New insights into how antibodies are made suggests new approach for anti-cancer drug targets
Research at the Babraham Institute, investigating how white blood cells known as B cells develop, has revealed that genes from the Phosphatidylinositol 3-kinase (PI3Ks) family of enzymes are critical in enabling the B cells to produce antibodies in the spleen and lymph nodes. PI3Ks are involved in a diverse range of activities inside cells, generating signalling molecules to control cell growth, proliferation, motility, survival and intracellular trafficking. Faults in these processes can lead to the development of cancer; consequently the PI3Ks are currently among the most hotly pursued drug targets in the pharmaceutical industry.
The PI3K enzymes are made up of two parts, a regulatory subunit and a catalytic subunit known as p110, of which there are four types (isoforms) - p110α, p110β, p110γ and p110δ. Mutations in p110α are seen in many cancers including breast and colon cancer and drugs inhibiting the activity of all four of these isoforms are being trialled as anti-cancer drugs. Published today online in the journal Science Signaling, this is the first description of p110α in immune cells.
The findings suggest that drugs targetting p110α specifically may retain significant anti-cancer effect without compromising immunity. B cells start to develop in the bone marrow, before they mature and populate the spleen and lymph nodes, where they make antibodies to eliminate viruses and bacteria from the body.
Previous studies suggested a non-essential role for the PI3K family in early B cell development. However, this research at the Babraham Institute, an institute of BBSRC, has shown that if both p110α and p110δ are inhibited, no B cells develop. The spleen and lymph nodes of mice lacking both p110α and p110δ genes were devoid of B cells and virtually no antibodies could be found in the blood. Hence, blocking these enzymes together would have a dramatic effect on the immune system. The p110γ and p110δ isoforms are produced in cells of the immune system but are not found in other organs and tissues. They are therefore potential therapeutic targets for autoimmune diseases and inflammation. However, it was unclear whether p110α was also important in immune cells.
Dr Klaus Okkenhaug leading the research explained, “Blocking p110α alone had no effect on B cells, nor did the inhibition of p110β or p110γ. However, if 110δ was blocked, B cells continued to develop but made fewer antibodies, thus potentially dampening unwanted immune responses. “It is possible to develop drugs that will inhibit one of these isoforms selectively. For instance, p110α, but neither of the other three isoforms, is frequently mutated and hyper-active in tumour cells and is therefore an obvious target in cancer therapy. Although drugs that target p110δ selectively could be useful to treat autoimmune and inflammatory diseases, anti-cancer drugs might be less toxic to the immune system if they are designed to inhibit p110α, but not p110δ,” he added. However, as pointed out by Jose Limon and David Fruman (UC Irvine) in a perspective on the article, inhibition of both p110 α and p110δ may be required to treat B cell malignancies.
The Babraham Institute is a centre for studying the basic biology of signalling inside and between cells, supporting BBSRC’s mission to drive advances in fundamental bioscience for better health and improved quality of life. With around 90 autoimmune diseases, 100 inherited immune deficiencies as well as the impact of ageing, malnutrition or the use of medications on immune function, a greater understanding of immunity and how the immune system is established is of direct relevance to promoting healthier lifespan. The Babraham researchers seek to discover and characterise important pathways controlling healthy immune function, which may be targeted pharmaceutically to either boost or curtail aspects of the immune response. Results from these investigations may provide rationale for the use of PI3K inhibitors in therapeutic settings. This work was a BBSRC-funded collaboration between the groups of Klaus Okkenhaug (Lymphocyte Signalling & Development ISP), Anne Corcoran (Nuclear Dynamics ISP), both at the Babraham Institute, and Bart Vanhaesebroeck, (Barts & The London School of Medicine).
Ramadani F, Bolland D, Garcon F, Emery JL, Vanhaesebroeck B, Corcoran AE, Okkenhaug K (2010) The PI3K isoforms p110α and p110δ are essential for pre-B cell receptor signaling and B cell development. Science Signaling 3 ra60 http://dx.doi.org/10.1126/scisignal.2001104
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About the Babraham Institute:
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, health and well-being and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.