Fairlie - Apoptosis, autophagy, cancer, drug development and peptides
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.
We use 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 key pro-survival protein proteins that keep cancers alive. Complementary projects in the lab focus on autophagy, a cell survival process that has significant cross-talk with apoptosis.
Research areas
Role of Bcl-2 pro-survival proteins in melanoma
Metastatic melanoma is one of the most difficult cancers to cure and recent advances in the development of targeted therapies have improved patient outcome. However, response is variable and almost all patients relapse with a cure remaining elusive. As such, there is an urgent need to identify new drug targets to treat melanoma. There is some evidence that Bcl-2 pro-survival proteins (which normally keep cells alive by inhibiting the cell death program of apoptosis) are expressed at unusually high levels in melanoma compared to normal melanocytes. Our hypothesis is that Bcl-2 pro-survival proteins provide a survival advantage for melanomas and might contribute to resistance to standard chemotherapeutic drugs.
Our research aims to identify the key Bcl-2 pro-survival proteins that are responsible for melanoma survival. This will be achieved through the use of Bcl-2 protein-selective reagents, which were engineered in the Fairlie laboratory, to profile melanoma cell lines, as well as samples from patients. The sensitivity to these reagents will be assessed in cell culture systems as well as in mouse models.
The second aim is to determine whether resistance to current melanoma treatment arises due to elevated levels of Bcl-2 pro-survival proteins, and whether treatment with Bcl-2-targeting molecules will resensitise tumours to standard drugs, informing potential drug treatment combinations. This aim will also explore whether immunotherapy approaches could benefit from Bcl-2 targeting.
Results from this project should identify potential drug targets for the treatment of metastatic melanoma.
Crosstalk between apoptosis and autophagy
Cells possess distinct pathways that promote their survival or death. Communication between the cell survival pathway of autophagy and the cell death pathway of apoptosis is crucial for determining the best outcome for the cell, and ultimately its fate. Our research identifies the molecular factors that are responsible for this crosstalk.
This can be achieved in a number of the ways. The first is to use an in vivo approach to analyse transgenic mice in which the autophagy regulator known as Beclin has been engineered to either disrupt or enhance its regulation by key components (i.e. proteins) of the apoptosis pathways. This will provide the first physiological readout to determine how important these interactions are in crosstalk between the pathways.
The second approach is to use either the new gene editing CRISPR/Cas9 technology or mass spectrometric/proteomics approaches (or both) to undertake screens to identify factors that can inhibit the cell death that occurs as a consequence of disarming the autophagy pathway through deletion of Beclin.
Results from this work will significantly advance our understanding of how the interplay between cell death and cell survival is regulated, which is still poorly understood despite its considerable biological importance. This crosstalk is fundamental to not only physiology but significantly contributes to the onset of diseases such as cancer, and hence impacts on treatment strategies.
Substituted sulfonyl hydrazides as inhibitors of lysine biosynthesis via the diaminopimelate pathway: Australian Provisional Patent Application 1079445
Heterocyclic compounds as inhibitors of lysine biosynthesis via the diaminopimelate pathway: Australian Provisional Patent Application 1079451
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