune cells. We are interested in GPCRs and the pathology of native and synthetic ligands for these receptors that play a central role in host defence [1].  Excessive receptor activation and disregulation has been linked to a number of different disease types, including rheumatoid arthritis [2], sepsis [3] and Alzheimer’s [4]. Whilst much effort (20 years+) has been put into the development of potent antagonists against this receptor, there are no marketed antagonists to date.

The phenomena of ligand directed signaling [5-7], whereby different ligands acting on one receptor may elicit qualitatively different response patterns, or one ligand may signal strongly through one pathway, yet weakly through another, is another significant component of this research. We have investigated this phenomenon using a panel of compounds targeted at the receptor using a range of secondary messenger assays and label-free detection platforms. Using these technologies we have analysed over-expressing transfected cells, native cells and null cells to derive a comprehensive map of ligand-directed signaling in different cell types and cell states. In this way we hope to be able to select for candidate drugs using the appropriate cellular model; for example there are reports in the literature which show that an agonist can behave as an antagonist when receptor expression levels are high [8,9].

Ultimately, our aim is to dissect individual signalling pathways, in the hope that we can understand what happens at the cellular and molecular level after a compound binds to a GPCR implicated in inflammation and cancer. We are using a number of different approaches, such as shRNA, fluorescent labelling, silencing using toxins, and others, to thoroughly dissect and attribute a signal to a specified signalling event. This will help us to identify compounds which specifically target, not only one receptor, but show bias for one signalling pathway towards a highly selective drug profile.

[1] Monk, P. N.; Scola, A. M.; Madala, P.; Fairlie, D. P., Br. J. Pharmacol. 2007, 152, 429.

[2] Jose, P. J.; Moss, I. K.; Maini, R. N.; Williams, T. J., Ann. Rheum. Dis. 1990, 49, 747.

[3] Czermak, B. J.; Sarma, V.; Pierson, C. L.; Warner, R. L.; Huber-Lang, M.; Bless, N. M.; Schmal, H.; Friedl, H. P.; Ward, P. A., Nat. Med. 1999, 5, 788

[4] Velazquez, P.; Cribbs, D. H.; Poulos, T. L.; and Tenner, A. J., Nat. Med. 1997, 3, 77.

[5] Gilchrist, A., Trends Pharmacol. Sci. 2007, 28, 431.

[6] Urban, J. D.; Clarke, W. P.; von Zastrow, M.; Nichols, D. E.; Kobilka, B.; Weinstein, H.; Javitch, J. A.; Roth, B. L.; Christopoulos, A.; Sexton, P. M.; Miller, K. J.; Spedding, M.; Mailman, R. B., J. Pharmacol. Exp. Ther. 2007, 320, 1.

[7] Michel, M. C.; Alewijnse, A. E., Mol. Pharmacol. 2007, 72, 1097.

[8] Hutchinson, D. S.; Chernogubova, E.; Sato, M.; Summers, R. J.; Bengtsson, T., Naunyn-Schmiedeberg's Arch. Pharmacol. 2006, 373, 158.

[9] Sato, M.; Horinouchi, T.; Hutchinson, D. S.; Evans, B. A.; Summers, R. J., Mol. Pharmacol. 2007, 72, 1359.

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