Research Collaborators
Department of Chemistry
Prof Steven Ley CBE, FRS, FMedSci (Ley Group Website)
The main focus of our research is developing new synthetic methods and applying them to the synthesis
of biologically and pharmacologically important molecules. The development of rigorous synthesis and
analytical skills is expected from all students. We are currently working with a number of collaborators
from the programme in the areas of antiangiogenesis, antivascular research and the development of new
antimitotic drug leads derived from natural sources.
PhD Students:
Charlotte Sutherell (Developing small molecule bromodomain probes to aid the study of ovarian cancer)
Ciorsdaidh Watts (Synthesis and Biological Evaluation of Selective Allosteric Inhibitors of the Kinesin Motor Protein, HSET )
Danny Allwood (Combating Chemoresistance in Glioblastoma: Interaction of Small Molecules with the Direct Reversal DNA Repair Pathway)
Tom Beale (Novel Antiangiogenic and Antimitotic Agents Inspired by Natural Products)
James Shearman (Disrupting Cellular Microtubules: Synthesis and Biological Investigation of Novel Antimitotic Agents)
Lab Rotation Students:
Lily Chan (2010/2011)
Ciorsdaidh Watts (2009/2010)
Danny Allwood (2008/2009)
Tom Beale (2007/2008)
Prof Ian Paterson FRS (Paterson Group Website)
Our research is focussed on the design and synthesis of novel antimitotic agents, based on natural product
leads, for biological evaluation, conformational analysis and studies of their protein-binding interactions.
We collaborate with cancer biologists and molecular biophysicists, with expertise in microtubule
dynamics and the analysis of protein-ligand interactions. Strong links have been built up with the
pharmaceutical industry in the oncology field, for example by our developing a practical total synthesis of
discodermolide (Novartis) that enabled its progression into clinical trials. Our research into new tubulin
binding agents is focussed on the discovery and development of novel microtubule-stabilising agents
(MSA) as new generation anti-cancer drugs. Analogues and hybrids of known natural MSAdiscodermolide,
dictyostatin, laulimalide and peloruside have been designed, synthesised and will be
evaluated as antiproliferative agents against a panel of cancer cell lines. The molecular basis of their
interactions with tubulin and microtubules will also be investigated. Microfilaments play an important
role in cell division and metastasis, yet represent a relatively undeveloped target for cancer therapeutics.
This project is focussed on the design and synthesis of structurally simplified analogues of the actinbinding
natural products swinholide and reidispongiolide that are potent antimitotic agents.
Lab Rotation Students:
Martin Bachman (2010/2011)
Rhian Holvey (2009/2010)
Christopher Stubbs (2008/2009)
Henning Stöckmann (2007/2008)
Samantha Cheung (2006/2007)
Prof Shankar Balasubramanian (Balasubramanian Group Website)
Nucleic acids are fundamental to cancer biology and serve as a
molecular target for most of the cancer therapeutic approaches practiced today.
Our research is focused
on the structure, function and recognition of DNA and RNA motifs that are of particular relevance to
cancer biology. We employ an integrated, interdisciplinary approach that involves synthetic chemistry
and structure-based ligand design, in addition to molecular biophysics and cancer biology. We are
interested in quadruplexes and telomerase.
PhD Students:
Olivia Walker (Investigating the interplay between a cell’s enzymatic, epigenetic and metabolic state in cancer progression)
Martin Bachman (Novel DNA Modifications and Epigenetic Processes in Cancer Progression and Metastasis)
Liang Wu (New Approaches in Epigenetic Therapy: non-coding RNA as a Target for Polycomb Inhibition )
Andrew Lewis (Unravelling Uncinatone: Piecing Together the Clues Towards a Potential Topoisomerase II Inhibitor)
Helen Lightfoot (Enhancing the Tumour Suppresser Properties of Let-7 using Small Molecules)
Lab Rotation Students:
James Sipthorp (2012/2013)
Olivia Walker (2011/2012)
Liang Wu (2009/2010)
Andrew Lewis (2008/2009)
Helen Lightfoot (2007/2008)
James Shearman (2006/2007)
Prof Chris Abell (Abell Group Website)
Chris Abell is interested in biological and synthetic chemistry, with a particular focus on enzyme mechanism, structure and inhibition. He has published extensively on enzymes in the shikimate and pantothenate pathways, and more recently has become interested in several cancer-related targets. In 1999 he co-founded Astex Therapeutics, a leading company in the area of fragment-based drug discovery. Chris is now collaborating with Professor Tom Blundell and Professor Ashok Venkitaraman to use the fragment-based approaches to find small molecules that disrupt protein-protein interactions involved in cancer. This research is within the Cambridge Molecular Therapeutics Programme.
