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Targeting target
cancer metabolism
what is fuelling the resurgence?
Targeting the metabolic pathways of cancer is a hot topic for drug discovery.
The central dogma is that cancers have a higher demand for metabolic inputs
to aid proliferation and survival and that this could be an Achilles heal which
could be exploited therapeutically. This central metabolic facet of cancer has
been known for more than 50 years so what are the recent discoveries that
have fuelled the renewed investment in metabolic targets in cancer?

I
By Dr Neil P. Jones n recent years there has been resurgence in
interest in metabolism as a possible area for
development of novel anti-cancer agents. This
has been fuelled by advances in technology and
understanding of cellular metabolism and how
targeting this area could be of therapeutic benefit.
The drivers behind these advances have come
from academic-led research pushing our under-
standing of cancer cell metabolism and the inter-
play between these pathways and other cancer
related signalling events linked to changes in onco-
gene or tumour suppressor gene status/function.
In the past few years this spiralling interest has
lead to a rapid increase in the number of publica-
tions on metabolism, multiple focused cancer
metabolism conferences and the renewed interest
from the pharmaceutical industry in this area of
anti-cancer research.
This interest has lead to the establishment of
several new companies focused on this area and to
the generation of partnerships between the
Pharma industry and research organisations to
understand this complicated field and hunt for
new targets. For example, Agios Pharmaceuticals
was founded by key academic experts in cancer,
oncogenic signalling and metabolism research
(Lewis Cantley, Craig Thompson and Tak Mak) to
focus on cancer metabolism as a new approach to
cancer treatment and has an active pipeline of
metabolism targets including isocitrate dehydroge-
nase (IDH1/2)1 and Pyruvate kinase-M2 (PK-
M2)2, targets which will be discussed in more
detail later. Agios has also recently entered into a
$130 million strategic alliance with Celgene to
explore novel drug targets in Cancer metabolism.
Cornerstone Pharmaceutical was also founded
through academic researchers (Paul Bingham and
Zuzana Zachar) with a focus on targeting cancer
metabolism and has a candidate drug, CPI-613,
which targets pyruvate dehydrogenase3 currently
in multiple Phase I/II clinical trials. Another
biotech, Advanced Cancer Therapeutics, has
invested in research at the James Graham Brown
Cancer Centre and the University of Louisville
Research Foundation to pursue cancer metabolism
targets for example; PFKFB3, a glycolytic regula-
tor4 and choline kinase ␣ component of lipid
metabolism pathways5. Likewise AstraZeneca is
midway through a multi-project three-year
alliance with Cancer Research Technology, Cancer
Research UK’s commercialisation and develop-
ment arm to work on a portfolio of targets select-
ed from Cancer Research UK’s biological research
in the emerging field of cancer metabolism.

64 Drug Discovery World Fall 2011

Metabolism_Layout 1 04/10/2011 17:39 Page 65
Many potential drug targets within the metabol-
ic field are currently being evaluated as potential
therapeutics in all stages of the drug development
progress from early development, through pre-clin-
ical development and into clinical trials although
as yet no agent targeting a core metabolic pathway
has been approved for cancer6. Figure 1 summaries
some of the core metabolic pathways and some of
the agents in development looking to target differ-
ent areas of cancer metabolism. In order to fully
understand why there are so many agents and
pathways under consideration in cancer metabo-
lism it is important to investigate the main drivers
for targeting cancer metabolism. The rest of this
review will therefore consider why cancer metabo-
lism could make an attractive area for therapeutic
intervention and how our understanding of these
pathways and advances in technology/knowledge
is driving the hunt for new therapeutics.
Cancer metabolism and
the Warburg Effect
Dividing cells require ATP to maintain energy sta-
tus, increased biosynthetic intermediates and
maintenance of cellular redox status. In order to
meet these needs carbohydrates, proteins,
nucleotide and lipid alterations are required. Both
Drug Discovery World Fall 2011
Drug Discovery
Figure 1
Targeting tumour metabolism.
