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HNC project summary
Stephan M. Feller, PhD
Research Group Head & University Research Lecturer
Head and Neck Cancer Cell Signalling Group
Weatherall Institute of Molecular Medicine
John Radcliffe Hospital
Oxford University
Oxford OX3 9DS
Tel.: +44-1865-22-2438
Fax: +44-1865-22-2431
Email: stephan.feller@imm.ox.ac.uk
Click here for Dr Feller’s webpage.
Research Group Head & University Research Lecturer
Head and Neck Cancer Cell Signalling Group
Weatherall Institute of Molecular Medicine
John Radcliffe Hospital
Oxford University
Oxford OX3 9DS
Tel.: +44-
Click here for Dr Feller’s webpage.
Lay summary
Cancers are a major group of human diseases affecting ca. 1 out of 3 individuals in the developed countries at some point in their lifetime. Despite considerable progress in cancer therapies over the last decades, many cancers are still associated with a very significant number of fatalities that are frequently caused by tumor metastases rather than the primary tumor. Although cancers are often classified according to the organ and cells from which they arise, the actual molecular causes, i.e. cancer-driving changes in a patients' genes and proteins, often vary dramatically between individuals, even if the affected tissue and cell type are identical. To target these molecular causes specifically, an in-depth understanding of deregulated molecular events that drive tumor growth and metastasis in different persons is
required. For this, many individual cases need to be analysed with a range of tools that can detect small changes in the DNA and proteins of patients. Using tumor biopsies, only very limited studies of metastasis-driving proteins are feasible at present. However, such studies can be initially conducted with cell lines established from patient tumors and key findings can subsequently be further investigated in biopsies. Squamous carcinoma cells (SCC) from head and neck cancers (HNC) are particularly useful for these experiments, because it is possible to establish SCC lines from a substantial fraction of these tumors. Hundreds of SCC lines exist currently worldwide, a number much larger than for virtually all other human tumor types. In the proposed project we intend to investigate several proteins well known to
drive the development of cancer metastases but not sufficiently analysed in HNC up to now. These studies will be carried out using a substantial panel of SCC lines readily available in our laboratory and are expected to lead in time to the development of new strategies of patient stratification for treatment and novel molecular therapies targeted to specific subset of HNC patients.
Cancers are a major group of human diseases affecting ca. 1 out of 3 individuals in the developed countries at some point in their lifetime. Despite considerable progress in cancer therapies over the last decades, many cancers are still associated with a very significant number of fatalities that are frequently caused by tumor metastases rather than the primary tumor. Although cancers are often classified according to the organ and cells from which they arise, the actual molecular causes, i.e. cancer-
Specialist Summary
The heterogeneity of molecular lesions that lead to the development of head and neck cancers (HNC) is a major obstacle for the development and effective application of new molecularly targeted therapies. Such therapies are urgently needed to improve the outcomes for many HNC patients. We intend to initially utilise a large panel of squamous carcinoma cell (SCC) lines to systematically investigate the expression, activity status and functional interactions of crucial signalling proteins implicated in the regulation of cancer cell migration and invasion that are currently not sufficiently studied in HNC. In this project, we will focus on the concerted action of EGFR, c-Met, Src family kinases (SFK) and their key signal mediators/integrators Gab1 and p130Cas, large docking proteins and multi-site kinase substrates. We plan to thereby identify molecularly distinct subsets of SCC lines for further analyses. Small molecule inhibitors, including those already in clinical use or clinical trials and siRNAs, will then be utilised alone or in combination to inhibit or downregulate EGFR, c-Met and/or SFK and the consequences of their inhibition on the noninhibited kinases, as well as Gab1 and p130Cas phosphorylation will be analysed. This should identify potential cross-talk between these metastasis driving kinases and clarify the molecular consequences for their signal-integrating docking proteins. Effects on metastatic SCC properties, using molecular readouts (GTPases, MMPs) as well as established motility and invasion assays, will also be applied to correlate molecular observations with biological outcomes. Key findings obtained with the SCC line panel will later on be followed up through analysing locally collected HNC biopsies. From these combined studies, we expect to find new SCC signalling pathway connections, new markers for molecularly defining patient subgroups and leads for novel therapeutic strategies, such as combination therapies using different signal transduction-modulating (STM) drugs.
The heterogeneity of molecular lesions that lead to the development of head and neck cancers (HNC) is a major obstacle for the development and effective application of new molecularly targeted therapies. Such therapies are urgently needed to improve the outcomes for many HNC patients. We intend to initially utilise a large panel of squamous carcinoma cell (SCC) lines to systematically investigate the expression, activity status and functional interactions of crucial signalling proteins implicated in the regulation of cancer cell migration and invasion that are currently not sufficiently studied in HNC. In this project, we will focus on the concerted action of EGFR, c-
Collaborators
Mr. Rogan Corbridge (Surgeon), Oxford; providing support with biopsy collection.
Prof. Adrian L. Harris/Shalini Patiar, Oxford; support w. biopsy collection and analyses.
Prof. Thomas E. Carey, University of Michigan, Ann Arbor, USA; providing SCC lines.
Prof. Susanne M. Gollin, University of Pittsburgh, PA, USA; providing SCC lines.
Prof. Raidar Grenman, Turku, Finland; providing SCC lines.
(A more detailed outline for specialists is available upon request).
Mr. Rogan Corbridge (Surgeon), Oxford; providing support with biopsy collection.
Prof. Adrian L. Harris/Shalini Patiar, Oxford; support w. biopsy collection and analyses.
Prof. Thomas E. Carey, University of Michigan, Ann Arbor, USA; providing SCC lines.
Prof. Susanne M. Gollin, University of Pittsburgh, PA, USA; providing SCC lines.
Prof. Raidar Grenman, Turku, Finland; providing SCC lines.
(A more detailed outline for specialists is available upon request).
Computer model of a newly generated crystal structure showing two cancer proteins fragments that bind to each other to promote cancer cell growth
Analysis of diversity and joint action of signalling proteins driving tumor metastasis in squamous carcinoma cells of head and neck