PhD Students:
Rhian Holvey (Fragment Based Design of Inhibitors of the TPX2 – Importin-α Interaction)
Christopher Stubbs (Allosteric Polo-like Kinase 1 Inhibitors: A Fragment-Based Approach)
Lab Rotation Students:
Matthew Cornwell (2012/2013)
Matthew Rowland (2011/2012)
Prof Jeremy Sanders FRS (Sanders Group Website)
We are interested in molecular recognition, aiming to uncover and exploit the rules governing non-covalent interactions. Hydrophobic, π–π, donor–acceptor, metal– ligand and hydrogen bonding interactions are used to create new supramolecular systems that may have useful recognition, catalytic or photophysical properties. Our building blocks include peptides and metalloporphyrins, and our products include macrocycles, rotaxanes, catenanes and nanotubes. Inspired by the mammalian immune system, we developed the idea of dynamic combinatorial chemistry. We create a mixture of building blocks and combine them using bond-forming reactions under thermodynamic equilibrating conditions. Despite the complexity of the reaction mixture, the optimum structure — which may be unpredictable — will be formed and can be isolated and identified. We can use templates to direct the formation of their best possible receptor, or we can use self-templating to create the optimum folded structure. Shown above is the synthesis of a "catenane": this unpredictable but fascinating structure consists of two interlocked rings that are not covalently connected. We have recently discovered a new class of supramolecular nanotubes that bind C60 and and ammonium ion pairs, and that may also have other interesting properties.
PhD Students:
Yelena Wainman (Developing Novel Chemical Probes for Molecular Imaging of Glycans in Cancer)
Dr David Spring (Spring Group Website)
Three approaches are used by our group to discover new lead compounds: 1) phenotypic screening of
structurally diverse drug-like small molecules synthesised by diversity oriented synthesis, 2) in silico
screening of compound databases on anti-cancer protein targets with structural information available, and
3) modification of natural products with anti-cancer properties. Initial leads will be optimised with highthroughput
chemistry to explore structure activity relationships. Our research is focussed on combining synthetic organic chemistry with cancer biology and medicine, inventing new technology where
necessary. In recent years a great deal of effort has been expended in trying to develop technologies that
would allow one to inhibit protein-protein interactions in cell signalling pathways. These have met with
very limited success. Instead, our aim is to develop a novel approach to altering cellular signalling, by
stabilizing protein complexes. The potential feasibility and utility of this approach is clearly based on
evidence from nature, where there are now several examples of small molecules - typically natural
products - that function by stabilizing protein interactions.
PhD Students:
David Russell (Design and synthesis of deguelin-inspired multi-target drugs to combat prostate cancer)
Matej Janecek (Genetic Instability and Cancer: Inhibiting Protein – Protein Interactions of Aurora Kinase A and TPX2)
Luca Laraia (Phenotypic screening of diverse chemical libraries identifies molecules which can disrupt mitosis for cancer therapy)
Samantha Cheung (Using Chemical Genetics to Dissect the Role of Signalling Enzymes in Drug-Resistant Prostate Cancer)
Lab Rotation Students:
Mareike Wiedmann (2012/2013)
David Russell (2011/2012)
Matej Janecek (2010/2011)
Luca Laraia (2009/2010)
Dr Sophie Jackson (Jackson Group Website)
Molecular chaperones are a large class of proteins that facilitate the folding, assembly and maturation of many cellular proteins. Under stress, cells over-express
molecular chaperones known to be up-regulated in many cancers. Hsp90, is a major cytosolic chaperone
which acts on a subset of cellular proteins (known collectively as client proteins) many of which are
involved in signal transduction processes and which are known to be over-expressed in cancers.
Disruption of Hsp90 activity leads to the accumulation and degradation of inactive forms of the client
proteins, and inhibitors of Hsp90 are performing well in Phase I and II clinical trials. Our research is
focussed on the structure, function and regulation of a group of molecular chaperones centred around
Hsp90 which form the cellular 'assembly machine'.
Lab Rotation Students:
David Russell (2011/2012)
Christopher Stubbs (2008/2009)
Henning Stöckmann (2007/2008)
Dr Laura Itzhaki (Itzhaki Group Website)
Our group is interested in the structural principles underlying the network of interactions in multi-protein
complexes in cell cycle control and targeted protein degradation. We are also exploring the structural
mechanisms of protein malfunction in cancer and diseases of protein misfolding and aggregation. We are
studying the mechanism of function of a multi-subunit protein complex, SCFSkp2, that attaches ubiquitin
protein molecules to a substrate protein, leading to the degradation of the substrate by the proteasome.
Certain substrates of SCFSkp2 are critical negative regulators of the cell cycle and their levels are altered in human cancers. Using the structural information that we have obtained, the aims will be to develop and
evaluate inhibitors of this enzyme. We have shown that many mis-sense mutations in the breast cancer
susceptibility protein BRCA1 cause loss of function by destabilising the protein's structure and leading to
the formation of misfolded states. Experiments will be undertaken, using a range of spectroscopic
techniques, to evaluate whether small molecules can be used to rescue these mis-sense mutations by
stabilising the native structure of the protein and restoring its function.
Dr Alessio Ciulli (Ciulli Group Website)
The goal of our research is to understand and exploit complex biological phenomena by means of carefully designed small molecule chemical probes. We are particularly interested in investigating "druggability" and structure-function relationships of protein interfaces within multi-subunit and multi-domain macromolecular complexes. These protein-protein interactions are often dictated by specific post-translational modifications (PTMs) of amino acids, thereby expanding Nature's arsenal of biomolecular recognition and regulatory mechanisms. Our chemical approaches are strongly guided by structural information we and others obtain using protein X-ray crystallographic and NMR spectroscopy. We further interrogate selectivity and hot spots of small molecule binding using biophysical techniques and fragment-based approaches.
