Drug Discovery
essential intermediate components and co-factors via branches off of the core glycolysis pathway including via the pentose phosphate pathway which supplies NADPH for redox balance and lipid metabolism and ribose-5-phosphate for nucleotide synthesis and via the serine biosynthesis pathway (Figure 1)9,10. Alongside this it has been postulated that glycolytic adaption could be the result of adaptations to hypoxic conditions during early tumour development and in order to generate ATP and metabolites at a higher rate when glucose is not limiting11. What is clear is the Warburg shift demands that tumour cells implement an abnor- mally high rate of glucose uptake to meeting their increased demands for biosynthesis, energy and reducing equivalents.
The advent of Flurodexoyglucose-positron emis- sion topography (18F-FDG-PET) imaging12, in which a radioactive glucose analogue is used to assess glucose uptake, has confirmed that many tumour types have high glucose uptake and is now used as part of clinical diagnostic packages for tumours. 18F-FDG (2-dexoy-2-(18F)fluoro-D-glu- cose), first synthesised in the 1970s is a glucose analogue which enters the cell in normal ways and is phosphorylated like normal glucose to prevent it being released again but cannot then be further processed by glycolytic pathways before radioac- tive decay and so is a good reflection of glucose uptake in the body13,14. This ability to monitor glucose within tumours and surrounding tissues and the clear increases in glucose uptake and utili- sation in tumours confirms aspects of Warburg’s hypothesis and underlies the important of glucose metabolism in many cancers15,16.
It has also been know for more than 50 years that many tumours have increased rates of gluta- mine uptake and consumption. In fact many cancer cells cannot survive without exogenous glutamine and display a glutamine addiction17. As was seen with glucose, the initial assumption was that the metabolism of glutamine by tumours is inefficient. However, recent studies have shown that gluta- mine is a key initial substrate in many processes essential for cancer cell maintenance and growth. Products of glutamine metabolism have been found to be essential for the generation of acetyl CoA (the starting block of lipid synthesis), for NADH generation (for lipid synthesis and redox balance), for glutathione synthesis (for redox bal- ance) and for serine synthesis (for nucleotide and protein synthesis)(Figure 1)18,19. A large propor- tion of glutamine is also converted to lactate in a process which generates NADPH an essential reducing equivalent in lipid and nucleotide synthe-
66
sis and in redox balance. The multi-step conversion of glutamine to lactate helps to explain high lactate levels in tumours even when glycolytic flux has been slowed to generate key intermediates via branched pathways20,21 (Figure 1).
For both glucose and glutamine metabolism improved imaging techniques coupled with enhanced methods to monitor metabolic flux and identify metabolites (nmr and mass spectroscopy) has really enabled researchers to elucidate what is happening to the key metabolic start points in can- cer cells compared with other tissues and help to understand how cancer cells adapt to use these effectively to maintain growth and survival22,23. The advent of technologies such as RNAi, along- side advances in genomic and proteomic profiling, metabolic modelling and improved access to tumour samples, have proved invaluable in allow- ing researches to really probe metabolic function- ality in cancer. Coupled with the enhanced under- standing into the fates of glucose and glutamine this has driven advances in understanding the com- plex nature of metabolic pathways in cells and how these are deregulated in cancers24,25.
Cancer metabolism pathways: drivers and their potential metabolic targets In recent years what has really catapulted cancer metabolism right back into the spotlight is the understanding of the mechanism by which meta- bolic adaptations are controlled and regulated in tumours by known oncogenic signalling mecha- nism25. Alongside this has been the discovery that within several metabolic components there are cancer-related mutations (ie IDH1/2)26,27 or can- cer-specific isoforms (ie PK-M2)28 that are critical- ly linked to progression of certain tumour types. The ability to sequence large sample banks of tumours and understand the data has unlocked many of the secrets of different cancers and helped us begin to understand what drives tumour forma- tion and progression with deregulation of cellular energetic now recognised as one of the hallmarks of cancer29.
It is now clear that many oncogenic
(Myc18,30,31, PI3k/AKT32-34, Ras10,35) and tumour suppressor proteins (p5336-38, PTEN39,40, LKB141,42) directly affect the expres- sion, regulation and activity of key components of metabolic pathways and it is now believed that these tumourigenic alterations act in part to drive cancer progression via promoting metabolic adap- tation towards enhanced glucose and glutamine dependence (see Table 1). For example, Myc has been shown to upregulate glutaminolysis via
Drug Discovery World Fall 2011
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