An international collaboration involving researchers from Queen Mary University of London, Memorial Sloan Kettering Cancer Center (MSK), New York and Dana-Farber Cancer Institute, Boston has secured a €1M research grant from Dutch blood cancer charity, Lymph&Co, to investigate a new treatment target for lymphoma.
The aim of the project is to determine how targeting a protein called KDM5 kills lymphoma cells, and to identify the patient groups most likely to benefit from this type of treatment.
Lymphoma is a type of blood cancer that arises from white blood cells called lymphocytes. Changes in the genetic code (mutations) of lymphocytes can cause them to grow uncontrollably and, as a result, these white blood cells collect in lymph nodes and other tissues, eventually giving rise to lymphoma. There are two main types of lymphoma: Hodgkin's and non-Hodgkin's lymphoma (NHL), which comprise over 60 subtypes.
Combatting the effects of common lymphoma mutations
Research has shown that many lymphoma patients have one or more mutations in a gene called KMT2D. The KMT2D gene codes for a protein involved in controlling gene expression within cells; however, mutations that stop KMT2D from functioning correctly (leading to changes in the expression of genes required for normal cell function) are the most common mutations detected in lymphoma.
The collaborating teams, led by Professors Jude Fitzgibbon at Queen Mary's Barts Cancer Institute (BCI), Hans-Guido Wendel, MD at MSK and David Weinstock, MD at Dana-Farber, are leaders in the study of lymphomas using cell lines and animal models. Based on recent experiments, the researchers believe that targeting a protein - called KDM5 - that usually acts against the effects of KMT2D may reverse the consequences of KMT2D mutations in lymphomas, causing the lymphoma cells to die.
The project will build upon previous work by the teams, including recent research led by BCI's Professor Fitzgibbon and former postdoctoral researcher Dr. James Heward, which found KDM5 inhibition to reverse the effects of KMT2D mutations in cell lines and preclinical models of a group of NHL called germinal centre lymphomas. It also builds on earlier work from the Wendel lab that first characterized the role of KMT2D mutations in lymphoma development.
Lead researcher from BCI, Professor Fitzgibbon, said: "Thanks to generous support from Lymph&Co, we have the opportunity to create a unique international collaboration, to build on our groups' understanding of KMT2D mutations and to determine if the potency of KDM5-inhibition is specific to germinal centre lymphomas or may have broader therapeutic potential in other non-Hodgkin's lymphomas."
A precision-medicine approach
Much research has focused on what distinguishes one type of lymphoma from another. KMT2D mutations are present in only 5-20% of some lymphoma subtypes but up to 80% of a lymphoma subtype called follicular lymphoma, which is the second most common lymphoma in the UK, US and Europe. Therefore, the teams will investigate whether targeting KDM5 may be an effective therapeutic approach across a variety of lymphoma subtypes. Indeed, KMT2D and related genes are mutated in many other types of cancers so an effective therapeutic targeting KDM5 could be broadly useful for many people with cancer.
If the research demonstrates that KDM5-directed therapy is effective at offsetting the effects of KMT2D mutations in lymphoma, then the study could offer a new approach to lymphoma treatment. As part of the project, the researchers aim to identify KDM5 inhibitors that would be suitable for evaluation as part of early phase clinical trials, and to establish patient populations most likely to benefit from these therapies.
In addition, by enhancing their understanding of the knock-on effects of KMT2D mutations within lymphocytes, the team endeavour to identify other molecules that could be targeted with drugs already approved for use in the clinic.
Dr. Weinstock, who is Lavine Family Chair for Preventative Cancer Therapies at Dana-Farber and a Professor of Medicine at Harvard Medical School, said: "It is a tremendous honour to be part of this team under Dr. Fitzgibbon's leadership. Our hope is to harness the talent and resources across our research programs to directly target one of the most important alterations in follicular lymphoma and other cancers."
This is a great time to translate understanding of cancer mechanisms into new lymphoma therapies."
Dr. Wendel, Professor, Cancer Biology & Genetics Program, MSK
Prof. Dr. Bob Lowenberg, chairman of Lymph&Co's scientific advisory board, said: "The aim of Lymph&Co is to provide the leading doctors and scientists researching lymph node cancer with means that allow them to carry out this research anywhere in the world. Within this unique Lymph&Co research project, an international consortium of top researchers from London, Boston and New York will join forces and have the opportunity to search for better treatment options for patients with common forms of lymph node cancer. Lymph&Co looks forward to working with these researchers."
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