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Project 1. Precision medicines for B-cell leukaemias
There is a plethora of new precision medicines 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 early phase clinical studies and may reduce or, in combination, even obviate the need for chemotherapy. Nevertheless, significant problems remain if these medicines are to be introduced into routine clinical practice in a rational and affordable manner. Firstly, precision medicines must be carefully matched in a mechanistic fashion with specific subtypes of disease. Functional assessment on viable primary malignant cells will be necessary using assays that faithfully mimic in vivo conditions. A second challenge is to define mechanism-based synergistic combinations associated with minimal toxicities rather than simply adding new precision medicines to existing chemotherapeutic regimens.  

We are following these approaches, in collaboration with Prof Martin Dyer's lab, to define novel personalized therapeutic strategies against B-cell malignancies that can be immediately applied in the clinic. For instance, we have recently studied the response of a patient with Hairy Cell Leukaemia to BRAF inhibitor vemurafenib (see figure), both from the clinical perspective and at a cellular and molecular level. 

Recent papers from this project:

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 MJ. Long-term follow-up of patients with CLL treated with the selective Bruton's tyrosine kinase inhibitor ONO/GS-4059. Blood. 2017 Apr 4. pii: blood-2017-02-765115. doi: 10.1182/blood-2017-02-765115.

Samuel J, Jayne S, Chen Y, Majid A, Wignall A, Wormull T, Najeeb H, Luo J, Jones GD, Macip S, Dyer MJ. Posttranscriptional upregulation of p53 by reactive oxygen species in chronic lymphocytic leukemia.Cancer Res. 2016 Sep 7. pii: canres.0843.2016.

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 Jul 29. doi: 10.1111/bjh.14285

Samuel J, Macip S, Dyer MJS. Efficacy of vemurafenib in hairy-cell leukemia. N Engl J Med. 2014 Jan 16;370(3):286-8.

Dyer MJS, Vogler M, Samuel J, Jayne S, Wagner S, Pritchard C and Macip S. Precision medicines for B-cell leukaemias and lymphomas; progress and potential pitfalls. Br J Haematol. 2013 Mar;160(6):725-33.

Project 2. Understanding the molecular mechanisms of ageing
Ageing is a biological process that affects all living creatures. Despite the scientific advances of the past decades, the mechanisms that lead to ageing in humans are not fully understood. Evidence suggests that accumulation of old cells in tissues plays a critical role in the appearance of the symptoms associated with age. Indeed, a recent experiment showed that if old cells are eliminated from tissues, fitness increases substantially. 

Our experiments on senescence (cellular ageing) will allow us to better understand why we age and also will provide the basis for new treatments that could be applied to slow down and improve ageing. We have already identified novel markers of senescence (see figure) that could be used to detect senescent cells in vivo and in vitro. Their expression correlates with better prognostic in certain cancers, which suggests they could be used clinically.

Recent papers from this project:

Althubiti M, Macip S. Detection of Senescent Cells by Extracellular Markers Using a Flow Cytometry-Based Approach. Methods Mol Biol. 2017;1534:147-153.

 

Althubiti M, Rada M, Samuel J, Escorsa JM, Najeeb H, Lee KG, Lam KP, Jones GD, Barlev NA, Macip S. BTK Modulates p53 Activity to Enhance Apoptotic and Senescent Responses.

Cancer Res. 2016 Sep 15;76(18):5405-14. doi: 10.1158/0008-5472.CAN-16-0690. Epub 2016 Jul 26.

 

Althubiti M, Lezina L, Carrera S, Jukes-Jones R, Giblett SM, Antonov A, Barlev N, Saldanha GS, Pritchard C, Cain K and Macip S. Characterization of novel markers of senescence and their prognostic potential in cancer. Cell Death Dis. 2014 Nov 20;5:e1528. doi: 10.1038/cddis.2014.489.

Project 3. Modulators, effectors and functions of the p53 tumour supressor pathway

Apoptosis and senescence have been identified as the two principal mechanisms by which p53 exerts its tumour suppressor capabilities. We and others have shown that the cellular responses to p53 expression can be modulated by a wide range of factors, including reactive oxygen species (ROS), the vitamin A (retinoic acid) pathway and pro-survival signals induced by p53 itself. Thus, identifying new pathways that contribute to p53 functions should help understand its antineoplastic mechanisms and hopefully lead to new therapies.

We study the p53 pathway at several levels (see figure below). We are characterising novel p53 target genes that will help us to better understand the cellular effects of p53. This is leading to the identification of new p53 functions beyond its classic antineoplastic activity. We also investigate how cell fate decisions after p53 activation can be modulated, with special interest in the mechanisms involved in senescence (see Project 2).

We are currently exploring how oxygen tension and reactive oxygen species can contribute or interfere with the p53 response. Of special interest is the crosstalk between the p53 and the retinoic acid pathway, which we have found may play an important role in p53 functions.

p53 pathway

Recent papers from this project:
Rada M, Vasileva E, Lezina L, Marouco D, Antonov AV, Macip S, Melino G, Barlev NA. Human EHMT2/G9a activates p53 through methylation-independent mechanism 2016 Jul 25. doi: 10.1038/onc.2016.258.

Carrera S, Senra J, Acosta MI, Althubiti M, Hammond EM, de Verdier PJ, Macip S. The role of the HIF-1 alpha transcription factor in increased cell division at physiological oxygen tensions. PLoS One. 2014 May 16;9(5):e97938.

Carrera S, Cuadrado-Castano S, Samuel J, Jones GD, Villar E, Lee SW, Macip S. Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage. Cell Death Differ. 2013 Jul;20(7):910-9.

Masgras I, Carrera S, de Verdier PJ, Brennan P, Majid A, Makhtar W, Tulchinsky E, Jones GD, Roninson IB, Macip S. Reactive oxygen species and mitochondrial sensitivity to oxidative stress determine induction of cancer cell death by p21. J Biol Chem. 2012 Mar 23;287(13):9845-54.


Carrera S, de Verdier PJ, Khan Z, Zhao B, Mahale A, Bowman KJ, Zainol M, Jones GD, Lee SW, Aaronson SA, Macip S. Protection of cells in physiological oxygen tensions against DNA damage-induced apoptosis. J Biol Chem. 2010 Mar 12.

Project 4. Genetic determinants of endometrial cancer prognosis.