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Monday, May 8, 2006

On-going research around the world


There are many countries which are involved in intense cancer research. Cancer is a widespread disease, which can occur to anyone, anytime. Nobody knows the cause nor the actual mechanism of events that lead to cancer, or neoplasm, as is the technical term. A lot of expertise from various areas of research ranging from genetics to structural biology are required to solve this mystery of cancer. I have taken the effort to make some list of on-going research only in UK, Institute of Cancer Research.

Cancer Research UK Centre for Cancer Therapeutics

Analytical Technology and Screening Team

Team Leader:
Dr Wynne Aherne
Location: Haddow Laboratories, Sutton

One of the key steps in target-directed cancer drug discovery is the identification of small molecule chemicals (hits) with activity against validated target proteins. This can be achieved by high throughput screening of large compound collections using appropriate assay formats. The role of the Analytical Technology and Screening Team is to run screens on selected cancer drug targets, and with others, to carry out the initial characterisation of the hits obtained. During the last year, screens completed include those for CHK1, CHK2, p70S6kinaseand HSP70, The Team is not only responsible for the high throughput screening but is also involved in the development of secondary and mechanistic assays used in other phases of the drug discovery process in which the pharmacological and drug-like properties of the hits are optimised.

Cell Cycle Control Team

Team Leader:
Dr Michelle Garrett
Location: Haddow Laboratories, Sutton

One of the principal characteristics of human cancer is the ability to proliferate in an uncontrolled manner. At the heart of cell proliferation is the cell division cycle and, when not regulated correctly, this process can be one of the underlying causes of cancer. The main aims of the Cell Cycle Control Team are:

(i) to further our understanding of how signalling pathways regulate the mammalian cell division cycle through the cyclin dependent kinase (CDK) family of serine/threonine kinases and to use this knowledge to identify and validate cell cycle regulators as targets for therapeutic intervention in cancer

(ii) to participate in drug discovery and development projects that can utilise our expertise in signalling pathways and cell cycle regulation

In particular, we are interested in the cyclin D-dependent kinases CDK4 and CDK6, which associate with the D-type cyclins to control G1 progression through phosphorylation of the tumour suppressor protein, pRb. Most human cancers contain genetic alterations that affect these kinases, their regulators including the D-type cyclins or pRB itself. In addition they act as a key integration point between extracellular signalling pathways such as those governed by Ras and PI3 kinase/protein kinase B and the cell division cycle. Thus, understanding the molecular basis of the CDK/cyclin D/pRb pathway and its regulation will be important in the identification of novel targets for new cancer treatments. We are also participating in four drug discovery and development projects. These are on PKB, pRb phosphorylation and the CHK1 and CHK2 cell cycle checkpoint kinases.

Cell Growth Regulation and Angiogenesis Team

Team Leader:
Dr Margaret Ashcroft
Location: Haddow Laboratories, Sutton

Like all normal tissues in the body, cancer cells within a tumour mass need oxygen and nutrients to grow and expand. A growing tumour mass expands beyond the microscopic level by developing its own blood supply by stimulating the growth and invasion of surrounding blood vessels into the growing tumour mass. This process is known as angiogenesis. Hypoxia-inducible factor (HIF) is a transcriptional complex that is central to mediating angiogenesis and tumour progression by upregulating specific targets such as vascular endothelial growth factor (VEGF). The main focus of the Cell Growth Regulation and Angiogenesis Team is to gain a better understanding of the molecular mechanisms underlying HIF regulation in normal and tumour cells, as a basis for the development of new cancer therapies.

Clinical Pharmacology and Trials Team

Team Leader:
Professor Ian Judson
Location: Sycamore House & Haddow Laboratories, Sutton

The Clinical Pharmacology and Trials Team is responsible for the study of the preclinical and clinical pharmacology of new anticancer agents developed in the Centre and for their early clinical trials. Such investigations may include the study of mechanisms of action and resistance, toxicology, pharmacokinetics, early dose-finding studies and the development of pharmacodynamic biomarkers for the measurement of drug action in tumour and surrogate tissues. These may be molecular assays or functional imaging studies. The emphasis is increasingly on hypothesis-testing clinical trials of agents acting on new molecular targets including cell signalling, cell survival, the cell cycle control machinery, chromatin modulation and angiogenesis.

In addition to studying the pharmacokinetics of agents in clinical trials, such as 17AAG, 17DMAG and abiraterone, Dr Florence Raynaud manages a group that evaluates the preclinical drug metabolism and pharmacokinetics (DMPK) of novel chemicals under development in the Centre. Early assessment of DMPK allows liabilities to be identified and the early implementation of strategies to optimise drug-like properties. The team is also interested in the development of novel PI3K inhibitors in collaboration with PIramed Ltd.

