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Author Castellví Domingo, Cecília |
Abstract Peripheral T-cell lymphoma (PTCL) is a group of lymphomas derived from mature T and NK cells, usually associated with an aggressive clinical course, dismal survival and poor responses to chemotherapy for which effective treatments are not available yet. Novel therapies focus on the development of small molecules targeting epigenetic modifiers, different signalling cascade inhibitors, and immunotherapy. Multiple data point towards a central role of T-cell receptor (TCR) signalling in the biology of these lymphomas. ZAP-70, a tyrosine kinase protein belonging to the Syk /ZAP-70 family expressed in T lymphocytes and in NK cells, is an essential kinase in the proximal signalling of the TCR. The hypothesis of this project is that the pharmacological inhibition of ZAP-70 could modify tumour growth and, therefore, it could be an interesting approach to treat PTCL. To validate this hypothesis, the main objective of this project is to study the therapeutic potential of blocking TCR signalling by the specific inhibition of ZAP-70 in malignant T cells. The effect of novel ZAP-70 inhibitors on malignant T cells survival, proliferation and TCR signalling were evaluated. IQS117 and IQS141 were selected as the most selective ZAP-70 inhibitors in a previous kinase inhibition panel against other 26 kinases. IQS117 inhibited ZAP-70 more specifically than IQS141. The effect of IQS117 and IQS141 on the proliferation and viability of malignant B- and T-cells suggested that ZAP-70 inhibition did not seem to be sufficient to inhibit BCR signalling on ZAP-70 transfected malignant B-cells. However, ZAP-70 inhibition on T cells decreased malignant T cells proliferation and survival in all 3 cell lines. To evaluate the effect of ZAP-70 inhibitors on TCR signalling, the optimization of the intracellular flow cytometry (ICFC) was also carried out. These results suggest that targeting ZAP-70 is an interesting approach to treat several subtypes of PTCL. |
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Director Fornaguera i Puigvert, Cristina |
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Degree IQS SE - Undergraduate Program in Biotechnology |
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Date 2021-06-21
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