About 10,000 new patients are diagnosed with myeloid cancers every year in the UK. These are cancers that develop from blood stem cells. We aim to improve the clinical management of these disorders by supporting collaboration between our own team and other expert groups.
We are currently carrying out studies on:
Acute Myeloid Leukaemia Research (AML)
Current projects are focused on finding out how the disease first starts and then progresses in adult AML and in Myeloid Leukaemia of Down’s Syndrome. We have established a large tissue bank of blood cell samples from patients with AML which have been screened for genetic mutations linked to the disease. We are trying to find out which faulty genes cause the leukaemia cells to multiply. If we can identify the mutant proteins that are produced by these genes, we may be able to find drugs that will block their activity and so stop the leukaemia cells in their tracks.
Children with Down’s Syndrome are at increased risk of developing AML, which appears to be linked to mutations in a gene called GATA1. The number of mutations can increase over time. We work with clinicians to identify Down’s syndrome patients with GATA1 mutations. These patients are then followed-up with regular tests to see if the numbers of gene mutations are increasing. This can aid diagnosis and guide therapy. We have collected more than 200 samples from children with Downs with a pre-leukaemic condition (TMD, Transient Myeloproliferative Disorder) and Myeloid Leukaemia of Down’s Syndrome (ML-DS) from around the world.
Looking for leukaemic stem cells
Acute myeloid leukaemia (AML) is a cancer of the white blood cells which develops in the bone marrow. It originates in marrow stem cells that develop abnormalities deep in their instruction manual, the DNA. These cells then become elusive “leukaemic stem cells”. Current chemotherapy can efficiently kill leukaemia cells in the bone marrow, but generally do not get rid of the leukaemic stem cells- this means that some time after chemotherapy, the leukaemia returns or “relapses”. These leukaemic stem cells are few and far between, and looking for them amongst the billions of other cells in the marrow is like looking for a needle in a haystack. We work on methods to find these cells and determine exactly how they have gone wrong in order to target them directly with new drugs.
Myelodysplasia (MDS) includes a diverse group of blood cell disorders, caused by abnormal bone marrow changes or ineffective blood cell production and development. These result in anaemia, infections and bleeding. MDS patients also have a high risk of developing acute myeloid leukaemia (AML).
Our research focuses on rare MDS bone marrow cells, known as MDS stem cells, which are responsible for the disease. Past and current research is looking at how to identify these cells in different types of MDS, and how they differ from normal cells.
Common genetic changes found in MDS bone marrow cells seem to be responsible for starting the disease as well as the progression to AML. We are using the results from our analysis of patients’ genes and blood cells to set up experiments in the lab that will help us work out how these genetic changes lead to the condition.
We are also investigating the process of normal blood cell production, in particular looking at why blood stem cells develop one way or another, as well as identifying the molecular signals that influence this decision. The better we understand normal blood development, the better we will be able to identify how this process can go wrong in leukaemia.
Finally, MDS stem cells are sometimes resistant to the drug treatments currently available, which means treatment options are very limited. We are therefore exploring novel ways to eliminate the problematic MDS stem cells in order to cure greater numbers of patients with MDS.
Lymphoid disorders include a wide range of blood diseases that involve cells from the immune system, known as lymphocytes. Our research covers a number of lymphoid disorders including: Hodgkin Lymphoma, B and T-cell non-Hodgkin lymphoma, myeloma (and other plasma cell disorders), chronic lymphocytic leukaemia (CLL) and multiple myeloma.
Our aims are:
- To investigate new therapies and novel combinations of drugs for lymphoid cancer.
- To investigate how the drugs work and how blood cancer cells become resistant to these drugs.
- To find ways to improve routine practice and the outcomes for patients with lymphoid cancer.
- To investigate what causes bone disease and kidney problems in patients with myeloma, and to find better ways to treat these symptoms.
Investigating new drugs and new drug combinations
Over the last few decades, our understanding of how immune system cells (lymphocytes and plasma cells) become cancerous has increased considerably. This has led to the development of targeted new therapies, some of which are already being used in routine clinical practice. However, the outcomes for patients with myeloma and relapsed lymphoma could still be improved.