We are currently focusing studies on two biological areas: (a) multi-subunit E3 ubiquitin ligases involved in protein degradation and homeostasis; and (b) multi-domain "readers" of epigenetic marks on histones. Protein-protein interactions of interest in both areas are implicated in a wide variety of diseases including cancer, and represent attractive new targets for drug discovery.
Lab Rotation Students:
Charlotte Sutherell (2011/2012)
Prof Jane Clarke (Clarke Group Website)
Description
Dr Paul Barker (Barker Group Website)
The structure of DNA is manipulated in biology through a variety of mechanisms involving protein and small
molecule binding. The energetics of these processes are poorly understood. By examining the structure,
dynamics and single molecule mechanics of protein DNA complexes we can begin to understand the
forces involved in DNA deformation and the processes that lead to DNA damage and DNA repair. The
MerR class of transcription factors bind tightly to DNA and deform it through twisting. This grip on
DNA is released by binding of the activator signal in vivo, which can be a metal ion (e.g. Hg2+, Cu2+,
Zn2+) or small drug molecules. We will examine by NMR the structure and dynamics of protein DNA
interaction and will use probe microscopy and other single molecule methods to measure the forces
exerted on the DNA. The effect of, for example, platinum drug binding on the mechanics of DNA
deformation will be probed.
PhD Students:
Simon Page (Augmenting Ligand Efficiency: Exploiting the Properties of Heavy Metals in Medicinal Chemistry)
Lab Rotation Students:
Simon Page (2008/2009)
Dr Matthew Gaunt (Gaunt Group Website)
We are pioneering the assembly of biologically important and structurally complex molecules using a
cascade strategy that enables the generation of the desired molecular architecture in a single step. We are
currently exploring cascade syntheses to generate complex natural products and their analogues that maybe considered as potential therapeutics towards the treatment of cancer. In contrast to traditional methods
of making these molecules, we are developing catalyst-triggered cascade processes to assemble them in a
single chemical step. This concept provides extremely rapid access to these molecules and their analogues
and will accelerate the investigation of their role in cancer biology.
PhD Students:
Lily Chan (Designing Novel Bioorthogonal Reactions for the Site-Selective Functionalisation of Proteins )
Elliott Bayle (Cyclopamine: Inspiration for Novel Inhibitors of the Hedgehog Signalling Pathway)
Annabelle Nicolas (Investigation of the Effect of Small Molecules on Chromatin Modification)
Lab Rotation Students:
Elliott Bayle (2008/2009)
Annabelle Nicolas (2006/2007)
Dr Finian Leeper (Leeper Group Website)
Research is focussed on the synthesis of compounds wanted for various biological investigations as well
as the subsequent study of these compounds, e.g. as modified substrates or inhibitors of target enzymes.
Some of our recent projects have included synthesis and testing of glycosidase inhibitors, synthesis of
novel contrast agents for MRI, development of new methods for the synthesis of PET tracers, and
elucidating the biosynthesis of prodigiosin, a bacterial pigment with immunosuppressive properties.
PhD Students:
Yelena Wainman (Developing Novel Chemical Probes for Molecular Imaging of Glycans in Cancer)
Henning Stöckmann (The Development of Novel Targeted Imaging Agents)
Melville Laboratory for Polymer Synthesis
Dr Oren Scherman (Scherman Group Website)
Our research interests include the synthesis of functional nanosystems, controlled polymer architectures
and dynamic supramolecular assemblies through molecular recognition processes. The underlying theme
lies at the interface between synthetic organic efforts on small molecules and macroscopic properties at
the materials level, developing a macro-organic approach to chemistry. Dynamic supramolecular selfassembly
of materials will be an area of great importance in the coming years, allowing for innovations in
nanotechnology and at the biological and chemical interfaces. We are particularly interested in exploring
topics such as water-soluble and stimuli-responsive materials, template and imprinting technologies of
functional polymers for use in chiral separations and enantioselective catalysis, and controlling material
morphologies and architectures both in solution and in the solid state through rational design and a multistep,
hierarchical self-assembly process.
PhD Students:
Matthew Rowland (Overcoming the Blood Brain Barrier: Hydrogel Materials Harnessing Cucurbit[n]uril Host-Guest Chemistry in Drug Delivery Applications for Glioblastoma Multiforme)
Lab Rotation Students:
Sabrina Huber (2012/2013)
Matthew Rowland (2011/2012)
Yelena Wainman (2010/2011)
Unilever Centre for Molecular Science Informatics
Prof Robert Glen (Glen Group Website)
We are generating and assimilating data to create new ways of linking and analysing data to extract
knowledge that can lead to a deeper understanding of molecules and their properties. This will allow
better predictive models to be devised and new theories to be created and explored using both data driven
and experimental approaches. The aim of our research is to devise new methods of creating, searching,
manipulating and storing molecular data such that scientists can devise experiments 'in-silico' which can
be tested both in the computer and in the lab. The research is hypothesis driven and aimed at collaborative
approaches to problem solving with other academic groups, institutes and industrial research groups. This
leads to multidisciplinary approaches that exploit molecular data to generate new insights into molecular
properties. Current research interests include molecular similarity and docking, complexity analysis,
functional foods, ADME/Tox prediction, gene expression analysis, molecular design, SAR and Grid
computing. There is a strong interest in the development of new molecular property calculations and data
analysis methods.
