EACR Travel Fellowships are co-sponsored by Worldwide Cancer Research and provide funds up to €3,000 to early-career cancer researchers. For more information on how to apply for Travel Fellowships, you can visit the EACR website.
Home Institution: Royal College of Surgeons in Ireland, Dublin, Ireland
Host Institution: Center for Medical Genetics, Ghent University, Ghent, Belgium
Date of the visit: 06 September 2017 – 14 September 2017
I recently started the second year of my postgraduate studies under the supervision of Dr. T. Ni Chonghaile at Royal College of Surgeons in Dublin, Ireland. My research project is focused on determining the effects of distinct tumour microenvironments on the anti-apoptotic BCL-2 dependence of T-cell acute lymphoblastic leukaemia (T-ALL). T-ALL is a hematologic malignancy resulting from the transformation of T-cell progenitors.
Despite the improvements in the combined chemotherapeutic protocols, the outcome of T-ALL for patients with primary resistant or relapsed leukaemia, accounting for ~15% of paediatric and 50% of adult cases, remains poor.
Early T-cell progenitor ALL (ETP-ALL) is a subgroup accounting for 5% to 10% of T-ALL cases and is associated with a poor prognosis and a very high risk of relapse. Recently Dr. T. Ni Chonghaile and Dr. P. Van Vlierberghe’s group have demonstrated that ETP-ALL is dependent on the anti-apoptotic protein BCL-2 for survival and sensitive to inhibition with the BH3 mimetic ABT-199. BH3 mimetics are small molecules with drug-like properties that have been developed to target the hydrophobic groove of pro-survival Bcl-2 proteins, and induce apoptosis. BH3 mimetic ABT-199 is a selective BCL-2 inhibitor and has the potential to be a powerful drug in the clinic, showing promising results in the treatment of chronic lymphocytic leukemia. Recently we have established a collaboration with Dr. P. Van Vlierberghe’s group to assess the in vivo mechanisms of ABT-199 resistance in a murine xenograft model of ETP –ALL using BH3 profiling. Dr. P. Van Vlierberghe’s lab have developed several T-cell acute lymphoblastic leukaemia mouse models to study novel therapeutics pre-clinically.
To study the development of resistance and the involvement of the surrounding tumour microenvironment, we plan to perform BH3 profiling on samples isolated from the xenograft animal model following two weeks of in vivo treatment. BH3 profiling is a tool developed to study the interaction between BCL-2 family proteins. It is a functional assay that measures the response of mitochondria to the exposure of known concentrations of synthetic BH3 peptides by measuring loss of mitochondrial membrane potential or cytochrome c release. The synthetic BH3 peptides have preferential binding for different anti-apoptotic proteins and therefore, distinct anti-apoptotic dependencies can be identified. BH3 profiling has been shown to be a powerful predictor biomarker of cellular response to BH3 mimetics and chemotherapeutics.
This was a valuable opportunity for my early career development and an enriching personal experience.
I visited the lab of Professor Pieter Van Vlierberghe from the 6th to the 14th of September 2017 to follow up the phase of in vivo drug treatment. The primary aim of my visit was to undertake short technical training in xenograft animal models, giving me the opportunity to gain experience in bioluminescence imaging, tail bleeding and the oral gavage procedures.
The time I spent in Prof. Van Vlierberghe’s lab has advanced my technical skill set and I now have experience in working with mouse models, which we will be essential as the project progresses. It was a pleasure to work with talented scientists in this stimulating scientific environment, where I had the opportunity to discuss my research with an expert in the field.
This was a valuable opportunity for my early career development and an enriching personal experience. I am incredibly grateful to be awarded an EACR Travel Fellowship that made it possible for this visit to happen. I would also like to thank Professor Pieter Van Vlierberghe for hosting me and Dr. Sofie Piers for introducing me to the in vivo research work.
