Joint Annual Research Report 2004 - The Royal Marsden

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studies have suggested that patients with different chromosomal characteristics have different prognoses. Characterising these differences further is important because identifying the damaged genes will allow us to target therapies to these genes. One important strategy to identify deregulated genes relies upon the identification and targeting of oncogenes (genes that have been deregulated, often because of recurrent chromosomal rearrangements). Oncogenes are regularly found in chromosome 14. An example is the oncogene FGFR3 (fibroblast growth factor receptor 3), which is deregulated by genetic translocation (where a section of DNA in the chromosome breaks but is then reinserted in the wrong place). The FGFR3 oncogene occurs in 15% of myeloma patients. Our previous studies have characterised where the FGFR3 translocation occurs (in position 4;14) and also demonstrated that cases with this translocation have a distinct gene expression profile. We are now investigating how to specifically target the FGFR3 oncogene in the clinical environment using small molecule tyrosine kinase inhibitors. Initial results, based on pre-clinical and clinical data suggest this may prove to be an excellent treatment option for well-defined subsets of patients. Another recurrent chromosome abnormality – a translocation in position 11;14 – deregulates a group of proteins called D group cyclins, which are involved in helping regulate cell growth and cell division. Targeting gene deregulations associated with D group cyclins may be a therapeutic option for 30–40% of myeloma patients. Defining new biologically relevant targets Proteosome inhibition Other important therapeutic advances have come from the study of the molecular pathogenesis of myeloma (Figure 2). The current, most clinically relevant of these therapeutic advances, is proteosome inhibition using bortezomib. The proteosome is an important intracellular organelle, which degrades signalling molecules in a structured fashion, allowing the complex inter- and intracellular cross-talk that is essential for either normal or malignant cell activity. It is possible to reversibly inhibit the proteosome, without causing excess toxicity, and it has now been shown that malignant plasma cells can be selectively killed in this way. Important targets of proteosome inhibition include the NFÎB/ÎIB complex and cell signalling molecules. In our laboratory programme we are trying to develop more such molecules, selectively targeting other pathways, to give us further therapeutic options aimed at long-term control of the myeloma clone. In this context, an important plasma-cell specific pathway, which may set plasma cells apart from other cells within the body, is their ability to produce paraprotein. The cellular response within the plasma cells enabling them to produce these paraproteins requires an adaptive change and this can be specifically targeted. With this in mind, we are specifically investigating the role of the HSP90 protein inhibitor, a drug developed in The Institute. By targeting different areas in the plasma-cell specific process we hope to increase the effects of the HSP90 inhibitor. Interestingly, based on its mode of action, bortezomib is likely to work synergistically with HSP90 inhibitors. It seems likely that many new agents will work better in combination and we are specifically working in the laboratory to develop model systems for the evaluation of such combinations, which may then be taken forward into the clinical setting.
CANCER THERAPEUTICS Integrating new drugs into the clinical treatment strategy In these ever changing times we feel Chromosome 14 translocations Early Late t(4;14) FGFR3/MMSET t(8;14) MYC t(6;14) MUM1 that it is important to integrate some of t(11;14) cyclin D1 the newer drugs into clinical treatment strategies quickly. Drugs which have t(14;16) CMAF Immortalisation Independent growth of malignant plasma cell been shown to be effective in recent years such as thalidomide, bortezomib and lenolidamide are being integrated into our routine practice, but importantly we are also running a number of investigational protocols, based on Increasing genetic instability 13q- Activating mutations p53 and RAS laboratory data, combining these targeted drugs with standard chemotherapies to try and further improve Normal plasma cell MGUS Myeloma Plasma cell leukaemia response rates and remission durations. The future As part of our Phase I trial commitment we are also Figure 2. A molecular model of investigating the potential therapeutic effects of a We are making excellent progress in our understanding multiple myeloma. number of new drugs. Importantly, all of these have of the use of novel small molecule chemotherapeutic Models of myeloma are based on a clinically been shown to be effective in laboratory studies, but approaches and how to integrate advances in these defined multi-step pathogenesis, where a have not been tested previously in cancer patients. areas with standard treatments. normal plasma cell is Therefore the emphasis of these trials is to investigate Over the next few years we expect to see significant envisaged to transform into a pre-malignant the drugs’ potential anti-myeloma effects, whilst closely advances in the quality of life and survival of patients stage (MGUS), which then transforms to monitoring for side effects. It is hoped that by with myeloma. Our combined clinical and laboratory myeloma. At the endstage performing trials such as this within the Royal Marsden organisation will directly facilitate the transition of new of the disease, these myeloma cells no that we can make quick and efficient steps forward in laboratory developments into the clinic, so that patients longer remain located within the bone marrow making useful and effective drugs more widely available can benefit at the earliest possible stage. and can now be found for patients. in the peripheral blood. The initiating events for myeloma are thought to involve chromosomal Modulating the translocations, whilst later events involve immune system mutations of either RAS or p53 oncogenes, together with other as yet ill-defined genetic lesions. We have shown that thalidomide can enhance the immune system – in particular natural killer (NK) cells – which work against the myeloma plasma cells. These laboratory and targeted treatment approaches are complemented by our transplant programme, which is aimed at using dual autologous (ie same person) and mini-allogeneic (ie different people) transplants to both stabilise the malignant clone and then to introduce donor T-cells in an environment where it is possible to benefit from the graft versus myeloma effect. This T-cell immunomodulation is relevant clinically and provides a way of safely performing an allogeneic transplant in older patients. We firmly anticipate that myeloma will become a chronic disease, which can be managed long-term without impacting significantly on the quality of life of patients. 37
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