About the Project
In this project, we propose to look for novel therapies for B-cell leukaemias and lymphomas in a translational and mechanistic fashion. There are many therapies for B-cell malignancy, including ‘classical’ kinase inhibitors, rationally designed inhibitors of anti-apoptotic proteins and antibody or antibody drug/toxin conjugates with functional properties. Some are showing spectacular single agent activity in clinical studies. Nevertheless, significant problems remain if these medicines are to be introduced into routine clinical practice in a rational and affordable manner. We will use functional assessment on primary malignant cells and mouse models that faithfully mimic in these diseases. We will focus on the p53 and MAPK pathways, among others, and we will study the mechanisms involved in drug sensitivity and resistance. We hope to define mechanism-based synergistic combinations associated with minimal toxicities, taking advantage of a closer interaction between academic and clinical medicine, thus changing how patients with B-cell malignancies are currently managed.
References
Chen Y, Germano S, Shelmani G, Kluczna D, Jayne S, Dyer MJS, Macip S. Paradoxical activation of alternative pro-survival pathways determines resistance to MEK inhibitors in chronic lymphocytic leukaemia. Br J Haematol. 2017 Aug 2. doi: 10.1111/bjh.14880. [Epub ahead of print] No abstract available.
Walter HS, Jayne S, Rule SA, Cartron G, Morschhauser F, Macip S, Karlin L, Jones C, Herbaux C, Quittet P, Shah N, Hutchinson CV, Fegan C, Yang Y, Mitra S, Salles G, Dyer MJS. Long-term follow-up of patients with CLL treated with the selective Bruton's tyrosine kinase inhibitor ONO/GS-4059.
Blood. 2017 May 18;129(20):2808-2810. doi: 10.1182/blood-2017-02-765115.
Samuel J, Jayne S, Chen Y, Majid A, Wignall A, Wormull T, Najeeb H, Luo JL, Jones GD, Macip S, Dyer MJ. Posttranscriptional Upregulation of p53 by Reactive Oxygen Species in Chronic Lymphocytic Leukemia. Cancer Res. 2016 Nov 1;76(21):6311-6319. Epub 2016 Sep 7.
Chen Y, Germano S, Clements C, Samuel J, Shelmani G, Jayne S, Dyer MJ, Macip S. Pro-survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia. Br J Haematol. 2016 Nov;175(4):641-651.
Samuel J, Macip S, Dyer MJ. Efficacy of vemurafenib in hairy-cell leukemia. N Engl J Med. 2014 Jan 16;370(3):286-8. doi: 10.1056/NEJMc1310849.
Dyer MJ, Vogler M, Samuel J, Jayne S, Wagner S, Pritchard C, Macip S. Precision medicines for B-cell leukaemias and lymphomas; progress and potential pitfalls. Br J Haematol. 2013 Mar;160(6):725-33. doi: 10.1111/bjh.12219.
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