Dr Michael Tilby
Senior Lecturer in Molecular Pharmacology

  • Email: michael.tilby@ncl.ac.uk
  • Telephone: +44 (0) 191 208 4419
  • Fax: +44 (0) 191 208 4301
  • Address: Northern Institute for Cancer Research
    Paul O'Gorman Building
    Medical School
    Framlington Place
    Newcastle upon Tyne
    NE2 4HH

Introduction

My research focusses opon the mechanism of action of
anticancer drugs that act through causing damage to DNA. A particularly significant aspect of these activities has been to develop and apply methods that permit analysis of drug action in patients undergoing therapy. There is very little information of this nature available because appropriate techniques have not been available.

Background

Having gradutaed in Botany, I pursued a PhD in microbial genetics. This was followed by a post-doc in which I developed methods for the study of ageing in the nematode C.elegans, including initiation and maintanence of age synchrony. An interest in morphogenesis took me to a post-doc post in the Max-Planck Institute (Tuebingen) working on bacterial morphogenesis. Several years working on effects of ionising radiation at the Institute for Cancer Research (London) developed into my current long-standing research interest of the mechanism of action of DNA damaging anti-cancer drugs.

Roles and Responsibilities

I played a major role in the design and construction phase of the Paul O'Gorman Building as the persaon responsible for detailed co-ordination of user requirements with the design team of architects, consultant engineers and constructors. I now retain an ongoing responsibility for overseeing certain key equipment installations.

Qualifications

BSc (London) 1st class honours degree in Botany.
PhD (London) In microbial genetics.

Previous Positions

Senior Research Associate, Department of Haematology Newcastle University
Scientist, Institute of Cancer Research, Surrey.
Research Associate, Max-Planck Institut fur Biologie, Tuebingen, Germany.
Post-doctoral post, University of London.

Research Interests

The mechanism of action of anticancer drugs that act through causing damage to DNA.

These drugs play a very important role in many current chemotherapy protocols. Little is understood about why treatment of some patients / tumours is successful while others show varying extents of treatment failure. A priori it is clear that differences in responses of individual tumours and different tumour types to treatment can result from variation in:
1. The extent of drug-DNA access,
2. The nature/location of drug-induced DNA modifications.
3. The ways that tumour cells respond to the damage.

In general, factors 1 and 2 have received relatively little attention. My work has focussed on the quantification of drug-DNA modifications, on the nature of the modifications and, more recently, on the distribution of the modifications in the genome.

A particular goal has been to study the drug-DNA interactions that occur in actual clinical tissues and this has entailed the development of a number of techniques for the quantification of clinically relevant levels of DNA modification. Such levels are very low (e.g. 1 modified base per million bases) and therefore challenging to quantify.

Techniques that we have developed include the creation and application of monoclonal antibodies that specifically recognise certain types of drug-induced DNA modifications.

Novel immunological techniques developed include:
1. Sensitive immunoassays for drug-DNA adducts based on
monoclonal antibodies.
2. The TARDIS method for quantification of DNA modifications
in individual cells using sensitive fluorescence microscopy.
3. Analysis of drug-induced modifications on immobilised DNA fragments.

Platinum-based drugs
Several very important anti-cancer drugs are derivatives of platinum. We are collaborating with geochemists at Durham (the group of Dr. DG Pearson) who have expertise in the analysis of trace quantities of platinum in geological samples. The mass spectrometric techniques that they employ provide new highly sensitive ways to detect small quantities of drug-modified sites on DNA and establishing this collaboration has dramatically extended the methodolg and possibilities for investiagtions of these drugs at the molecular level.

In addition to the contuing importance of DNA-inerative drugs in their own right, these agents are the focus of much current interest in relation to combining them with newer drugs which have been developed to either (a). specifically modulate the cells ability to repair or respond to the DNA damage, or (b). to affect tumour growth in other ways. In both cases it is important to understand how best to combine the two classes of drug and to monitor the effects of new drug combinations at the molecular level in clinical trials. Achieveing these goals requires an understanding of basic mechanisms and the availbility of techniques to permit appropriate clinical studies.

Other Expertise

Low light level immunofluorescence microscopy and image analysis.
Development of sensitive immunoassays.
Chromatographic and immunological techniques for analysis of DNA modifications.
Radiobiology – radiation dosimetry etc.

Current Work

1. Characterisation of new classes of DNA modifications induced in cells by platinum-based drugs.

2. Analysis of levels of DNA modifications formed in biopsies of human solid tumours removed during therapy.
(Virtulally no information is available about the levels of DNA modification in tumour tissues that are actually achieved during therapy. The way that cells respond to damage will depend very much on the magnitude of these levels and it is clear that much current research is based on damage levels far above the realms of clinical reality).

3. The combination of DNA damaging agents with newer targetted drugs that modulate cell response to damage.

Future Research

To determine whether DNA damage is formed and / or repaired to different extents in different major regions of the human genome.

Postgraduate Supervision

3 current students.

Undergraduate Teaching

BMS3008 Integrated Biomedical Sciences - Module Leader.

BGM 324 and BMS305 Cancer Biology and Therapy. 4 lectures on: 1. Carcinogenesis, 2. Therapy with cytotoxic agents, 3. Mechanisms of resistance to therapy and apoptosis, 4. Treatments that exploit tumour-specific chracteristics.

PED 306 1 lecture on anti-cancer drugs acting on DNA topoisomerases.

PED102 1 lecture on "Principles of selective toxicity" regarding antimicrobial and anti-cancer drugs.

Postgraduate Teaching

Supervison currently of 3 PhD students + 1 MSc research student.