Drug Discovery
profile corresponding to the oligodendrocyte sub- type of glioma26. Similar changes in DNA methy- lation profiling were also seen in human AML samples. A decrease in -KG levels (probably due to heterodimerisation between -KG producing WT IDH and -KG metabolising mutant IDH [Figure 3]) coupled with an increase in 2-HG lev- els is reported to block epigenetic events including histone demethylase and TET1/2 (hydroxylases which usually produce 5-hydorxymethylcytosine) activity and are believed to be the major mecha- nism by which IDH mutants function in tumours1. 2HG has also been reported to stabilise HIF1 which can regulate many metabolic components and also promote VEGF signalling, a driver of tumour angiogenesis123.
Therefore, IDH mutants represent an attractive target for targeted therapy as they show a unique cancer specific function and generate a potential cancer biomarker in 2HG for disease stratification. However, one intriguing recent piece of evidence is that in IDH mutant appear to have slightly pro- longed survival which adds more complexity to this intriguing target124.
Future challenges in targeting cancer metabolism
The challenges around targeting metabolism will involve a clear understanding of how a cancer cell differs in its metabolism to that of a rapidly pro- liferating normal cell. It has long been known the neurological cells also have high glucose demands and also a reliance on other metabolites linked to some of the canonical metabolism pathways and linked to cancer, for example glutamine and ser- ine. For example, it has been shown in normal T- lymphocytes125 and astrocytes126 that siRNA depletion of metabolic enzymes such as PFKFB3 decreases the proliferation rates of these ‘normal’ cell lines127,128. Therefore it will be important to fully understand the metabolic drivers by which a cancer cells may differ from normal cells and also the potential toxicity risk associated with target- ing metabolism.
Another challenge will be around patient strati- fication/selection. While many tumours may dis- play high glucose or glutamine uptake/utilisation, this alone is likely to be insufficient as a predictive marker for therapeutic potential of an anti-metab- olism agent. It will be important to fully under- stand how known oncogenic drivers of cancer (ie myc, ras, PI3K) or loss of tumour suppressor genes (ie p53, PTEN, LKB1) impact on metabolic flux and/or regulation of key metabolic points in differ- ent tumour types. While a few mutations in metab-
72
Dr Neil P Jones is a Principal Target Validation Scientist at Cancer Research Technology and involved in the drug discovery alliance between Cancer Research Technology and AstraZeneca to identify new cancer therapies targeting cancer metabolism. He received his PhD at the University of Southampton in the Cell and Molecular Bioscience Laboratory and has previously worked in lipid signalling pathways and cancer at the Institute of Cancer Research, London.
Drug Discovery World Fall 2011
olism enzymes in cancer have been identified, it is likely that in many tumours the impact of metabo- lism targets will be a complex interplay between expression, regulation, flux and oncogenic changes. It will also be important to consider that within metabolism pathway there are plenty of opportunities for tumour cells to evade metabolic blocks through bypass pathways and redundancy, so understanding key nodal points and possible combination strategies or synthetic lethality approaches will be essential. Likewise the interplay between metabolism targets and current chemotherapies (many of which create increased demand for biosynthetic intermediates as the tumour attempts to survive these agents) could be an important therapeutic strategy to consider as more metabolism targeting agents reach clinical trials in the future.
Pharma is rapidly adapting to these needs by the way it is approaching this area with ties to leading academic experts in cancer metabolism and utili- sation of existing expertise against metabolic dis- orders for which many companies already have a platform. It is hoped that with this approach and the renewed interest in cancer metabolism the way is paved for a new generation of cancer metabo- lism therapeutics.
DDW
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