Dr. Tony Mc Elligott

Chronic Lymphocytic leukaemia (CLL) is an incurable B-lymphoid malignancy accounting for 38% of leukaemias in the western world. CLL has a variable clinical course due differences in underlying genetic lesions, degree of clonal evolution, activated signalling pathways and interaction with the microenvironment within lymph nodes and the bone marrow. The aim of this project is to assess the functional impact of NOTCH1 mutations in CLL by utilizing in vitro micro-environment models to analyse aberrant signalling pathways in NOTCH1 mutated cells, allowing the determination of potential 'precision medicine' strategies for these patients.

This collaborative study between Trinity, St James's Hospital and Legend Biotech is to utilize blood cancer patient samples for the purpose of building 3D ex-vivo modelling platforms suitable for validation of anti-cancer therapeutics, including cellular therapies. Single cell genetic profiling will determine the critical factors of the tumour microenvironment that hinder therapies. This project will identify tumour-specific targets that are most likely to be successful in a clinical setting and will assist in the validation of tumour targets by utilising the 3D platforms to screen therapies.

Multiple myeloma is a plasma cell malignancy that accounts for around 10% of all haematological cancers. It remains generally incurable, with most patients experiencing relapse after first-line treatment. In the EU, MM incidence is projected to increase from 35,000 new cases per annum to over 43,000 by 2030 whilst deaths due to MM are also projected to increase. Therefore new drugs are urgently required to improve the anti-myeloma arsenal. Aberrant activation of a number of oncogenic signalling pathways in myeloma leads to cell growth and survival, as well as to angiogenesis and to the development of drug resistance. Targeting one or more of these pathways is therefore a promising anti-MM strategy. We have recently designed and synthesized novel guanidinium compounds which have demonstrated anti-tumour activity in myeloma. A lead compound VP79s has been identified and its ability to induce apoptosis and to target oncogenic signalling pathways in MM including the STAT3 pathway has been examined. VP79s potently reduced the viability of drug resistant and sensitive MM cell lines through induction of apoptosis. Importantly, VP79s rapidly inhibited both constitutive and IL-6 induced STAT3 activation and, consequently, decreased expression of STAT3-mediated anti-apoptotic gene products, Mcl-1 and survivin. In conclusion, the novel compound VP79s can target dysregulated STAT3 activation and induce apoptosis in myeloma cells in vitro, suggesting its potential as a novel anti-cancer therapeutic which can overcome tumour microenvironment induced resistance. Identification and development of novel drugs that can target STAT3 remains an important scientific and clinical challenge.

Blood Cancer Network Ireland (BCNI) is a national clinical research network that benefits blood cancer patients in Ireland. BCNI offers early stage clinical trials to blood cancer patients, a biobank of blood cancer patient material and a blood cancer registry. This biobank of clinically and molecularly annotated patient material (RNA, DNA and cryopreserved cells) allows us to perform high quality clinical and translational research and allows us to collaborate with groups investigating novel therapeutic agents and immunotherapy strategies.

Fungal secondary metabolites represent a diverse array of natural products, and bioactive compounds from these organisms have yielded some of the most important natural products for the pharmaceutical industry. Genome sequencing projects have revealed that fungi are rich in biosynthethic clusters that direct the synthesis of these secondary metabolites. R. emersonii is a thermophilic ascomycete that represents a reservoir of undiscovered bioactive compounds. This project seeks to investigate the therapeutic potential of secondary metabolites isolated from R. emersonii. A two-pronged approach will be adopted, employing functional genomics and a laboratory scale screening programme. Initially, the project is designed as a two year master's programme. However, given the huge diversity and structural types of known fungal secondary metabolites and the fact that more and more are continually being discovered, it is highly likely that R. emersonii will produce an array of secondary metabolite products. Thus, the potential for this project to continue to a PhD programme is extremely promising.