Core metabolic pathways and
enzymes against which
inhibitors (shown in red) have
been reported. Key enzymes
are shown in green boxes and
key biosynthetic endpoints
listed in purple. Abbreviations:
GLUT – Glucose transporter;
HK2 – Hexokinase-2; PFK1 –
Phosphofructokinase 1;
PFKFB3 – 6-phosphofructo-2-
kinase/fructose-2,6-
biphosphatase 3; PK-M2 –
pyruvate kinase-M2; LDHa –
lactate dehydrogenase-A;
MCT1/4 – Monocarboxylate
transporter’s 1/4; AMPK –
AMP activated protein kinase;
G6PD – glucose-6-phosphate
dehydrogenase; TKT –
transketolase; TKTL1 –
transketolase like -1; ASCT2 –
solute carrier family 1,
member 5 [SLC1A5]; GLS1 –
Glutaminase 1; ME – malic
enzyme; FH – fumarate
hydratase; SDH – succinate
dehydrogenase; PDH –
pyruvate dehydrogenase; PDK1
– pyruvate dehydrogenase
kinase 1; ACLY – ATP citrate
lyase; ACACA – acetyl-CoA
cancer cells and rapidly proliferating normal cells carboxylase alpha; FASN –
require some of these adaptations for prolifera- fatty acid synthase; CA9/12 –
tion, however cancer cells must implement these carbonic anhydrase 9/12;
processes in very different and often harsh or NHE1- Na+-H+ exchanger
stressful environments where nutrients supplies [SLC9A1]
may be low and where redox balance, pH and
oxygen levels may not be maintained. Cancer cells
have found ways to adapt to these dynamic situa-
tions and regulate their metabolic status in order
to survive, grow and even prosper.
The links between cancer and altered metabo-
lism is not a new phenomenon. Otto Warburg, a
Nobel prize-winning scientist (for the discovery of
cytochrome oxidase) noted more than 80 years ago
that in tumour tissue slices ATP is generated from
glucose via aerobic glycolysis which is an oxygen
independent process rather than by oxygen
dependent oxidative phosphorylation even when
oxygen is present7,8. This switch in ATP generation
which has been termed the Warburg Effect is ini-
tially paradoxical as while ATP generation is more
rapid via glycolytic pathways, far less ATP is gen-
erated (2 molecules ATP/molecule glucose) than via
oxidative phosphorylation (up to 36 molecules
ATP/molecule glucose).
In more recent times this switch has been attrib-
uted to the ability of glycolytic pathways to supply
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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,
PTEN 39,40 , LKB1 41,42 ) 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
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increasing the expression key components of the cers

Table predominantly involves
1: Control of metabolic the by
processes transporters
oncogenes and tumour suppressor genes
glutamine metabolic pathway43 and to enhance
oxidative metabolism of glucose via increased
pyruvate dehydrogenase44 and lactate dehydroge-
nase expression/activity45. HIF1␣11,46-48, a tran-
scription factor which can be upregulated in
hypoxic conditions or by enhanced oncogenic (ie
Myc49,50) or decreased tumour suppressor (ie Von
Hippel-Lindau51) function is also known to
upregulate the expression of many metabolic
enzymes including glucose transporters
(GLUT448), metabolic regulators (PFKFB352,53,
PFKFB452, pyruvate dehydrogenase kinase
(PDK1)44,54) and glycolytic enzymes (hexokinase-
2 (HK2)44, PK-M255, lactate dehydrogenase
(LDHa)56, monocarboxylate transporter 4
(MCT4)57). This suggests that metabolic adapta-
tions also play a role in maintaining tumour
growth and survival in hypoxic conditions. Akt
also increases glycolysis by increasing glucose
transporter expression32 and facilitating hexoki-
nase translocation to the mitochondria where it
functions to initiate glycolytic flux 34,58. The
tumour suppressor protein p5359,60 has also been
shown to regulate expression of various glycolytic
proteins including upregulation of hexokinase and
of a protein called TIGAR which acts as a negative
regulator of glycolysis61,62. p53 also promotes
oxidative phosphorylation via upregulation of GLUT1 and GLUT4 for glucose65 and
SCO263 and suppresses glycolysis via expression ASCT2(SLC1A5) for glutamine66. GLUT1 and
of PTEN, a negative regulator of the PI3K path- GLUT4 have been found to be overexpressed in
way64. Therefore, while loss of p53 may drive many cancers and to be upregulated by ras and
acquisition of the glycolytic phenotype it will be myc signalling65,67. Currently there are no clear
important to understand metabolic regulation in inhibitors of GLUT1/4 published although the
p53 wild type and mutant tumours. natural dihydrochalcone, Phloretin is reported to
Understanding the interplay between oncogenes have GLUT inhibitory activity and be effective in
and tumour suppressors and metabolic pathways inducing apoptosis in in vivo cancer models68.
will be key to deciphering how metabolism inte- ASCT2 is also overexpressed in some tumours69
grates into tumour initiation and progression and and reported to be directly upregulated by
in looking for potential therapeutic targets with myc18,70 although as yet no clear inhibitors of this
clear clinical stratification. The rest of this review transporter have been reported. The oncogenic
will take a stripped-down look at metabolism and upregulation of glucose and/or glutamine trans-
introduce a couple of potential metabolism targets porters in cancer helps to explain how tumours
which are currently being extensively investigated adapt to facilitate their increased reliance on glu-
both by academia and industry. cose and/or glutamine and how tumours can accu-
mulate high levels of these metabolites.
