Chemosensitizing Non-Hodgkin Lymphoma cells with protein synthesis inhibitors

A problem presented at the UK MMSG Nottingham 2006.

Presented by:
Prof Anne Willis (School of Pharmacy, University of Nottingham)
J King, A Lamb, G Mirams, P Murray, J Perez-Velazquez, A Willis

Problem Description

Non-Hodgkin lymphomas (NHL) comprise at least thirty distinct subtypes of B and T cell malignancies although over 90% of NHL are of B cell origin. At present NHL account for 2.6% of all cancer deaths in England and Wales and the incidence is increasing by approximately 5% per year, although reasons for this increase are unknown.

Experimental data suggest that in NHL cells there are changes that would lead to an up-regulation of anti-apoptotic proteins, down regulation of pro-apoptotic signals, and up-regulation of proteins involved in cell adhesion. Chemicals that inhibit translational initiation include inhibitors of p38Mapkinase pathways (e.g. SB203580), ERK pathway (e.g. PD98059) and FRAP/mTOR pathway (e.g. Rapamycin and Wortmanin). We present a mathematical model of the signalling pathways associated with capped translation and use the model to predict whether it is possible to use translational inhibitors to chemosensitise NHL cells. We wish to determine whether it is possible to alter the expression of the anti-/pro-apoptotic mRNAs by treating NHL cell lines with these inhibitors.

Download the full problem description

Study Group Report

One of the initial motivations to write down a mathematical model was to establish if blocking signalling through translation inhibition may lead to control of NHL cells, the simulation results show that indeed the addition of drugs to the NHL-cell model reduces the capped translation to a healthy-cell level, with Rapamycin being the most eective individual drug for the given parameters. The model also predicts that capped translation in healthy cells can fall below the level of uncapped translation when growth factors are removed, leading to apoptosis. Furthermore, the model suggests that untreated NHL cells will always have an excess of capped translation and can therefore no longer undergo apoptosis.

Download the full report