Lab Rotation Students:
Danny Allwood (2008/2009)
Dr Jonathan Goodman (Goodman Group Website)
Polypropionates of marine origin have structures of great complexity, some of which are extremely active
against cancer. What makes some of them good cancer targets? Synthetic accessibility and chemical
stability are both important, in addition to having the right shape to interact specifically with targets for
cancer therapeutic approaches. Current research in the Goodman group includes: conformation analysis;
reactivity analysis; applications to synthesis; informatics analysis of libraries of structures; docking into
proposed binding sites.
Lab Rotation Students:
Martin Bachman (2010/2011)
Rhian Holvey (2009/2010)
Christopher Stubbs (2008/2009)
Dr Andreas Bender (Bender Group Website)
There are lots of terrific synthetic chemists around - but *which* of all those possible compounds should you actually synthesize to obtain bioactivity against your protein of interest? This is one of the questions our group is trying to answer, which is working in the domain of so-called 'cheminformatics'. Cheminformatics means learning from historical bioactivity data, and to ask the computer what the chemical structure is that is most likely to show the bioactivity (or bioactivity profile) of interest. Given that companies routinely screen millions of compounds in High-Throughput Screening (HTS), and that also millions of bioactivity data points are publicly available, it is obvious that learning from past data improves the odds when designing future compounds. Projects in our group are particularly suited to you if you are interested in both organic/medicinal chemistry and have a certain affinity to computers - such as from using statistical or modeling packages or the like before. They generally obtain best results when integrated with synthetic and biology work, so that computer predictions can be tested in the wet lab afterwards. Also joint projects with Dr Peter Bond are very well possible, so computer-aided drug design projects can be performed simultaneously from a ligand-based as well as a structure-based perspective.
PhD Students:
Martin Bachman (Novel DNA Modifications and Epigenetic Processes in Cancer Progression and Metastasis)
Dr Peter Bond (Bond Group Website)
Our research is focused on the use and development of computational / simulation tools to study biomolecular systems. By collaborating with experimentalists, we can help to interpret novel data, to provide molecular insights into the "biological machinery" essential to fundamental cellular processes such as folding, transport, and signalling, as well as to identify the causes of associated diseases. Work in our group also benefits from close interactions with Dr Andreas Bender, enabling computational structure-based drug design projects to be supplemented by ligand-based approaches. Key areas of research include: Understanding the structure, dynamics, and energetics of ligand recognition; Characterizing the molecular mechanisms of regulation in multi-component receptor complexes; Modelling the self-assembly of biomolecules; Predicting membrane permeation by peptides and small molecules.
CRUK Cambridge Research Institute
Prof David Neal FRCS, FMedSci (Neal Group Website)
Our research interests include trials in clinical and translational uro-oncology and basic studies of
androgen receptor signalling. The group has published over 300 articles, chapters and books and has
raised over £ 40 million for research. Research interests in androgen resistant prostate cancer; studying
neuroendocrine differentiation and novel transcription factors, use of ChIP on ChIp to detect novel
binding sites for the androgen receptor, and the study of putative biomarkers including HiP1 and LYRIC
in prostate cancer.
PhD Students:
David Russell (Design and synthesis of deguelin-inspired multi-target drugs to combat prostate cancer)
Rhian Holvey (Fragment Based Design of Inhibitors of the TPX2 – Importin-α Interaction)
Samantha Cheung (Using Chemical Genetics to Dissect the Role of Signalling Enzymes in Drug-Resistant Prostate Cancer)
Lab Rotation Students:
James Sipthorp (2012/2013)
David Russell (2011/2012)
Samantha Cheung (2006/2007)
Prof Carlos Caldas FACP, FRCP, FMedSci (Caldas Group Website)
Our laboratory studies the genetic alterations underlying human cancers, with a focus on epithelial
malignancies. We are interested in understanding how genetic alterations accumulate and how they
determine the biological behaviour of cancers. Ultimately we aim to identify patterns that are predictive
of outcome and can be used to guide therapy. The research uses genomics tools (sequencing, molecular
cytogenetics, array-CGH, mRNA/miRNA profiling, tissue microarrays, targeted gene disruption) to
analyse breast cancers with the following aims: generate better classifications and validate
prognostic/predictive markers; identify novel therapeutic targets; characterise pathways of tumorigenesis
and epithelial transformation.
Lab Rotation Students:
Henning Stöckmann (2007/2008)
Prof Kevin Brindle (Brindle Group Website)
The early detection of tumour responses to drug treatment using non-invasive imaging techniques will
play an increasingly important role in drug development. These techniques can be used to obtain an early
indication of the efficacy of a new drug when in Phase I clinical trials and subsequently in the clinic,
where they could be used in the selection of drug and treatment regimes for individual patients, allowing
the clinician to abandon those treatments that are not working at an early stage and to try alternative
approaches. This could improve outcome while reducing patient suffering and financial costs.
