REVIEWS
Modifying IGF1 activity: an approach
to treat endocrine disorders,
atherosclerosis and cancer
David R. Clemmons
Abstract | Insulin-like growth factor 1 (IGF1) is a polypeptide hormone that has a high degree
of structural similarity to human proinsulin. Owing to its ubiquitous nature and its role in
promoting cell growth, strategies to inhibit IGF1 actions are being pursued as potential
adjunctive measures for treating diseases such as short stature, atherosclerosis and diabetes.
In addition, most tumour cell types possess IGF1 receptors and conditions in the tumour
microenvironment, such as hypoxia, can lead to enhanced responsiveness to IGF1. Therefore,
inhibiting IGF1 action has been proposed as a specific mechanism for potentiating the
effects of existing anticancer therapies or for directly inhibiting tumour cell growth.
Stromal cells
Connective tissue cells,
primarily fibroblasts, that are
present in nearly every organ.
Division of Endocrinology,
Department of Medicine,
University of North Carolina,
Chapel Hill, North Carolina
27599‑7170, USA.
e-mail: [email protected]
doi:10.1038/nrd2359
Insulin-like growth factor 1 (IGF1), a small polypeptide
(7,500 kDa) involved in cellular growth, and is a member
of a family of structurally related peptides that also include
insulin-like growth factor 2 (IGF2) and human proinsulin.
IGF1 circulates in relatively high concentrations (150–400
ng per ml) in plasma, predominantly as the protein-bound
form, with the free active peptide representing only a small
percentage (less than 1%) of the total1. Despite structural
similarities between family members, each peptide binds
selectively to distinct cell surface receptors, which accounts
for much of the specificity of each peptide’s actions. The
type 1 IGF receptor is a heterotetramer composed of two
α subunits that contain the hormone binding domain,
which are linked to two β subunits that contain tyrosine
kinase catalytic activity domains by disulphide bonds2.
Upon ligand occupancy the receptor undergoes a conformational change that activates the tyrosine kinase activity,
which then activates downstream signalling molecules by
protein phosphorylation. The regulation and synthesis of
IGF1, IGF2 and insulin is quite distinct3. IGF1 synthesis is
controlled by several factors, including the human pituitary growth hormone (GH, also known as somatotropin),
whereas insulin concentrations are controlled primarily
by changes in blood glucose. IGF2 concentrations are
high during fetal growth but are less GH-dependent
in adult life compared with IGF1. These three peptides
have complementary roles in growth regulation. Because
of its anabolic and insulin-like properties, strategies are
being pursued for treating short stature, catabolism and
controlling blood glucose in diabetes. IGF1 also has an
important role in promoting cell growth and consequently
nature reviews | drug discovery
IGF1 inhibition is being pursued as a potential adjunctive
measure for treating atherosclerosis. Inhibiting IGF1
action has been proposed as a specific treatment either
for potentiating the effects of other forms of anticancer
therapies or for directly inhibiting tumour cell growth.
This Review will encompass a discussion of the factors
that regulate IGF1 synthesis and secretion, and focus
on the strategies that have been used to modify IGF1
actions in tissues principally for developing drugs for
the treatment of growth disorders, catabolism, diabetes,
atherosclerosis and cancer.
IGF1 synthesis and tissue growth
IGF1 is synthesized in multiple tissues including liver,
skeletal muscle, bone and cartilage. The changes in
blood concentrations of IGF1 reflect changes in its
synthesis and secretion from the liver, which accounts
for 80% of the total serum IGF1 in experimental
animals4. The remainder of the IGF1 is synthesized in the
periphery, usually by connective tissue cell types, such
as stromal cells that are present in most tissues. IGF1 that
is synthesized in the periphery can function to regulate
cell growth by autocrine and paracrine mechanisms3.