Our group is leading several early trials of new treatments, particularly for B and T cell lymphomas. We are collaborating with other expert groups in the UK to test new agents that reduce inflammation in myeloma and a new anti-cancer virus. We also work closely with biotech partners, enabling them to bring some of their new treatments to patients with lymphoid cancers.
Investigating how drugs work and what causes resistance
Crucial to the success of new drugs, is understanding how they work biologically, as this can lead to tests that predict who is likely to respond. One such test is for the protein HR23B, which may predict the outcome of two different types of anti-cancer drug. Biological samples from patients with T cell lymphoma and multiple myeloma being treated with different drugs are being analysed to see how well HR23B levels predict the patient’s response.
Analysing the genetic material (DNA) in the blood that comes from tumour cells is another area of growing interest. This analysis can reveal which genetic mutations are present in the tumour, which may help guide treatment. The speed with which this DNA disappears from the blood might also prove to be a good measure of whether a tumour is responding to treatment. This is being tested in one of our clinical trials.
In another study, we are looking at a signalling molecule called bone morphogenetic protein (BMP), to see how it affects tumour growth in the bone marrow and leads to bone disease in myeloma. We’re also interested in whether this BMP molecule affects red blood cells to cause anaemia in myeloma. Find out more
Improving practice and outcomes
Members of our group are leading large clinical trials at a national and international level, in both myeloma and lymphoma. These trials aim to find better ways of treating patients than current approaches. Our centre is one of the top five centres in the UK for recruiting patients into trials.
Bone disease and kidney problems in patients with myeloma
Optimising bone health is one of the most important areas of unmet need for cancer patients. Maintaining bone strength is an important part of comprehensive cancer care, in early stages of myeloma bone disease and later, if the cancer has spread. We are collaborating on a study to find out how many patients have myeloma bone disease and how best to treat it. We aim to find out which treatments are the most cost-effective and which bring about the biggest increases in patients’ quality of life.
In another study, we are collaborating with bone experts, to test whether using MRI (magnetic resonance imaging) scans to measure bone loss is a useful way to monitor the progression of myeloma bone disease.
We are also trying to identify which molecules signal pain in patients with myeloma-induced bone disease. If we can find out which molecular signals are being activated in the bone tumour, and how these signals are controlled, we may be able to identify novel treatments to stop the pain.
Some patients with plasma cell disease experience kidney problems caused by an abnormal immune reaction to the kidneys. This is a rare condition and we are aiming to find out more about what happens to these patients following treatment, by setting up a national registry and closely monitoring their progress.
Bone Marrow Transplantation
Bone marrow transplantation (stem and immune cell transplantation) is the only routine stem cell therapy used in medicine. It is one of the most common cures for blood cancers, and is now being used for other blood disorders.
Much of the research at our transplant service is about finding ways to increase the chances of a cure, and reducing the risk of serious problems caused by the transplant. Bone marrow transplants use cells from either the patient themselves or from donors. With donor transplantation, the donor’s immune cells attack the patient’s blood cancer cells (called graft versus leukaemia, GvL) leading to a cure. Donor immune cells can also attack the patient’s normal cells (called graft-versus-host disease, GvHD). GvHD can cause serious problems and even lead to death. We therefore want to find ways to increase GvL and reduce GvHD.
Everyone’s cells are different in terms of the molecules they have on their surface. These molecules – like flags – signal to the immune system which cells are our own and which cells are foreign. Research on GvL is aiming to find out which of these molecular flags are involved when the donor immune cells attack the patient’s cancer cells. This might identify ways in which to enhance the immune response and bring about a cure.
Previous research at our Centre has shown that if a stem cell or immune cell transplant from a donor includes high numbers of a particular type of immune cell called regulatory T cells (Tregs), this results in better outcomes. We are therefore following up this initial observation to see if there are ways we can increase the number of Tregs in healthy blood and marrow donors and to find out how the number of Tregs makes a difference.
National and international collaborations
The doctors working in our transplant centre are involved in national and international collaborations to ensure useful data is collected as part of clinical care and to support the development of new clinical trials. We are also analysing the data that is routinely collected from transplant patients to find out whether we can predict which patients will develop complications, and whether anything can be done sooner to prevent problems occurring.