Areas of research
Regulatory genomics of multiple myeloma
Primary and secondary genetic events underpin the transcriptional changes that drive myeloma oncogenic transcriptional programmes. These are executed by deregulated transcription factors and chromatin binding proteins. Our aim is to understand the role of known and novel transcription factors/chromatin modifiers in the biology of multiple myeloma and discover and validate therapeutic targets.
Our experimental tools include -omics assays (ChIP-seq, ATAC-seq, RNA-seq, Capture-C), chromatin proteomics, gene editing approaches including CRISPRi and relevant in vitro and in vivo models of multiple myeloma.
Immunotherapy of multiple myeloma
The Karadimitris group have been studying the biology and therapeutic potential of invariant NKT cells (iNKT) in acute graft-versus-host disease (aGVHD) and blood cancers. They showed that donor iNKT cells protect recipients of allogeneic stem cell transplant from aGVHD and iNKT cell equipped with chimaeric antigen receptor against CD19 (CAR19-iNKT) outperform CAR19-T cells in pre-clinical models of B cell lymphoma. Following this lead, the group is now developing CAR-iNKT cell-based immunotherapy against MM that includes development and validation of CAR against established and novel targets.
Our experimental tools include short- and long term in vitro assays (including longitudinal Incucyte live-cell imaging) and xenograft animal models of blood cancers and myeloma.
In parallel to pre-clinical studies, the group are pursuing clinical development of the CAR-iNKT cell platform for blood cancers.
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Journal articleSpanoudakis E, Papoutselis M, Terpos E, et al., 2016,
Journal articleRotolo A, Caputo V, Karadimitris A, 2016,
Despite encouraging therapeutic advances, multiple myeloma (MM) remains an incurable malignancy. The exciting results of chimaeric antigen receptor (CAR)-based immunotherapy in CD19+ B-cell malignancies have spurred a great interest in extending the use of the CAR technology to other cancers, including MM.Availability of a specific, tumour-restricted antigen is crucial for the design of successful antibody-based CAR therapy. However, in MM, as in other malignancies, the relative dearth of such antigens-targets represents the main obstacle for the wider pre-clinical development and clinical application of the CAR technology.Here we provide an overview of the current progress and future promises of CAR technology in MM therapy. We highlight that, owing to its complexity, phenotypic and functional heterogeneity and the impact of the microenvironment, MM poses several challenges for CAR-based therapeutic approaches. Nevertheless, for the same reasons, MM can serve as a paradigm for better understanding, optimization and overall improvement of the CAR technology for the benefit of cancer and myeloma patients.
Journal articleErsek A, Xu K, Antonopoulos A, et al., 2015,
Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell–derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB-DNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM.
Journal articleJohnston AC, Naresh K, Barwick T, et al., 2015,
Journal articleAuner HW, Moody AM, Ward TH, et al., 2013,
Combined Inhibition of p97 and the Proteasome Causes Lethal Disruption of the Secretory Apparatus in Multiple Myeloma Cells, PLOS One, Vol: 8, ISSN: 1932-6203
Inhibition of the proteasome is a widely used strategy for treating multiple myeloma that takes advantage of the heavy secretory load that multiple myeloma cells (MMCs) have to deal with. Resistance of MMCs to proteasome inhibition has been linked to incomplete disruption of proteasomal endoplasmic-reticulum (ER)-associated degradation (ERAD) and activation of non-proteasomal protein degradation pathways. The ATPase p97 (VCP/Cdc48) has key roles in mediating both ERAD and non-proteasomal protein degradation and can be targeted pharmacologically by small molecule inhibition. In this study, we compared the effects of p97 inhibition with Eeyarestatin 1 and DBeQ on the secretory apparatus of MMCs with the effects induced by the proteasome inhibitor bortezomib, and the effects caused by combined inhibition of p97 and the proteasome. We found that p97 inhibition elicits cellular responses that are different from those induced by proteasome inhibition, and that the responses differ considerably between MMC lines. Moreover, we found that dual inhibition of both p97 and the proteasome terminally disrupts ER configuration and intracellular protein metabolism in MMCs. Dual inhibition of p97 and the proteasome induced high levels of apoptosis in all of the MMC lines that we analysed, including bortezomib-adapted AMO-1 cells, and was also effective in killing primary MMCs. Only minor toxicity was observed in untransformed and non-secretory cells. Our observations highlight non-redundant roles of p97 and the proteasome in maintaining secretory homeostasis in MMCs and provide a preclinical conceptual framework for dual targeting of p97 and the proteasome as a potential new therapeutic strategy in multiple myeloma.
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