|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
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.
papers from this project:
Chen Y, Peubez C, Jayne S, Kocsis-Fodor G, Dyer MJS, Macip S. Differential activation of pro-survival pathways in response to CD40LG/IL4 stimulation in chronic lymphocytic leukaemia cells. Br J Haematol. 2018 Apr 20. doi: 10.1111/bjh.15197.
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.
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
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.
papers from this project:
Ekpenyong-Akiba AE, Canfarotta F, Abd B, Poblocka M, Casulleras M, Castilla-Vallmanya L, Kocsis-Fodor G, Kelly ME, Janus J, Althubiti M, Macip S. Detecting and targeting senescent cells using molecularly imprinted nanoparticles. Nanoscale Horizons 4(3):757-768 01 May 2019Tabasso AFS, Jones DJL, Jones GDD, Macip S. Radiotherapy-Induced Senescence and its Effects on Responses to Treatment. Clin Oncol (R Coll Radiol). 2019 May;31(5):283-289.
Rada M, Barlev N, Macip S. BTK: a two-faced effector in cancer and tumour suppression. Cell Death Dis. 2018 Oct 18;9(11):1064. doi: 10.1038/s41419-018-1122-8.
Rada M, Barlev N, Macip S. BTK modulates p73 activity to induce
apoptosis independently of p53. Cell Death Discov. 2018 Sep 11;5:30.
doi: 10.1038/s41420-018-0097-7 .
Rada M, Althubiti M, Ekpenyong-Akiba AE, Lee KG, Lam KP, Fedorova O, Barlev NA, Macip S. BTK blocks the inhibitory effects of MDM2 on p53 activity. Oncotarget. 2017 Nov 20;8(63):106639-106647. doi: 10.18632/oncotarget.22543.
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.
|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.
papers from this project:
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.
Recent papers from this project:
Guttery DS, Blighe K, Polymeros K, Symonds RP, Macip S, Moss EL. Racial differences in endometrial cancer molecular portraits in The Cancer Genome Atlas. Oncotarget. 2018 Mar 30;9(24):17093-17103. doi: 10.18632/oncotarget.24907