My group have been developing non-invasive, magnetic resonance (MR)-based molecular imaging
approaches for detecting the early responses of tumours to therapy. Our initial targets have been detection
of tumour cell apoptosis post-chemotherapy, and measurements of tumour perfusion and pH following
treatment with antiangiogenic or anti-vascular drugs. Our approach has been to design novel, Gd3+-based
contrast agents, which report on some aspect of the physiological behaviour of the tumour post therapy.
These have included protein- or peptide-targeted contrast agents that bind to apoptotic cells or angiogenic
vasculature or 'smart' contrast agents whose relaxation properties respond to factors in their
environment, such as pH. We are also starting to develop an exciting new approach based on
hyperpolarised 13C. A fundamental limitation of magnetic resonance is its relatively low sensitivity due to
the very low levels of nuclear spin polarisation that can be achieved, even in high-field magnets. Recently
a practical method has been developed to enhance the nuclear spin polarisation of nuclei such that gains
in sensitivity as great as 10,000-fold can be achieved. This has enabled the imaging of 13C-labelled
cellular metabolites in vivo and, more importantly, their enzymatic transformation into other species. This
is a very important development that could presage a paradigm shift in the way in which we conduct
molecular imaging experiments using MR. We are currently investigating the potential of this technology
to: 1) measure tumour cell death; and 2) measure tumour pH. Initially there will be only two polarisers in
the U.K., one in Oxford dedicated to imaging in cardiology, the other in Cambridge and dedicated to oncology. Therefore, should this work be successful we will be very well placed to exploit this exciting
new technology. The work in my lab will therefore both support chemistry, in that we can assess early
responses to new drugs in pre-clinical animal models, and benefit from chemistry input, in that many of
the 'smart' contrast agents that we are seeking to develop require expertise in chemistry.
PhD Students:
Olivia Walker (Investigating the interplay between a cell’s enzymatic, epigenetic and metabolic state in cancer progression)
Yelena Wainman (Developing Novel Chemical Probes for Molecular Imaging of Glycans in Cancer)
Henning Stöckmann (The Development of Novel Targeted Imaging Agents)
Lab Rotation Students:
Yelena Wainman (2010/2011)
Dr James Brenton (Brenton Group Website)
The Cancer Genomics Programme studies the genetic alterations underlying human cancers, with a focus
on epithelial malignancies including breast, ovarian and gastric cancer. We are interested in
understanding how genetic alterations accumulate and how they determine the clinical behaviour of
cancers. Molecular profiling of human cancer tissues is vital in order to identify new biomarkers that are
predictive of outcome or treatment response.
PhD Students:
Charlotte Sutherell (Developing small molecule bromodomain probes to aid the study of ovarian cancer)
Tom Beale (Novel Antiangiogenic and Antimitotic Agents Inspired by Natural Products)
James Shearman (Disrupting Cellular Microtubules: Synthesis and Biological Investigation of Novel Antimitotic Agents)
Lab Rotation Students:
Mareike Wiedmann (2012/2013)
Charlotte Sutherell (2011/2012)
Lily Chan (2010/2011)
Danny Allwood (2008/2009)
Tom Beale (2007/2008)
James Shearman (2006/2007)
Dr Adele Murrell (Murrell Group Website)
'Epigenetic' refers to mitotically stable changes in gene expression that are not attributable to DNA
sequence changes. At a molecular level, these epigenetic phenomena occur through chemical
modifications to the DNA and underlying chromatin such as cytosine methylation, histone methylation,
acetylation, phosphorylation and ubiquitination. Since the epigenetic status of a cell, unlike the DNA
sequence is potentially reversible cancer therapies that target epigenetic mechanisms will be more
tractable. Our research is focussed on the consequence of DNA methylation on higher order chromatin
structure and its relevance to reprogrammeming gene expression during tumour development. We are
currently bisulphite sequencing a panel of cancer patients to identify whether loss of methylation of
specific imprinted genes can be used as biomarkers to detect cancer predisposition and are using cell
culture based and mouse models to identify the mechanisms whereby chromatin can be remodelled (i.e
gain or loss of DNA and histone methylation). Our cell culture and chromatin modification reporter
system provides an excellent tool to assay the epigenetic effects of small molecules that can target either
DNA directly or indirectly through DNA regulatory proteins (transcription factors and co factors,
topoisomerases, telomerases) on gene expression.
