From genes to disease
Professor Tony Green in Cambridge will analyse how the genes of patients with the blood disorder essential thrombocythaemia (ET) affect their disease. Researchers have already identified a number of genetic abnormalities in patients with ET, and some are used to help diagnose this disorder. Tony will study patient samples to see which genetic faults are associated with different disease features at diagnosis, patient response to therapy, and disease progression or clots. This will help improve diagnostic tests and shed light on how genetic information could be used to guide treatment choices.
Professor Ghulam Mufti at King’s College London will map out the time-ordered sequence of genetic faults acquired by patients with deficient blood cell production – aplastic anaemias (AA) and myelodysplastic syndromes (MDS) and how the immune system shapes this. This will not only reveal how and why some AA and MDS cases develop into more aggressive diseases, but also guide therapies to block the disease by manipulating the immune environment.
What turns genes on
We now realise that it isn't just the sequence of DNA letters that matters in cancer. Southampton’s Professor Jon Strefford, for example, is studying chemical flags stuck on DNA that influence how gene activity is turned up and down in chronic lymphocytic leukaemia (CLL). This is to better predict at diagnosis which patients require immediate treatment and which patients will not respond to existing standard therapies.
Another way genes can be opened or closed to activating signals is through structural changes involving proteins – called ‘histones’ – that wrap up DNA into chromosomes. Using cells from patients and mice with leukaemuia, Professor Eric So's team at King's will ask how misfiring enzymes can lead to histone changes that activate genes whose products can drive the initiation or progression of leukaemia. At Imperial College London, Professor Tassos Karadimitris’ team will scan samples from patients for new genes whose activity levels are disrupted in myeloma, including those involved in destruction of bone. Both these programmes will help identify new biological targets for drugs that are more effective and less toxic.
And some projects are already homing in on these biological targets. Dr Gordon Strathdee at Newcastle, for instance, is focusing on a gene called HOXA4 that is frequently switched off in CLL, particularly in patients whose disease progresses more rapidly. Gordon will test whether switching HOXA4 back on in cells from patients may in turn activate other genes that cause leukaemia cells to die.
When signals go wrong
A key role of genes is to provide a template to code for new proteins that keep cells and tissues working normally. So a change to a gene (Green/Mufti) or its activity (Strefford/So/Karadimitris) can send things out of control.
Cancers that affect immune cells called B-cells, such as CLL and some lymphomas, are often driven by signals that stimulate a receptor protein stuck on the cancerous B-cell’s surface. Professor Ten Feizi at Imperial will use state-of-the-art technology to screen hundreds of carbohydrate molecules to find new signals the B-cell receptors recognise, and to examine their contribution to the growth and persistence of CLL cells.
Professor Anne Willis at Leicester will work with Dr Martin Turner of The Babraham Institute in Cambridge on the same protein, eIF4B. It helps send signals within a cell but when faulty plays an important role in the progression of a type of non-Hodgkin lymphoma, called diffuse large B-cell lymphoma (DLBCL). High levels of eIF4B helps DLBCL cells grow and resist chemotherapy, and is a sign that patients may fare poorly. Anne will study the interplay between eIF4B and other proteins involved in repairing damaged DNA and preventing cell suicide, so as to allow the development of new therapies that can inhibit these key signals. Martin will use mice to test whether reducing activity levels of eIF4B can reverse this and make DLBCL cells more sensitive to chemotherapy.
And hoping to show this approach to treatment can work, Dr Graham Collins in Oxford will run a clinical trial through our pioneering Trials Acceleration Programme to see whether he can target another signalling pathway in DLBCL, particulary for hard-to-treat relapsed cases. Drugs that block a protein called mTOR, which is involved in cancer cell growth and survival, only work in a minority of lymphoma patients, possibly because the drugs do not block mTOR completely. Graham’s new trial will test whether a new drug, AZD2014, that inhibits a wider range of mTOR functions works effectively against DLBCL. He also plans to check the safety of combining AZD2014 with rituximab, an agent commonly used in DLBCL.
Immunity: defence and attack
Aside from a cell's internal machinery going awry, a critical hallmark of cancer is the ability to evade destruction by the immune system. An example of this is in CLL, where leukaemia cells form ‘safe havens’ in the lymph nodes by corrupting the supporting tissue to dampen any inflammatory signals. Dr Alan Ramsay at King’s will first look in mice at the identity of these immune-avoidance signals to give clues how they operate in humans.
A type of cell that is already known to control the level of inflammatory response within a tissue is a mesenchymal stromal cell (MSC). Also at King’s, Professor Francesco Dazzi's team is exploring the biological events that allow leukaemia cells to hijack MSCs to protect against immune attacks. Alan’s and Francesco’s work will help find ways to remove this invisibility cloak, potentially releasing the brakes on cancer-killing immune attack. It could also be harnessed to prevent a complication after a stem cell transplant, known as Graft-versus-Host disease.
And an immune attack can come in the form of specialised white blood cells called ‘gamma-delta’ cells, which can target a range of tumours, especially leukaemias and lymphomas. There is, however, wide variability in the function of these cells within patients and they can become unresponsive after long-term cancer exposure. Professor Daniel Pennington at Queen Mary University of London will study this variability to devise better ways of tailoring cancer treatments to different patients. He will also aim to generate ‘fresh’ gamma-delta cells, without the negative exposure effects, for potential use as a treatment.
We’re leaving no stone unturned in our mission to beat blood cancers – and neither are our researchers.
This article is licensed under a Creative Commons Attribution 4.0 International License .Image 1: Flickr user: Shaury Image 2: Wikipedia user: Pleiotrope Image 3: Flickr user: Microbe World