Clonal heterogeneity and therapy resistance in Burkitt lymphoma

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Burkitt lymphoma is a rare aggressive cancer of the lymph glands affecting approximately 200 people per year in the UK. Current treatment can be very successful, but this involves intensive chemotherapy and antibody therapies. For some people this type of treatment, carrying the greatest chance of cure, is too toxic and cannot be given. The outcome for these patients is much less good. For those people, both children and adults, able to tolerate the more intensive treatments, there is a high risk of severe infections and patients often have to spend long periods in hospital receiving strong antibiotics to fight infection, painkillers and support with feeding. Unfortunately, for patients in whom the lymphoma relapses there are few additional therapies and very limited chance of cure.Currently, very little is known about why Burkitt lymphoma relapses. We do not fully understand the genetic changes which make a patient's lymphoma more likely to come back and we do not understand why it is that relapsed Burkitt lymphoma tends to be unresponsive to second-line therapies. Importantly, we have no information about how initial treatment with chemotherapy causes, or selects out, chemotherapy resistant cells which are then able to grow and cause a relapse. This fellowship will develop our understanding of the natural variability which exists in a patient's lymphoma at the point when they are diagnosed and then track how this changes, or evolves, in response to chemotherapy treatment. These two factors are believed to be important both for a patient's chance of suffering a relapse and in determining the nature of the relapse, for example whether it might respond to different chemotherapies. As Burkitt lymphoma is a rare cancer and, overall, patients have a good chance of cure, there are limited numbers of relapsed Burkitt lymphoma samples with which to carry out such work. In order to address this problem, we have been developing a collection of patients' samples, taken at diagnosis of Burkitt lymphoma, which we are able to study using mice with an immune system which has been altered to allow them to accept and grow the human lymphoma. These immune deficient mice are currently the only way to keep the lymphoma cells alive long enough to study how they respond to simulated chemotherapy treatment. Mice which have been transplanted with a patient's lymphoma cells will be treated with similar but less intensive chemotherapy to that used in humans. As the most intensive therapies are not used, these mice will eventually develop chemotherapy resistant lymphoma, and we are then able to study the differences between this model of relapsed disease and the initial sample taken from the same patient. Patients' samples will be studied by looking at how the genetic variability, known as tumour heterogeneity, affects the chance of developing therapy resistance and how that heterogeneity changes over time when chemotherapy is given. The effect of chemotherapy on the behaviour of the cells and especially on which parts of a cell's biological machinery, known as its transcriptome, are turned on or off. Initially this will be done by looking at whole tumours from individual patients and mice, but more recent technological developments mean that we will also be able to look at a patient's tumour one cell at a time. By understanding the factors which drive the risk of relapse it will be possible to more accurately predict those patients in need of aggressive therapy and those that may be adequately treated with less intensive treatments. Such an approach may open up potentially curative treatments to older or less fit patients who would currently not be eligible for curative chemotherapy. For patients who relapse, understanding what drives their therapy resistance will allow the rational design of new treatment strategies with a greater chance of cure.