The basic stages of glucose and The next step is the initial processing of these
glutamine metabolism in cancer imported metabolises by conversion into the first
At its simplest level the complex process of glucose metabolic product which can act as an entry sub-
and glutamine metabolism can be split into four strate into the main metabolic processing path-
key phases (Figure 2). The first phase is the uptake ways. This conversion acts to trap the imported
of these essential metabolic substrates into the cell metabolite within the cell and to commit it to fur-
via transporter proteins. The process actively ther processing into downstream intermediates as
imports high concentrations of glucose or gluta- well as shift equilibrium balances to allow the
mine into the cell ready for utilisation and in can- influx of more glucose or glutamine to meet the

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cell’s high demand for these metabolites. For glu-
cose, this initial step is conversion to glucose-6-
phosphate by the hexokinase’s of which hexoki-
nase 2 appears to predominant in many cancers71
and has shown to be regulated by both AKT58 and
mutant p5372. siRNA studies or use of non-
hydrolysable glucose mimics which have been
shown to inhibit Hexokinase-2 activity, suggest
that modulating Hexokinase-2 activity could be of
therapeutic benefit in cancer73-75. Two of these
potential hexokinase inhibitors; 2-doexyglucose76-
78 and 3-bromopyruvate71,74 have shown promis-
ing anti-cancer activity in multiple pre-clinical
models but as yet data from clinical trials has not
supported their use as clinical anti-cancer agents.
For glutamine the first step is conversion of glu-
tamine to glutamate by glutaminase proteins
(GLS1/2)79. GLS1 expression has been shown to
be increased in several tumour types and to be
under indirect control from Myc via myc-depend-
ent regulation of miR23a/b levels31,80. Studies
using siRNA technology81 or potential inhibitors
of GLS1 (DON82, 96883) have suggested that inhi-
bition of this target could be of benefit in gluta-
mine dependent tumour cells.
The next phase of metabolite processing involves
the conversion of these metabolites into a series of
Figure 2
Key phases of cancer cell
metabolism. Dashed boxes
represent the four key phases
of metabolism and illustrate
the key proteins, intermediates
or biosynthetic products
within each phase.
Abbreviations: GLUT –
Glucose transporter; ASCT2 –
solute carrier family 1;
member 5 [SLC1A5]; HK –
Hexokinase; GLS –
Glutaminase; MCT –
Monocarboxylate transporter
68
intermediates through metabolic cascades. This
process is not a liner and intermediates can be fur-
ther processed through branched pathways (ie tri-
carboxylic acid cycle, pentose phosphate pathway
or serine biosynthesis pathway) to yield additional
products (see Figure 1). The net result of all the pro-
cessing pathways of core metabolism is; the genera-
tion of biosynthetic intermediates for the manufac-
ture of lipids, proteins, nucleotides and complexes
sugars, the generation of energy in the form of ATP
and the generation of key co-factors, ie glutathione,
NADH and NADPH, which are essential for the
functionality of many protein and have key roles in
protecting the cell from oxidative stress. Multiple
proteins on these pathways have been shown to be
over expressed in cancer, dependent on oncogenic
control or in inhibition studies (RNAi or tool com-
pounds) been shown to be involved in cell prolifer-
ation and/or survival mechanisms. Proteins which
are of potential interest as possible therapeutic tar-
gets include the glycolytic enzymes 84 (eg
Hexokinase-271, Phosphoglycerate kinase-185,86,
Phosphoglycerate mutase87,88 and Pyruvate kinase-
m228,89-91); the pentose phosphate proteins (eg
Glucose-6-phosphate dehydrogenase92-94, transal-
dolase95 and transketolase96-98) and lipid synthe-
sis/fatty acid metabolism targets (eg ATP citrate
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Metabolism_Layout 1 04/10/2011 17:39 Page 69
lyase99,100, fatty acid synthase101,102, monoglyc-
eride lipase103,104 and carnitine palmitoyltrans-
ferase 1C105). See 6,84,106 for more detailed reviews
of some of these.
