Cambridge PhD Training Programme in Chemical Biology and Molecular Medicine

Research Collaborators

Department of Chemistry

Prof Steven Ley CBE, FRS, FMedSci (Ley Group Website)

Steven LeyThe 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:
James Sipthorp (Development of 4E-BP Stapled Peptide Mimetic to Target eIF4E/eIF4G Protein Protein Interaction)
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)

Ian PatersonOur 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)

Shankar BalasubramanianNucleic 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:
Sabrina Huber (Cytosine Modifications in Regulatory RNA and Their Role in Cancer Biology )
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:
Sabrina Huber (2012/2013)
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 AbellChris 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:
Matthew Cornwell (Fragment-Based Discovery of Ubiquitin Conjugating Enzyme Inhibitors)
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)

Dr David Spring (Spring Group Website)

David SpringThree 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:
Mareike Wiedmann (Importance of transcription factor HNF1b in ovarian clear cell carcinoma (OCCC) and chemical strategies to inhibit HNF1b for the development of novel therapeutics)
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)

Sophie JacksonMolecular 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 Paul Barker (Barker Group Website)

Paul BarkerThe 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)

Matthew GauntWe 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)

Finian LeeperResearch 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)

Oren SchermanOur 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)

Robert GlenWe 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)

Jonathan GoodmanPolypropionates 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)

Andreas BenderThere 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)

Peter BondOur 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)

David NealOur 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)

Carlos CaldasOur 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:
Matthew Cornwell (2012/2013)
Henning Stöckmann (2007/2008)

Prof Kevin Brindle (Brindle Group Website)

Kevin BrindleThe 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)

James BrentonThe 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:
Mareike Wiedmann (Importance of transcription factor HNF1b in ovarian clear cell carcinoma (OCCC) and chemical strategies to inhibit HNF1b for the development of novel therapeutics)
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 Fanni Gergely (Gergely Group Website)

Fanni GergelyWe 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)

Duncan JodrellThe 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)

Ashok VenkitaramanHuman 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)

Anna PhilpottWe 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)

Hendrik van VeenIn 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)

Murray StewartOur 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)

Jason ChinBiomolecules 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)

KJ PatelWe 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)

Steve Charnock-JonesThe 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)

Eric MiskaOur 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:
Sabrina Huber (Cytosine Modifications in Regulatory RNA and Their Role in Cancer Biology )
Helen Lightfoot (Enhancing the Tumour Suppresser Properties of Let-7 using Small Molecules)
Lab Rotation Students:
Sabrina Huber (2012/2013)
Olivia Walker (2011/2012)
Andrew Lewis (2008/2009)

Prof Stephen Jackson (Jackson Group Website)

Stephen JacksonWork 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.

PhD Students:
Matthew Cornwell (Fragment-Based Discovery of Ubiquitin Conjugating Enzyme Inhibitors)
Lab Rotation Students:
Matthew Cornwell (2012/2013)

Cambridge Centre for Brain Repair

Dr Colin Watts (Watts Group Website)

Colin WattsUsing 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)

The Babraham Institute

Dr Simon Cook (Cook Group Website)

Simon CookWe study how protein kinase signalling pathways are regulated and how they control key cell fate decisions such as cell proliferation, senescence, differentiation and cell survival or cell death. We have a long-standing interest in the ERK1/2MAPK pathway but also study the mTOR pathway and members of the DYRK family of protein kinases. We make extensive use of protein kinase inhibitors, RNAi and conditional mutants to probe the normal function of these kinases. In addition, these signal pathways are frequently de-regulated in human cancer due to mutations in growth factor receptors, KRAS, BRAF, PI3K (or PTEN loss) or DYRK1B amplification. As a result, tumours evolve to be 'addicted' to these signalling pathways. This makes them attractive targets for therapeutic intervention and new drugs that target these pathways are in development or are entering the clinic. We areinterested in understanding why some tumours are intrinsically resistant tosuch drugs, how cells adapt to long-term exposure to these drugs ('acquiredresistance'), the remodelling of signalling pathways that this entails and strategies to overcome acquired resistance.

PhD Students:
James Sipthorp (Development of 4E-BP Stapled Peptide Mimetic to Target eIF4E/eIF4G Protein Protein Interaction)
Lab Rotation Students:
James Sipthorp (2012/2013)