Section of Cell and Molecular Biology (including the Cancer Research UK Centre for Cell and Molecular Biology)

Scientific Overview

Introduction

The Section of Cell and Molecular Biology encompasses a wide range of activities, from studies of gene therapy of cancer to studies on the mechanism of protein folding.  This range of activities reflects the underlying approach of studying basic molecular and cell biology to underpin the identification of new strategies for cancer therapeutics.  Much of the work of the Section is devoted to the study of cancer genes such as the oncogenes Ras and B-RAF and the tumour suppressor genes Rb and TSC 1/2.  These studies on cancer genes are integrated with investigations on other cell signalling molecules such as phospholipase C.  Through studying these molecules and pathways we are identifying new targets for drug development.  In collaboration with the Cancer Research UK Centre for Cancer Therapeutics we are developing high throughput screens against cell cycle, cell invasion and signalling targets.

Highlights

• Identification of the role of ERK-MAPK in regulating Rock signalling during angiogenesis
• Demonstration that MAPK-ERK5 is involved in cell transformation
• Demonstration of redundancy between MRCK and ROCK signalling in controlling actomyosin contractility
• Gaining structural and mechanistic insights into ras association domains of phospholipase C epsilon
• Description of the systemic delivery of CPG2 and prodrug to provide the first description of fully targeted GDEPT.  (Schepelmann et al, Cancer Research 65:5003)
• Demonstration that the transcription factor MITF is anti-proliferative in melanomas with mutant B-RAF and that oncogenic B-RAF suppresses MITF expression to allow cells to proliferate (Wellbrock and Marais, JCB 170:703 2005)
• Rational explanation of why C-RAF and A-RAF are not mutated in cancer, demonstrating that it is due to a lack of charge in the N-region (Emuss et al, Cancer Research 65:9719 2005)
• Demonstration that B-RAF is an HSP90 client protein and therefore a target of the anti-cancer drug 17-AAG (da Rocha Dias et al, Cancer Research 65:10686 2005)
• Demonstration that B-RAF activates C-RAF through a mechanism that is distinct from the mechanism by which Ras activates C-RAF (Garnett et al, Molecular Cell 20:963 2005)
• Optimisation of ultrasound/microbubble-mediated gene delivery with respect to ultrasound exposure parameters, including characterisation of spatial localisation
• Achieved spatially-controlled retroviral gene delivery using defined ultrasound exposure conditions and gas-filled microbubble contrast agents, in particular using retroviruses that have deliberately been rendered non-infectious (patent filed)
• Characterisation of retroviral attachment to cells via incorporated heparan sulphate proteoglycan as a step preceding receptor interaction)
• Discovery that MYB is important for positive selection of CD4 single positive cells during T cell development
• Demonstration that the loss of MYB activity in oesophageal cancer cells results in apoptosis
• Demonstration that MYB can regulate expression of the histone variant H2A.Z in T cell development
• Successful achievement of a Rheb knock-out mouse
• Identification of novel kinase in mTOR signalling
• Determination of the structure of the Retinoblastoma protein N terminal domain.  This explained how mutations in this region lead to cancer and it provided a much needed tool to predict the oncogenic potential of sequence aberrations found in this region in cancer patients
• Identification of eIf2 alpha mediated translation control as an important pathway involved in transmitting stress signalling to the retinoblastoma protein
• Completion of in vitro and in vivo laboratory studies that have resulted in patient recruitment into a Phase I trial of human herpes simplex virus expressing GM-CSF plus radical chemo-radiotherapy in patients with stage III and IV head and neck cancer
• Demonstration of the cytotoxic effect of combining oncolytic reovirus with radiation in tumour cell lines in vitro and in vivo and subsequent translation of this work into a Phase I trial in the clinic
• Analysis of the effect of combining genetic radioisotopic therapy with external beam radiotherapy and novel radiosensitising agents

Future Aims

• Continue our studies on ERK-MAPK and Rho family GTPase signalling pathways in angiogenesis
• To determine how Rho family GTPases are activated in tumour cells
• Further our research into Ral signalling in tumour cells
• Study the control of PLC epsilon activity by multiple regulatory pathways
• Continue to progress mouse models of melanoma and inducible activation of B-RAF
• Further develop anti-B-RAF drugs in collaboration with the Wellcome Trust and CRT
• Continue to study C-RAF function in melanoma, in particular trying to determine how C-RAF mutants activate the kinase and the biological signalling from these mutants 
• Understand how MITF regulates the cell cycle of melanoma cells and how its expression is regulated by B-RAF
• Achieve localised gene delivery to tumours in vivo using ultrasound/microbubble technology
• Explore the use of molecularly-targeted microbubbles for ultrasound-mediated gene delivery
• Identify further transcription factors involved in lineage commitment in T cells
• Pursue how MYB might be regulating positive selection
• Set up screens to identify factors lying upstream and downstream of MYB in oesophageal cancer cells
• The characterisation of Rheb knock-out phenotype
• Identification of Rheb GEF
• Determine how the Retinoblastoma protein N terminus contributes to Retinoblastoma protein functioning
• Establish screens to identify signal transduction towards regulating retinoblastoma protein activity
• Continued patient recruitment into 4 ongoing trials of gene therapy/virotherapy in the Royal Marsden Hospital
• Progress towards opening a Cancer Research UK funded Phase I trial of virally-directed enzyme prodrug therapy using a selectively replication-competent adenovirus