The final process within centralised metabolism
is the export of end-point products/waste from the
cell in order to protect the cell from build up of
potentially toxic components and also to modify
the extracellular vicinity around the cell which may
act to assist the cell’s establishment in this environ-
ment. In cancer cells the main exported substance
from glucose metabolism is lactate which is
effluxed via the transporter proteins MCT1 and
MCT457,66. Studies have found MCT transporters
to be overexpressed in multiple tumour types107-
110 and that chemical or genetic inhibition of MCT
function can reduce tumour growth suggesting that
molecular targeted therapy against MCT trans-
porters could be a possible mechanism for target-
ing cancer metabolism57,111. Inhibitors targeting
MCT1 have been successfully shown to affect in
vitro and in vivo tumour growth and a MCT1
inhibitor designed by AstraZeneca (AZD-3965) is
about to enter clinical trials as part of the CR:UK
clinical development partnership. For glutamine
metabolism it is believed ammonia released during
the process of glutaminolysis diffuses into the
extracellular environment by as yet undefined
Drug Discovery World Fall 2011
Drug Discovery
Figure 3
Oncogenic regulation of
Pyruvate kinase M2 and ATP
production. The active
tetramer PK-M2 promotes
glycolytic flux and ATP
generation with a reduced
output to other biosynthetic
pathways. High ATP levels can
have a negative feedback effect
on this flux to reduce
additional ATP generation (left
panel). As a result of oncogenic
driven phosphorylation, PK-M2
switches to the low activity
dimeric form which results in
less ATP production, a slowing
of glycolytic flux and enhanced
biosynthesis to meet the
cancer cell biosynthetic
demands. In cancer cells,
pyruvate generation can also
be uncoupled from ATP
production by a novel
mechanism by which
phosphoenolpyruvate is
converted to pyruvate by
transference of a phosphate
group to histidine-11 of
phosphoglycerate mutase
(PGAM1). This process also
activates PGAM1 and so
mechanisms. Understanding what these mecha- enhances flux at this point of
glycolysis (right panel).
nisms could be may offer an attractive therapeutic Abbreviations: PGAM1 –
strategy as inhibiting ammonia removal could phosphoglycerate mutase 1;
cause build up of this toxic product and thereby ENO – enolase; PKM2 –
potentially kill the tumour cell. pyruvate kinase M2; LDHa –
Therefore even in this stripped-down version of lactate dehydrogenase-A; X? –
Unknown phosphotransfer
metabolism it is clear that tumours are adapting to protein
maximise the usage of glucose and glutamine to
promote survival and even growth in potential hos-
tile environments and targeting these adaptions
could be a therapeutic mechanism.
As understanding of cancer metabolism devel-
ops, potential therapeutic targets are identified
based on their roles in cancer metabolism coupled
with cancer specific expression/isoforms, potential
mutations and oncogenic control mechanisms.
Targets which fit these profiles have been at the
forefront of the new push for cancer metabolism
drugs and examples include Pyruvate kinase M2
and Isocitrate dehydrogenase.
Pyruvate kinase M2 (PKM2)
Pyruvate kinase (PK) catalyses the conversion of
phosphoenolpyruvate (PEP) into pyruvate in a rate
limiting and ATP generating step within glycolysis
(Figure 3)2. There are multiple isoforms of PK of
which the muscle form is of key interest in cancer
cells89. PKM1 is found in muscle and brain and is
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reported to be constitutively active whereas PKM2
is present in embryonic and adult stem cells and
controlled by various regulator mechanisms. It has
been widely reported that PKM2 is also over-
expressed in many tumour cells and a switch from
PKM1 to PKM2 expression in cancer has been pro-
posed2,28,89. The PKM2 isoform is generated by
alternative splicing of exon 10 on the PK gene, an
event shown to be under myc regulation suggesting
a potential oncogenic driver for PKM2 expression
in cancers30,112. However, the PKM2 expression
hypothesis has been recently questioned in a study
which used mass-spectroscopy to identify PK iso-
forms and reported that PKM2 is expressed in nor-
mal tissues as well as cancers and that PKM1 had
low expression in cancers as well as in normal tis-
sue113. Although the ratio of PKM2 to PKM1
expression was similar between cancers and
matched normal tissues, the actual amounts of
each protein were much higher in the tumours sug-
gesting that both PKM2 and PKM1 were over-
expressed in tumour samples113.
Studies in which PKM2 is knockdown or replaced
by PKM1 have shown that PKM2 is involved in
tumour progression and that PKM2 expression con-
fers a tumourigenic advantage over PKM1 expres-
sion89. However, it has also been shown that while
PKM1 can efficiently promote glycolysis, PKM2 is
characteristically found in an inactive state and is
inefficient in promoting glycolysis2,28,89,114. PKM2
exists in two possible conformations, an inactive
dimer and more active tetramer (Figure 3).
