Packham, Graham - University of Southampton

个人简介

Professor Graham Packham is Professor of Molecular Oncology within Medicine at the University of Southampton. Graham Packham has a first class honours degree in Biochemistry from the University of Leeds. He was awarded his PhD in 1992 from the University of London, following studies on regulation of Epstein-Barr virus gene expression at the Ludwig Institute for Cancer Research at St Mary’s Hospital, London. Professor Packham carried out his postdoctoral research at St Jude Children’s Research Hospital in Memphis, USA, where he was the recipient of the Martin Morrison Fellowship, investigating mechanisms of action of the c-Myc oncoprotein in the laboratory of Dr John Cleveland. He returned to the Ludwig Institute for Cancer Research in 1995 to establish an independent research group studying the molecular regulation of apoptotic in cancer cells. Professor Packham joined the Cancer Sciences Division of the University of Southampton as a Senior Lecturer in 2000 and was appointed Professor of Molecular Oncology in 2006. Professor Packham leads a research group investigating molecular mechanisms controlling proliferation and survival in malignant lymphocytes and developing novel chemical compounds to interfere with key cancer promoting pathways. He has published more than 130 peer-reviewed papers and patents. Graham Packham is also a cofounder of Karus Therapeutics, a University spin-out company involved in the development of novel therapeutics for cancer and inflammatory disease.

研究领域

The research group has two major long-term interests The molecular mechanisms controlling proliferation and survival in malignant lymphocytes The development of novel chemical compounds to interfere with cancer promoting pathways The goal of our work is to exploit our findings in the biology of cancer cells and the characterization of small molecule inhibitors, to develop novel treatments for cancer. Molecular mechanisms controlling proliferation and survival in malignant lymphocytes Our on-going research in this area is focused on chronic lymphocytic leukaemia (CLL), a disease of malignant B cells and the most common leukaemia in the Western world. The clinical course of CLL is highly heterogeneous with some patients having an indolent disease and others a rapidly progressing disease. Improved understand of the underlying biology mechanisms that cause this clinical heterogeneity is likely to lead to novel therapeutic approaches, especially for patients with the progressive disease subtype. Our research is targeted at understanding signalling via the B-cell receptor and the microenvironment in CLL. In vitro analysis of signalling has demonstrated that individual CLL samples differ in their ability to transmit signals via the cell surface B-cell receptor. Retained signalling is associated with the presence of poor prognostic markers and a poor clinical outcome. Thus, antigen signalling via the B-cell receptor, in the context of specific tissue microenvironments, is considered to play a key role in driving cell proliferation and survival, leading to disease progression. Our current research aims to identify determinants of the differential responsiveness of CLL cells and the biological consequences of signalling via the B-cell receptor in this disease. Key research questions include; How does “positive” signalling via the B-cell receptor drive malignant cell survival and proliferation in CLL? How does the balance between BCR-driven “positive” signalling and anergy influence disease behaviour? What are the functional and clinical significance of altered N-linked glycosylation sites of the BCR in malignant B cells? How can we best select patients for treatment with novel inhibitors targeted towards BCR-associated signalling kinases? Novel chemical compounds to interfere with cancer promoting pathways Small chemical agonists and antagonists are key experimental tools and offer opportunities for drug discovery. Our laboratory has a long term track record in the biological characterisation of novel chemical compounds. A major area of interest is the biological characterisation of chemical modulators of chromatin. Histone proteins are subject to a diverse array of post-translational modifications and alterations in these modifications can contribute to a range of diseases, including cancer and inflammatory conditions. We have performed extensive characterization of natural product histone deacetylase inhibitors, including spiruchostatin A, FK228 and azumamides. Our studies on bicyclic depsipeptide histone deacetylase inhibitors led to the creation of Karus Therapeutics, a University of Southampton spin-out company developing novel therapeutics for the treatment of cancer and inflammatory disease. We continue to characterize novel histone deacetylase inhibitors and to study chemical modulation of other chromatin modifying enzymes, including histone lysine methyltransferases and demethylases. A recent target for study is the histone methyltransferase EZH2 which is activated by mutation in follicular lymphoma. In collaboration with Professor Jude Fitzgibbon (Bart’s, London), we are evaluating the responses of primary lymphoma cells to new EZH2 inhibitors, as part of a programme to develop new personalised therapy approaches in this malignancy.

近期论文

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IL-10 production by CLL cells is enhanced in the anergic IGHV mutated subset and associates with reduced DNA methylation of the IL10 locus - Drennan, S., D'Avola, A., Gao, Y., Weigel, C., Chrysostomou, E., Steele, A.J., Zenz, T., Plass, C., Johnson, P.W., Williams, A.O., Packham, G., Stevenson, F.K., Oakes, C.C. and Forconi, F. Published:2017Publication:LeukemiaPage Range:1-9doi:10.1038/leu.2016.356PMID:27890932 PI3K[delta] inhibition elicits anti-leukemic effects through Bim-dependent apoptosis - Carter, Matthew, Cox, Kerry, Blakemore, Stuart, Turaj, Anna, Oldham, Robert, Dahal, Lekh, Tannheimer, Stacey, Forconi, Francesco, Packham, Graham and Cragg, Mark Published:2016Publication:LeukemiaPage Range:1-36 Epigenetic modulators as therapeutic targets in prostate cancer. - Graça, Inês, Pereira-Silva, Eva, Henrique, Rui, Packham, Graham, Crabb, Simon J. and Jerónimo, Carmen Published:2016Publication:Clinical EpigeneticsVolume:8, (98)Page Range:1-24doi:10.1186/s13148-016-0264-8PMID:27651838 PEITC-mediated inhibition of mRNA translation is associated with both inhibition of mTORC1 and increased eIF2alpha phosphorylation in established cell lines and primary human leukemia cells - Yeomans, Alison, Lemm, Elizabeth, Wilmore, Sarah, Cavell, Breeze, Valle-Argos, Beatriz, Krysov, Sergey, Hidalgo, Marina, Leonard, Elodie, Willis, Anne E., Forconi, Francesco, Stevenson, Freda, Steele, Andrew, Coldwell, Mark and Packham, Graham Published:2016Publication:OncotargetPage Range:1-13doi:10.18632/oncotarget.11655PMID:27579538 Surface IgM expression and function associate with clinical behavior, genetic abnormalities and DNA methylation in CLL - D'Avola, Annalisa, Drennan, Samantha, Tracy, Ian, Henderson, Isla, Chiecchio, Laura, Larrayoz, Marta, Rose-Zerilli, Matthew, Strefford, Jonathan, Plass, Christoph, Johnson, Peter W., Steele, Andrew J., Packham, Graham, Stevenson, Freda K., Oakes, Christopher C. and Forconi, Francesco Published:2016Publication:BloodPage Range:1-25doi:10.1182/blood-2016-03-707786PMID:27301861