dr. howard fearnhead

Background

In 1991 Dr Fearnhead completed a BSc. in Pharmacology and Toxicology at the London School of Pharmacy, before beginning a PhD. in apoptosis at the MRC-Toxicology Centre, Leicester, UK.  In 1995 Dr Fearnhead began a post-doctoral fellowship at Cold Spring Harbor Laboratory, NY before moving to the National Cancer Institute in Maryland as a tenure track principle investigator.  In 2004 Dr Fearnhead moved to the National Centre of Biomedical Engineering Science (NCBES), National University of Ireland, Galway and in 2006 was appointed a lecturer in Pharmacology and Therapeutics.

Research Background

All our cells carry a genetic program that enables a cell to quickly and cleanly kill itself, a form of cell death called apoptosis. This program is found in all metazoans examined and plays important roles at different stages of an organism’s life. Apoptosis is activated at various stages during normal embryonic development, removing unwanted cells and so sculpting our tissue and organs. It is also activated in bacterially or virally infected cells, and serves to limit the success of these pathogens. Apoptosis is also a stress response, acting to remove damaged cells that can no longer serve a purpose or that pose a threat to the organism as a whole. A failure in the regulation of apoptosis is associated with auto-immune diseases and degenerative diseases (too much apoptosis) and cancer (too little apoptosis).

Programmed cell death or apoptosis is of fundamental importance to cancer as it both limits tumorigenesis and is also triggered by many cancer chemotherapeutics.

Importantly, cancer cells often acquire mutations that compromise the apoptotic process, allowing these cells to both escape normal growth constraints and to become resistant to many anti-cancer drugs, resulting in the emergence of drug-resistant malignancies.  Thus discovering how apoptosis is regulated and why it fails in cancer is central to both understanding cancer progression and developing new therapies to counter chemo-resistant cancers.

Biochemical and genetic studies in a range of model systems have identified the key components of the apoptotic machinery. One gene family that contributes to the commitment to apoptosis and execution of the death program encodes a family of cysteine proteases called caspases.  Caspases are expressed in cells as inactive zymogens and are activated at the onset of apoptosis. In many cases (but not all) this is sufficient to kill the cell. Different types of apoptotic signals initiate apoptosis by activating different “initiator” caspases. These “initiator” caspases then activate a common set of “effector” caspases by proteolysis. Ultimately, it is these effector caspases that produce the apoptotic phenotype by cleaving a wide range of intracellular substrates.

Caspases also play non-apoptotic roles, being important in the regulation of inflammation.  More recently, caspases normally associated with inducing cell death have also been implicated in the induction of differentiation of stem and progenitor cells.

Research Projects

Caspases and Differentiation

Caspases play a central role in the induction of apoptosis and inflammation.  More recently, caspases normally associated with inducing cell death have also been implicated in the induction of differentiation of stem and progenitor cells.  The research is focussed on stem cell apoptosis and how caspases might control cellular differentiation.  Specifically, the experiments investigate how stem cells regulate caspases, proteases that are key components of the apoptotic machinery.  Caspase-3 activity has been implicated as vital for osteogenic and myogenic and oligodentritic differentiation.  These raises intriguing questions; (1) how is caspase-3 activated in these cases, (2) why doesn’t caspase-3 kill the cells and (3) what molecular events in the differentiation process are caspase dependent?  Addressing these issues is expected to significantly improve our understanding of both stem cell biology and caspase function.

There are also ramifications for stem cell therapy. In principle, stem cell-based therapies for replacing dead or failing cells may limit or even reverse degenerative diseases. For this approach to be successful stem cells must survive and function in a damaged tissue where the diseased environment may cause stem cell apoptosis. However, strategies for engineering apoptosis resistance into stem cell raise concerns. First, the failure of the apoptotic process is a hallmark of cancer and modifying stem cells may increase cancer risk. Second, if apoptotic genes affect cell differentiation, interfering with apoptotic pathways could compromise the cells’ therapeutic value. Understanding of how the programs that control stem cell differentiation and apoptosis interlock is necessary for a critical assessment of this risk.