PhD Students:
Martin Bachman (Novel DNA Modifications and Epigenetic Processes in Cancer Progression and Metastasis)
Liang Wu (New Approaches in Epigenetic Therapy: non-coding RNA as a Target for Polycomb Inhibition )
Annabelle Nicolas (Investigation of the Effect of Small Molecules on Chromatin Modification)
Lab Rotation Students:
Martin Bachman (2010/2011)
Liang Wu (2009/2010)
Annabelle Nicolas (2006/2007)
Dr Fanni Gergely (Gergely Group Website)
We aim to understand the normal behaviour of the microtubule cytoskeleton both in cell division and
tissue organisation and its perturbation in cancer. Asymmetric chromosome segregation is a hallmark of
many human cancers. Gain or loss of chromosomes (also termed genomic instability) during mitosis or
multipolar cell divisions leads to defective chromosome partitioning and hence aneuploidy. Multipolar
mitotic spindles are generated by numerical, structural or functional abnormalities of the centrosome, the
main microtubule organizing centre in animal cells. Such aberrant spindle formations are particularly
dangerous to cells as no surveillance mechanisms exist for their elimination. Centrosome anomalies are
present in many aneuploid tumours including malignancies of breast, bladder and pancreas amongst
others. Despite the apparent link between centrosome and cancer, we are at an early stage in
understanding the normal function of the centrosome and we know even less about the mechanisms and
consequences of its deregulation in disease. Our long term aim is to gain better understanding of the
molecular basis of centrosome function in cell division and tissue organisation.
The TACC family of centrosomal proteins regulate the activity of ch-Tog, an essential microtubulestabilising
factor. Using RNA interference in human cells, I previously showed that reducing ch-Tog
levels is sufficient to induce multipolar spindle formation, without the need for abnormal centrosome
numbers. Cells with multipolar spindles often exit from mitosis, leading to aberrant interphase cells with
multiple or satellite nuclei. We are now using a vertebrate reverse genetic system, DT40 cells, to create
mutations in ch-Tog and the TACC proteins in order to quantify the rate of chromosome gain and loss
over many cellular generations in the mutant backgrounds. We hope this approach will provide a
molecular link between centrosome function and genomic instability. Disruption of tissue organisation
and polarity is a common feature of many tumours. Polarisation in cells must be accompanied by changes
in centrosome behaviour, however these changes are not well characterised. Cultured cells have serious
limitations for modelling complex diseases such as cancer.Cells isolated from their normal
microenvironment do not behave like their counterparts within an intact tissue. Therefore, in order to
learn about centrosomal abnormalities in epithelial cancer, it is essential to use a model system that
mimics tissue organisation. Currently, we are establishing three-dimensional cell culture models for the
study of centrosome and microtubule function in polarised epithelial cells.
PhD Students:
Ciorsdaidh Watts (Synthesis and Biological Evaluation of Selective Allosteric Inhibitors of the Kinesin Motor Protein, HSET )
Lab Rotation Students:
Christopher Stubbs (2008/2009)
Prof Duncan Jodrell DM MSc FRCP (Edin) (Jodrell Group Website)
The Cancer Research UK Pharmacology and Drug Development Group (PDDG) and the Early Phase Trials Team based in Addenbrooke's Hospital, facilitate the preclinical and clinical development of novel anti-cancer drugs. The group has participated in drug discovery projects including the development of ruthenium based organometallic compounds and novel pyrrolo-benzodiazepine based, sequence specific, DNA binding agents.
Early phase (including phase I or "First into Man") clinical studies are performed in purpose built facilities at Addenbrooke's Hospital. The PDDG provides laboratory support for the early phase trials of novel agents and for PK/PD studies involving drugs already established as therapies for cancer. Collaborations exist with other groups within the University of Cambridge, around the UK (through the Cancer Research UK Drug Development Office) and internationally, through membership of the Pharmacology and Molecular Mechanisms (PAMM) Group of the EORTC.
Other projects focus on the identification of factors, both pharmacokinetic and molecular, which predict outcome in patients receiving novel agents, leading to the development of individualised treatment strategies. Current work is focussing on the transport properties of DNA interactive drugs (PBDs), the metabolism and downstream effects of existing drugs for patients with colorectal cancer (e.g. irinotecan, oxaliplatin and capecitabine), including DNA damage recognition pathways. Metabolism pathways for capecitabine are being mapped using non-invasive imaging techniques.
PhD Students:
Ciorsdaidh Watts (Synthesis and Biological Evaluation of Selective Allosteric Inhibitors of the Kinesin Motor Protein, HSET )
Lab Rotation Students:
Sabrina Huber (2012/2013)
Ciorsdaidh Watts (2009/2010)
Hutchinson - MRC Research Unit
Prof Ashok Venkitaraman (Venkitaraman Group Website)
Human cancer cells almost always contain abnormal chromosomes, yet the connections between chromosomal
instability and carcinogenesis are poorly understood. We aim not only to understand how cells maintain
normal chromosome structure and number and why maintenance should break down in cancer cells, but
also to translate this knowledge to improvements in cancer diagnosis and treatment.
Many genes whose inactivation predisposes to cancer work in
pathways for DNA replication and recombination, which monitor and repair DNA lesions during the Sphase
of cell cycle. We study these pathways to understand how their inactivation causes human genetic
diseases - including inherited breast cancer susceptibility, Bloom syndrome and Fanconi anaemia - in
which chromosomal instability triggers cancer predisposition. This work has engendered insights into
novel approaches for cancer treatment, involving the design, screening and synthesis of small molecule
inhibitors of replication/recombination molecules.
