Research

 

Lab Home Page (external link). Click here for more information on the Mechanisms of Cancer and Ageing Lab.

 

The following projects are currently ongoing in Salvador Macip's lab:

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 thse approaches, in cooperation 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, both from the clinical perspective and at a cellular and molecular level (N Engl J Med. 2014 Jan 16;370(3):286-8.).

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. 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 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.

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

Figure 1

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Contact Details

Department of Molecular and Cell Biology
Henry Wellcome Building
Lancaster Road
Leicester
LE1 7RH (Postal)

LE1 7HB (Sat Nav/Online maps)

T:  +44(0)116 229 7038
F:  +44(0)116 229 7123
MolCellBiol@le.ac.uk

Redfearn Lecture 2017

To Be Confirmed