Oncogenic tyrosine kinases (eg fibroblast growth
factor receptor kinase) have been found to promote
the formation of the inactive dimer via the phos-
phorylation of tyrosine 705 on PKM290,114. PKM2
activity has also been shown to be negatively regu-
lated by acetylation induced by high levels of glu-
cose115. This data collectively suggests that expres-
sion of PKM2 in cancer could actually decrease gly-
colytic flux. While this was initially thought to be
counterintuitive, when considered in terms of the
cancer cell’s metabolic needs, a mechanism which
slows glycolysis is actually potential advantageous.
By slowing glycolytic flux the cancer is able to
obtain building block, co-factors and precursors by

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70 Drug Discovery World Fall 2011

Metabolism_Layout 1 04/10/2011 17:39 Page 71
allowing glucose metabolites to enter subsidiary
pathways including pentose phosphate, serine
biosynthesis, hexcosamine and glycerol synthesis
pathway which support cancer proliferation and
survival. Another metabolic role for PKM2 is a pro-
posed direct interaction and stabilisation of Hif1␣
which in turn acts to promote glycolytic metabo-
lism, angiogenesis and cancer progression55. An
alternative glycolytic route which bypasses PK in the
conversion of PEP into Pyruvate has recently been
identified88,116. This route uncouples ATP and
Pyruvate generation and could provide biosynthetic
intermediates without potential feedback inhibition
of glycolysis from ATP accumulation (Figure 3).
The key question around PKM2 is whether acti-
vators or inhibitors or PKM2 kinase activity would
be the best strategy and if PK-M2 would really be
a cancer specific target. Recent publications have
shown that progress is being made in designing
tool compounds117,118 to test out the PKM2
hypothesis and it will be interesting to monitor the
outcome of studies with these and other PKM2
modulation agents to see if a clear rationale and
patient selection strategy can be defined for this
complex metabolic target.
Isocitrate dehydrogenase (IDH1/2)
Advances in large scale sequencing technologies has
enabled more in-depth profiling of the genetics of
multiple metabolism and oncogenic components in
Drug Discovery World Fall 2011
Drug Discovery
far larger sample sets (often more than 200 samples) Figure 4
and in multiple tumour types. Using these tech- Isocitrate dehydrogenase
mutations and the TCA cycle.
niques it has been found that 60-90% of secondary
In the normal mitochondrial
gliomas (around 5% of primary gliomas)27,119 and TCA cycle IDH2/3 enzymes
12-18% of acute myeloid leukaemias have muta- convert isocitrate to ␣-
tions in the oxidative phosphorylation/TCA cycle ketoglutarate (␣-KG) and
components IDH1 or IDH226,120,121. For gliomas IDH1 converts cytoplasmic
isocitrate to ␣-KG. However,
the common mutations are IDH1 Arg132 and IDH2
mutant IDH1/2 enzymes
Arg140 and Arg172 whereas for glioma most muta- (shown in red boxes) have a
tions are in the IDH2 protein1,27,120. It is also neomorphic enzyme capacity
worth noting that the vast majority of these muta- and convert ␣-KG into 2-
tions are heterozygous. hdyroxyglutarate (2-HG). 2-
HG is believed to inhibit ␣-KG
Mutations affecting the catalytic sites of IDH1
dependent processes including
or 2 are thought to be functionally equivalent and TET1/2 methyltransferase and
were initially reported to negatively affect IDH the histone demethylase
catalytic activity by reducing isocitrate binding KDMa2 leading to epigenetic
and the ability to convert isocitrate into alpha- disregulation. 2HG may also
act to stabilise HIF1␣.
ketoglutarate (␣-KG). However, recent mass-spec-
Abbreviations: CS – citrate
troscopy data has discovered IDH mutations synthase; ACO1/2 – Aconitase
exhibit an altered catalytic activity and convert ␣- 1/2; IDH – isocitrate
KG (the product of wild type IDH proteins) to 2- dehydrogenase; mIDH –
hydorxyglutarate (Figure 4)120-122. This altered mutant isocitrate
dehydrogenase; OGDH –
metabolite is found to be 100-fold increased in
oxoglutarate (␣-ketoglutarate)
glioma or AML patients with IDH mutations sug- dehydrogenase; SCS – succinyl-
gesting it could act as a clinical biomarker120. CoA synthetase; SDH –
Large scale analysis of DNA methylation in succinate dehydrogenase; FH –
human gliomas provided a key insight into the Fumarate hydratase; MDH2 –
malate dehydrogenase 2; PDH
role of this mutation in cancer. This study showed
– pyruvate dehydrogenase;
that nearly all IDH1 and IDH2 mutations were GLS1 – glutaminase 1
associated with a highly specific DNA methylation
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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
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
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
Metabolism_Layout 1 04/10/2011 17:39 Page 73
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