13dougfairlieteam

Cell death & survival

Laboratory overview

The Cell Death and Survival Laboratory uses a combination of biochemical, cell biology, structural biology and medicinal chemistry approaches to understand the precise molecular mechanisms that control apoptosis. Our aim is to develop new reagents, including drugs, that could target and inhibit the actions of the Bcl-2 proteins that keep cancers such as melanoma alive, or which make them more resistant to current therapies used in the clinic.

By understanding the survival factors of a cancer cell we can then develop treatments to activate their death. Dr. Doug Fairlie. Group Leader, Cell Death & Survival Group
study-at-ONJCRI 140404-jamesbraund- 1588 140904-jamesbraund-0984

Our focus

Apoptosis

Cellular fate is controlled by multiple molecular pathways. The best studied is apoptosis, a form of programmed cell death used by all multicellular organisms to eliminate cells that are damaged, no longer needed or which might become a threat to the organism. This process is often deregulated in cancer cells allowing them to survive and proliferate when otherwise they should be eliminated.

BH3 mimetics

Dysfunctional apoptosis can cause or accelerate cancer development, but also underlies resistance to common cancer treatment approaches such as chemotherapy. Members of the Bcl-2 family of proteins are critical regulators of apoptosis with some members promoting cell survival and others promoting cell death. Recently, a new class of drugs called “BH3 mimetics” have been developed to target some Bcl-2 pro-survival proteins, and these are showing significant promise in clinical trials for the treatment of cancers such as leukemia and lymphoma.

Autophagy

Our ultimate goal is to develop drugs that will be used to treat cancer patients. Complementary projects in the lab focus on autophagy, a cell survival process that has significant cross-talk with apoptosis. Similar approaches will be used to understand the molecular details of authophagy regulation, how it influences apoptosis, and its role in cancer development and treatment.

 

Quick facts

What cell signalling?

Cell signalling refers to a cell receiving external cues (e.g. from factors like proteins in the blood) and transmitting them inside the cell to activate processes such as cell division or movement. Cells can also signal to other cells by secreting molecules such as proteins.

What is apoptosis?

Apoptosis is a normal process of cell death which is required to remove old, damaged or dangerous cells. In cancer this process is often switched off allowing abnormal cells to survive and grow when they should otherwise be killed and eliminated.

What is autophagy?

Autophagy is primarily a cell survival process meaning to “self eat”. In times of stress, nutrient deprivation or infection, the cell eats its own components in order to maintain cellular energy levels hence allowing itself to survive.

1.     Lee EF, Fairlie WD. Repurposing apoptosis-inducing cancer drugs to treat schistosomiasis. Future Med Chem.;7(6):707-11, 2015

2.     Lee, E.F., Takiguchi, M., Pettikiriarachchi, A., Evangelista, M., Huang, D.C.S., Dickins, R.A., Fairlie, W.D. A transgenic mouse model to inducibly target prosurvival Bcl2 proteins with selective BH3 peptides in vivo. Cell Death Dis. 6: e1679 (2015)

3.     Peterson-Kaufman KJ, Haase HS, Boersma MD, Lee EF, Fairlie WD, Gellman SH. Residue-Based Preorganization of BH3-Derived α/β-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in α-Helix Mimics. ACS Chem Biol. 17;10(7):1667-75., 2015

4.     Lee, E.F., Dewson, G., Evangelista, M., Pettikiriarachchi, A., Gold, G.J., Zhu, H., Colman, P.M., Fairlie, W.D. The functional differences between pro-survival and pro-apoptotic B cell lymphoma 2 (Bcl-2) proteins depend on structural differences in their Bcl-2 homology 3 (BH3) domains. J. Biol. Chem. 289:36001-36017 (2014)

5.     Smith, B.J., Lee, E.F., Checco, J.W., Evangelista, M., Gellman, S.H., Fairlie, W.D  Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins. Chembiochem 14: 1564-1572 (2013)

For a complete list of Doug Fairlie’s publications, click here

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