This research is funded through a Marie Curie Reintegration grant from the EU.

Putative Serine proteases and apoptosis

Many chemotherapeutics exert their anti-cancer activity through the induction of programmed cell death or apoptosis. Much recent research into the mechanisms of apoptosis has identified new therapeutic targets within the apoptotic machinery and is driving the development of novel chemotherapeutics. Proteases, most notably the caspase cysteine proteases, are critical in the induction of apoptosis. However, roles for serine proteases have also been suggested based, in part, on the ability of protease inhibitors like N-a-tosyl-e-phenylalanine chloromethyl ketone (TPCK) to block apoptosis. Despite these data, the relevant target for TPCK has not been identified. Identifying this target is the first step in assessing whether it represents a valid target for cancer chemotherapy. The research aims to identify TPCK targets by a biochemical approach and then to test the roles of these candidates in apoptosis.

This research is funded through a project grant from the Cancer Research Ireland.

MicroRNAs, apoptosis and cancer

Breast cancers are phenotypically diverse, presumably reflecting a spectrum of distinct molecular defects in processes controlling cell proliferation and survival. This complexity makes breast cancer progression hard to predict and treatment difficult to manage.  Currently, clinicians rely heavily on the status of two receptors, the estrogen receptor and HER2/neu receptor for clinical decisions relating to prognosis and treatment.  These markers, while enormously valuable, do not adequately define different types of breast cancers or predict their sensitivity to therapy.  Improving breast cancer treatment will require identification of more molecules that control the proliferation and survival of breast cancer cells.

In recent years, many instances of post-transcriptional control of eukaryotic protein expression by non-coding micro RNA (miRNA) molecules have been identified. miRNAs are small (~21-25 nucleotide), highly conserved RNAs which bind specifically to the 3’-untranslated regions of target messenger RNAs (mRNAs) and prevent their translation.  Importantly, in mammalian cells this process can reduce protein levels without decreasing mRNA levels. These alterations would therefore not be detected by conventional RNA microarray analysis, as these provide estimates only of mRNA abundance without reference to translation.  Recent reports have indicated that miRNAs are key regulators of fundamental biological processes including cell proliferation and death, development and stem cell differentiation. Several recent high impact publications have demonstrated that determining relative miRNA levels is a powerful technique which has been instrumental in leading to an understanding of aspects of the regulation of important biological processes.

Genomic approaches have been employed to compare gene expression profiles in normal and cancer cells, but these expression patterns do not allow good discrimination between the two cell types. More recently, the patterns of microRNA expression in normal and cancer cells have been compared and observed to differentiate between non-tumour cell and tumour cell.  Subsequently, specific miRNAs were found to correlate with the stage of breast cancer.  Moreover, some of these miRNAs regulate genes that control cancer cell proliferation and survival, providing a mechanistic underpinning for the correlative studies.

Through a collaboration with Professor Michael Kerin, Professor of Surgery at NUI, Galway, the strategy is to use clinical cancer samples in a genomics-based approach to identify miRNAs associated with aspects of cancer biology.  More specifically to identify miRNAs associated with tumour stage and grade, with sensitivity or resistance to particular treatments or with a particular prognosis.  The identification of these miRNAs will drive both basic research through collaborations inside and outside of NUIG and also translational research aimed at developing diagnostic tools for cancer. The Breast Cancer Research group also headed by Professor of Surgery, Michael Kerin, maintains The Breast Cancer Tissue Bank.  This consists of matched non-tumour and tumour frozen tissue specimens from 200 patients and the associated detailed clinical histories.  This tissue bank and the accompanying clinical histories is an enormously valuable, and so far untapped, resource for Breast cancer research.

This research is funded through a Marie Curie Transfer of Knowledge grant from the EU and a grant from Enterprise Ireland.

Link to Recent Publications

Contact details

Email: howard.fearnheadnuigalway.ie

Tel: 00 353 91 495240, Ext. 5240

Fax: 00 353 91 495586

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