HNC research work

Heads Up

The head and neck cancer research charity

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HNC Research

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The HNC Research Work

4. EGF receptor (EGFR) heterogeneity in HNCs

Our Head and Neck Cancer (HNC) Research Projects

1. Role of Src family kinases (SFK) in HNCs

Src was the first oncogene to be discovered and is known to play roles in multiple tumour types. In initial studies we could show by video monitoring of cells and detailed molecular analyses that SFK play multiple roles in HNCs. They appear to control HNC cell proliferation, movements, shapes and survival. We are now investigating the molecular mechanisms of these actions. This may lead to new therapeutic strategies for HNCs. More...

In collaboration with the Technical University in Munich (TUM, Prof. Bernhard Küster) cutting-edge proteomics technology known as KinobeadsTM is used to analyse a large part of the human kinase superfamily (over 300 of 520 in total). For this, beads coated with multiple drug-like molecules are used to pull out kinases from our large collection of HNC cells. These are then automatically quantified by an LTQ Orbitrap XL mass spectrometer. First promising leads for novel kinases that could drive different subsets of HNCs have emerged from this already and are currently under further scrutiny.

Kinase tree depicting the ca. 520 different members of the human kinase superfamily (a.k.a. kinome). Red dots indicate the more than 300 kinases that have been shown to bind to KinobeadsTM

Chemical structure of staurosporine, one of the kinase inhibitors coupled onto KinobeadsTM

Schematic structure of a kinobeadTM. Different drug-like molecules are covalently coupled to the bead.

2. Global analysis of kinase deregulation in HNC

3. The multifunctional protein Survivin is an interesting candidate for molecular HNC therapies

Inspired by a phase I ‘first in man’ clinical trial conducted at Oxford’s Churchill Hospital by Dr. Denis Talbot et al. we have initiated an investigation to analyse the effects of the new anti-Survivin drug candidate on cells from our HNC cell line panel. This has revealed interesting novel molecular actions of Survivin and supports the supposition that HNC patients should be included in future trials with anti-Survivin drugs. More...

All of the projects described above would not be possible without the very generous support from many national and international collaborators, as well as several cancer charities and foundations, Oxford University and the European Union.

Scientist interested in more information and/or collaborations should contact the principal investigator Dr. Stephan Feller (stephan.feller@imm.ox.ac.uk).

7. Using protein modification ‘reader’ domains to monitor drug responses of HNC cells

Many proteins that control the signal flow and processing in normal cells and cancers have acquired during evolution well-folded protein regions (domains) that can read modifications on amino acids of partner proteins. In principle these naturally occurring reading devices should be usable to monitor the action of some anti-cancer drugs in patient materials (blood samples, tumour biopsies etc.) and possibly also have value as diagnostic tools, for example in classifying molecular subtypes of HNCs and other cancers. However, up to now these potential uses have not been put into clinical practice. We are therefore developing such assays with reader domains as molecular probes, in the hope that this will enable us to support in the near future additional clinical trials in Oxford and beyond. Using our substantial HNC cell line panel we are testing different anti-cancer drugs and attempt to monitor the molecular effects using reader domains recombinantly expressed in bacteria. The first results are promising, but more work needs to be done to establish reliable assays for clinical routine uses.

6. A role for the DNA repair complex protein FANCD2 in sporadic HNCs?

It is solidly established that patients with Fanconi anemia (a rare genetic disorder) have a more than 500-fold increased risk to develop HNCs. However, very little is known about the possible roles of the FANC proteins (which form a DNA repair complex composed of at least 13 different proteins) in promoting some spontaneously arising HNCs. We have just started to look into this using our extensive panel of HNC cell lines and focussing one prominent member, FANCD2.

5. Looking at ‘molecular computers’ in cancer cells

Cells need to monitor constantly their environment through receptors on their surfaces and respond to the signals they receive from these via a complex network of signalling proteins. The numerous incoming signals are not only transmitted and sometimes amplified, they also need to be integrated to finally steer multiple fundamentally important processes within cells. These integration processes (addition, multiplication, subtraction etc.) are performed by protein complexes that are assembled on large platform proteins, also known as large multi-site docking (LMD) proteins, which are repeatedly taken hostage by cancer cells to mediate their often fatal actions. Based on our biophysical and biochemical analyses we have developed a new hypothesis on how these molecular computers are assembled on LMD proteins. This N-terminal folding nucleation (NFN) hypothesis, if confirmed, should in time allow an understanding of cancer driving signals at a new level thus enabling new therapeutic strategies. Targeting signal integration points rather than single surface receptors may reduce the development drug resistance, a frequent phenomenon seen in cancer patients undergoing treatments. More details can be found in a PLoS Biology journal publication (Simister PC et al., February 2011) that is freely available to all [www.plosbiology.org].

The EGFR is well known as a protein overexpressed and activated in many HNCs. It therefore serves as a positive control in our KinobeadTM project. It is also a target for several experimental HNC therapies with anti-EGFR monoclonal antibodies or EGFR kinase inhibiting drugs. We are now starting to analyse how EGFR levels vary in individual cases and how it may be functionally linked to other HNC driving proteins.

Variable levels of EGF receptor (EGFR) are expressed in different HNC cells by the ‘western blot’ method. The size and darkness of the spots (protein bands) correspond to the amount of EGFR present in an individual HNC cell line.