Cell cycle checkpoints during
G2 and M-phases work together with replication/recombination pathways in preserving chromosome
integrity and are the principal targets for cancer drugs like taxol. We study these checkpoints to
understand how checkpoint dysfunction contributes to cancer progression and resistance to cancer
chemotherapy. This work has identified novel bio-markers to define the sensitivity of cancer cells to taxol
and related drugs, and several new targets for the design of small molecules to overcome drug resistance.
We have close collaborations with structural biologists (Prof. Blundell & Dr. Pellegrini in the Department
of Biochemistry) and chemists (Dr. Balasubramanian in the Department of Chemistry) in Cambridge,
besides with bio-tech, which facilitates our work in both project areas, and ensures that it has a strong
foundation in both chemistry and cancer biology.
PhD Students:
Matej Janecek (Genetic Instability and Cancer: Inhibiting Protein – Protein Interactions of Aurora Kinase A and TPX2)
Luca Laraia (Phenotypic screening of diverse chemical libraries identifies molecules which can disrupt mitosis for cancer therapy)
Andrew Lewis (Unravelling Uncinatone: Piecing Together the Clues Towards a Potential Topoisomerase II Inhibitor)
Christopher Stubbs (Allosteric Polo-like Kinase 1 Inhibitors: A Fragment-Based Approach)
Lab Rotation Students:
Matej Janecek (2010/2011)
Luca Laraia (2009/2010)
Andrew Lewis (2008/2009)
Dr Anna Philpott (Philpott Group Website)
We am interested in the balance between proliferation and differentiation during development, using
embryos of the frog Xenopus laevis as an in vivo and biochemical system. We are studying the roles of
cell cycle regulators, and in particular cyclin-dependent kinase inhibitors, in the direct control of
differentiation events primarily in nerve and muscle. Additionally, we study cell-cycle regulated
ubiquitination and degradation of key transcription factors that drive the differentiation process. We
would assert that cancer is primarily a disease of differentiation. Ultimately, our studies on these
fundamental mechanisms in action during development will illuminate the pathways that are disrupted in
tumorigenesis.
Lab Rotation Students:
Elliott Bayle (2008/2009)
Helen Lightfoot (2007/2008)
Department of Pharmacology
Dr Hendrik van Veen (van Veen Group Website)
In this laboratory, we are interested in the molecular mechanisms by which multidrug transporters in human and bacterial cells, recognize and translocate multiple drugs. We apply a variety of techniques in the areas of biochemistry, biophysics, molecular biology, and structural biology. The following sections give an overview of some of the ongoing projects.
MRC Laboratory of Molecular Biology
Dr Murray Stewart (Stewart Group Website)
Our group concentrates on understanding cellular functions in terms of the molecules involved and the
interactions between them. We use a combination of structural, cellular and protein engineering methods
to determine the structure of key proteins, how they interact, and how these interactions generate
function. Structures are being determined using X-ray crystallography and NMR; interactions defined
using biochemical and EM methods; and protein engineering is being used to produce modified proteins
and constructs. In addition, a range of in vitro assays is being used to investigate the functions of these
interactions in a cell biology context. Overall, we aim to integrate the structural and biochemical data in
corder to understand the machinery and mechanism of key cellular functions at the molecular level. We
are concentrating on investigating in detail four specific questions: (i) the molecular mechanism of
nucleocytoplasmic transport; (ii) the role of nuclear trafficking components in mitosis; (iii) how
components of the nuclear trafficking machinery orchestrate gene expression and mitosis; and (iv) the
molecular mechanism of locomotion of amoeboid cells.
PhD Students:
Rhian Holvey (Fragment Based Design of Inhibitors of the TPX2 – Importin-α Interaction)
Lab Rotation Students:
Rhian Holvey (2009/2010)
Dr Jason Chin (Chin Group Website)
Biomolecules and their dynamic assemblies, in collaboration with the energy provided by NTP hydrolysis, perform a spectacular range of mechanical and chemical manipulations on nanometre scale objects in the cell; molecular motors perform mechanical work, while enzymes rearrange atoms in ways, and at rates that synthetic chemists have difficulty emulating. The biomolecules and assemblies that perform these diverse functions form the basis of a toolkit for the evolution and synthesis of new function. Recent advances in genome sequencing and structural biology are expanding this toolkit, and beginning to provide a molecular understanding of its parts. We are using this toolkit for the creation of useful nanoscale molecular devices and systems that can perform novel mechanical tasks, convert energy from one form to another, or catalyse novel chemical reactions. These functions may arise from the directed evolution of particular modules to perform new functions or from the assembly of novel combinations of modules to produce molecules and even organisms with novel and potentially emergent properties.
PhD Students:
Olivia Walker (Investigating the interplay between a cell’s enzymatic, epigenetic and metabolic state in cancer progression)
Lily Chan (Designing Novel Bioorthogonal Reactions for the Site-Selective Functionalisation of Proteins )
Lab Rotation Students:
Olivia Walker (2011/2012)
Dr KJ Patel (Patel Group Website)
We aim to understand the molecular basis of chromosome stability in human cells. Genetic predisposition to cancer is commonly precipitated by mutations in genes that result in chromosome breakage. Studies of the inherited chromosomal instability diseases in humans have led to the discovery of some of these genes, and the characterization of their products may profoundly contribute to our understanding of pathways that maintain genetic integrity. By utilising a variety of complementary approaches, we are probing the function of these essential proteins.
