What causes treatment resistance?
Transcription factors have an important role in a wide range of blood cancers because they can bind to DNA and change the activity of many different genes. Thus just one regulatory protein can control multiple aspects of tumour biology. We know that high-risk diffuse large B-cell lymphomas, which are incurable with current R-CHOP therapy, contain large amounts of a protein called FOXP1. Gene pathways regulated by FOXP1 suggest that it adversely affects patients’ survival by helping tumour cells hide from their immune system and we will test this further in laboratory models. B-cell tumours which have progressed through development towards antibody producing plasma cells, and whose further development may be blocked, are particularly aggressive. We will study the role of FOXP1 and FOXP2 in controlling this process. We have also identified FOXP1 as a target affected by experimental therapies currently being tested in lymphoma patients. Understanding the mechanisms may help determine why these drugs work in some patients but not others and enable us to identify opportunities for more specific therapies. We will also investigate whether our new therapeutic antibodies that block activation of Notch transcription factors represent novel drugs that can be used to treat patients with blood cancers.