Gene and Oncogene Targeting Team

Team Leader:
Professor Caroline Springer
Location: Haddow Laboratories, Sutton

Gene targeting
Conventional cytotoxic chemotherapy has often suffers from the shortcoming that it es results in serious side effects. Antibody- or gene-directed enzyme prodrug therapy (ADEPT or GDEPT) aim to prevent this problem. In ADEPT and GDEPT the cytotoxic drugs have been converted into non-toxic prodrugs that do side effects. An enzyme capable of regenerating the drug from the prodrug is targeted to the tumour either by coupling the enzyme to an antibody that binds selectively to tumours (ADEPT), or by having the gene for the enzyme expressed by a tumour selective gene vector (GDEPT). Our aim is to express the prodrug-activating enzyme carboxypeptidase G2 (CPG2) in replicating adenoviral vectors, and to use these vectors to target CPG2 to tumours following injection either intravenously, or directly into the tumour. CPG2 has advantages over other enzyme prodrug converting A/GDEPT systems in that it releases a drug directly from the prodrug with no further cellular processing requirements. In addition, a large number of prodrugs can be designed that are converted to a range of different classes of drugs. Thus the prodrug/drug system selected can be tailored for the tumour type. We intend to administer prodrug following CPG2 expression in the tumours so it will be activated to cytotoxic drug selectively in the cancer cells. . The adenoviruses have been modified so that they are no longer pathogenic. . Replicating adenoviruses have been modified so that they can target specific tumour types, such as liver, , and colon. We have measured ratios of CPG2 activity of between 1,000:1 and 10,000:1 in tumour:liver, where liver is the next highest tissue after tumour to be targeted. We have demonstrated therapeutic efficacy in two human hepatoma models and a GDEPT clinical trials has just been approved with this system.

Oncogene targeting
The Cancer Genome Project has identified mutations in the enzyme B-RAF as its first major discovery. Mutations are present in 70% of melanomas, 10% of colorectal cancers and a smaller number of other cancers including early ovarian cancer. The mutations lead to activation of this enzyme, resulting in the tumour cell being in a state of continual growth. We havediscovered ipotent inhibitorsof B-RAF, with selectivity for the mutant form for use in malignant melanoma and potentially other tumour types. Inhibitors of B-RAF should reverse the cells' tumour-forming characteristics, and probably will induce the cells to self-destruct.

Signal Transduction and Molecular Pharmacology Team

Team Leader:
Professor Paul Workman
Location: Haddow Laboratories, Sutton

This Team has two major complementary roles:
To understand the molecular mechanism of action of drugs that affect, or are affected by, signal transduction pathways that regulate proliferation, cell cycle and survival in cancer cells
To discover and develop innovative new drugs that act on novel molecular targets, defined by the genomics and molecular pathology of cancer.

The Team is particularly involved in the development of inhibitors of the heat shock protein 90 molecular chaperone, PI3 kinase and cyclin-dependent kinases. In addition we are interested in applying gene expression microarray and RNAi technology to understand the cellular pharmacology of molecular therapeutics and existing cancer drugs.

Target Discovery and Apoptosis Team

Team Leader:
Dr Spiros Linardopoulos
Location: Chester Beatty Laboratories, London

Chromosomal abnormalities are a hallmark of human cancer, reflecting the deleterious consequences of the gain or loss of genetic information. These abnormalities may be a consequence of tumour progression, mis-segregated chromosomes and aneuploidy. The fidelity of chromosome segregation is monitored by mitotic checkpoints that delay entry into mitosis until a functional centrosome is present. During this complex process, protein kinases play important roles in promoting or retarding transitions between different stages and checkpoints of the cell cycle. We aim to further understand mitotic control and use this information to identify and validate mitotic regulators as targets for cancer therapy. Currently one of our targets is the STK15 (Aurora2) gene, a mitotic kinase which has been found to be amplified in more than 50% of primary colorectal cancers and 12% of primary breast tumours as well as in breast, ovarian, colon, prostate, neuroblastoma and cervical cell lines. Thus, STK15 represents an attractive target for anticancer drug discovery. An additional field for identification and validation of genes involved in cancer is programmed cell death, also known as apoptosis. Apoptosis represents the defence mechanism of the cell with accumulated oncogenic mutations. Thus, defects in apoptotic signalling are thought to play an important role in the development of different types of cancers. It is not a surprise that the cell cycle and apoptosis are often deregulated in tumours. Therefore, they represent an attractive field for drug target discovery.

Tumour Biology and Metastasis Team

Team Leader:
Dr Suzanne Eccles
Location: McElwain Laboratories, Sutton

The major problem in cancer therapy is the treatment of disease that has invaded normal tissues and spread to secondary sites (metastasis). Our main aims are to understand more about the molecular mechanisms of tumour progression, and to develop better models to investigate the therapeutic potential of novel agents for translation into the clinic. Many of the signalling pathways and molecular processes used by tumour cells during invasion are also utilised by endothelial cells during neoangiogenesis (the process of development of new blood and lymphatic vessels on which tumour growth and spread depends). Recognising key 'nodal points' in these pathways will enable us to develop dual function inhibitors which can target both tumour cells and activated endothelial cells. Our work falls into two parts:

Investigation of signalling pathways in invasion and angiogenesis and their potential as targets for therapy;

Evaluation of markers of metastatic potential (and organ site selectivity) in human cancers.
We are also actively evaluating the therapeutic activity of a wide range of molecular therapeutics in in vitro and in vivo models relevant to human cancer.

I know that they are all very long deacriptions of the research work they are doing. Even I myself have not taken the time to read them thoroughly cos i have no time today. I've got to go back and do an AQ question for tomorrow. See Ya!


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