Lab Rotation Students:
Charlotte Sutherell (2011/2012)
Department of Obstetrics & Gynaecology
Dr Steve Charnock-Jones (Charnock-Jones Group Website)
The control of blood vessel growth, differentiation and function is critical to the development of a multicellular
organism. Such control is achieved by the local action of numerous factors, both soluble and
those that require cell or matrix contact for their effect. Under normal physiological conditions a complex
network of stable vessels is formed which is sufficient to meet the metabolic demands of the tissue. Our
laboratory aims to identify the factors and determine how these interact to regulate vessel growth and
remodelling under physiological and pathological conditions. Much of this is focussed on the female
reproductive tract as this is one of the few places in the normal adult where vessels grow. We employ an
integrated multidisciplinary approach that includes gene-array technology, in vitro models of endothelial
growth and death, animal models of physiological and pathological angiogenesis and evaluation of
clinical specimens. This work is relevant to pathological angiogenesis such as occurs during solid tumour
growth and previous work has lead to the characterisation, patenting, and licensing of anti-angiogenic
agents to biotech and pharmaceutical companies. The use of these molecular, cellular and in vivo assays is
necessary in a drug development programme and would be an essential component in evaluating and
refining anti-endothelial agents.
PhD Students:
Charlotte Sutherell (Developing small molecule bromodomain probes to aid the study of ovarian cancer)
Tom Beale (Novel Antiangiogenic and Antimitotic Agents Inspired by Natural Products)
Ceri Parfitt (Investigating Endothelial Biology: The Role of Caspase-4)
Lab Rotation Students:
Mareike Wiedmann (2012/2013)
Charlotte Sutherell (2011/2012)
Helen Lightfoot (2007/2008)
Ceri Parfitt (2006/2007)
Department of Biochemistry / Gurdon Institute
Dr Eric Miska (Miska Group Website)
Our main goal is to understand how cells interpret genetic and epigenetic information as well as
environmental cues to determine their correct cell fate, i.e. to make the decision to divide, die or
differentiate. For cells to assume their correct fate is essential for development, epistasis and regeneration
of any tissue, organ or organism. Elucidating the principles and molecular pathways underlying cell fate
decisions is crucial for understanding how cells become corrupted in disease. The recent discovery of a
large conserved class of small RNA genes, through the study of the control of developmental timing in
the nematode Caenorhabditis elegans, opened up a new and unexpected dimension of gene regulation.
Although we know very little about the biology of these small RNAs, the few examples that have been
studied suggest that these genes are likely to have a major impact in many areas of biology. We will
concentrate on basic questions on how microRNAs control gene expression. Specifically, we are
currently addressing the following questions: Where and when are microRNAs expressed? What are the
direct targets of microRNAs? How do microRNAs interface with the pathways regulatng cell division,
programmed cell death and differentiation? What are the mechanisms of microRNA action? Our
approach is multi-facetted, combining molecular genetics in C. elegans and the mouse, microarray
expression analysis, bioinformatics and functional studies in mammalian cell lines.
PhD Students:
Helen Lightfoot (Enhancing the Tumour Suppresser Properties of Let-7 using Small Molecules)
Lab Rotation Students:
Olivia Walker (2011/2012)
Andrew Lewis (2008/2009)
Prof Stephen Jackson (Jackson Group Website)
Work in my laboratory aims to decipher the mechanisms by which cells detect DNA damage, signal its presence and mediate its repair. Much of our work focuses on DNA double-strand breaks (DSBs) that are generated by ionizing radiation and radiomimetic chemicals, and when the DNA replication apparatus encounters naturally-arising DNA damage or other impediments to replication-fork progression.
Lab Rotation Students:
Matthew Cornwell (2012/2013)
Cambridge Centre for Brain Repair
Dr Colin Watts (Watts Group Website)
Using animal models of clinical disease we have begun to investigate the role of endogenous progenitors
as a source of astrocytes that contribute to the gliotic response associated with acute brain injury. We
have shown that astrocyte fate specification of endogenous progenitors in the adult involves cytoplasmic
translocation of the transcriptional repressor Olig2. This represents a potential mechanism for therapeutic
manipulation. Stem cells also appear to demonstrate tropism for various pathologies including traumatic,
inflammatory and malignant disease. By exploring the mechanisms underlying this process we hope to
learn how to better target stem cells towards areas of brain damage. Stem cells could then be used to
deliver new drugs or compounds to manipulate the disease process or to promote regeneration and repair
mechanisms. We have also modified our protocols for culture of normal adult neural stem cells to derive
brain cancer stem cells.
PhD Students:
Matthew Rowland (Overcoming the Blood Brain Barrier: Hydrogel Materials Harnessing Cucurbit[n]uril Host-Guest Chemistry in Drug Delivery Applications for Glioblastoma Multiforme)
Danny Allwood (Combating Chemoresistance in Glioblastoma: Interaction of Small Molecules with the Direct Reversal DNA Repair Pathway)
Lab Rotation Students:
Matthew Rowland (2011/2012)
Danny Allwood (2008/2009)