Within these tissues, the newly synthesized and secreted
IGF1 can bind to receptors that are present either on the
connective tissue cells themselves and stimulate growth
(autocrine), or it can bind to receptors on adjacent cell
types (often epithelial cell types) that do not actually
synthesize IGF1 but are stimulated to grow by locally
secreted IGF1 (paracrine) (FIG. 1). Several experimental
animal model systems have been analysed to determine
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GH
Blood vessel
GH
GH
receptor
IGF1
Paracrine
action
IGF1
Autocrine
action
IGF1
receptor
IGF1
Extracellular
matrix
synthesis
IGFBP5
reservoir
Extracellular matrix
IGF1 receptor
GH receptor
Figure 1 | Autocrine and paracrine actions of IGF1. Insulin-like growth factor 1
(IGF1) is synthesized in peripheral tissues by connective tissue
cell
types |such
Nature
Reviews
Drugas
Discovery
fibroblasts. These cells contain growth hormone receptors and can respond to growth
hormone (GH) that enters the tissues from blood vessels. Newly synthesized IGF1 is
secreted and transported to adjacent cells (paracrine action), where it stimulates
coordinated cellular growth. It can also be secreted and then rebind to the cell of
origin, where it stimulates cell growth (autocrine action). Similarly, locally produced
IGF1 can bind to IGF binding proteins (IGFBPs) such as IGFBP5 localized in the
extracellular matrix where a reservoir of IGF1, which can be released following tissue
injury or during repair, is created. Stimuli other than GH, such as platelet-derived
growth factor, can increase IGF1 synthesis; these factors are important for initiating
the response of tissue repair after injury.
the variables that regulate autocrine and paracrine secretion of IGF1 and its actions5,6. Following tissue or cellular
injury there is a wave of IGF1 synthesis that stimulates
reparative cell types to replicate; this response has been
shown to occur in injured blood vessels6, skeletal muscle5, cartilage7 and in the brain8. Other growth factors
that are involved in the repair process, such as plateletderived growth factor (PDGF), fibroblast growth factor
(FGF) and epidermal growth factor (EGF), can stimulate
local synthesis of IGF1 (refs 9–11). When transplanted
into experimental animal models, tumour cell types produce IGF1 and/or IGF2, which can stimulate tumour
growth. Additionally the mesenchymal cells surrounding
the tumour also provide an important paracrine source
of IGF112. Autocrine and paracrine IGF1 signalling is
believed to be important in determining normal fetal
growth13, and fetal brain expression of IGF1 is thought
to be crucial for determining brain growth and head
circumference14.
SOCS3
SOCS proteins bind to
signalling elements in cytokine
signalling pathways and inhibit
their function.
Control of IGF1 synthesis and secretion
The connective tissue cell types that synthesize IGF1
contain growth hormone receptors and increases in
pituitary GH secretion stimulate IGF1 synthesis15. This
stimulation of Igf1 synthesis by GH in peripheral tissues
is an important determinant of somatic growth. In mice,
germline Igf1 gene deletion results in a 50% reduction
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in birth weight and a 70% reduction in final adult size16.
By contrast, selective deletion of IGF1 synthesis in the
liver (which leaves peripheral synthesis intact), decreases
serum IGF1 by 80% but results in less than a 10%
reduction in adult size13. These results imply that IGF1
produced in the periphery is the main determinant of
somatic growth in mice, whereas hepatic synthesis is the
primary determinant of plasma concentrations3. Hepatic
synthesis of IGF1 is regulated by several hormones,
principally GH, but the ability of GH to stimulate IGF1
is strongly influenced by nutritional status. Following
GH administration there is a major increase in blood
IGF1 concentrations17. This increase in blood IGF1 acts
to suppress GH synthesis in the pituitary gland through
a process termed negative-feedback regulation18, which
represents an important homeostatic mechanism for
maintaining normal plasma IGF1 concentrations. After
5 days of fasting, hepatic synthesis of IGF1 is relatively
refractory to GH stimulation and plasma IGF1 declines
by 50% (ref. 19). Upon refeeding, GH sensitivity is
restored within 72 hours. Other hormones, including
thyroxine, cortisol, oestradiol and testosterone20 participate with GH in regulating hepatic IGF1 synthesis.
Thyroxine enhances sensitivity to GH, whereas cortisol
acts to inhibit IGF1 synthesis. High cortisol concentrations can lead to growth attenuation by this mechanism. Oestradiol inhibits IGF1 synthesis in the liver by
inducing suppressor of cytokine signalling 3 (SOCS3),
which inhibits GH stimulated signal transduction21.
Testosterone not only enhances hepatic IGF1 synthesis,
but also alters the sensitivity of the pituitary gland to
negative-feedback regulation of GH secretion, thus leading to increases in GH and IGF1. IGF2 concentrations in
blood, which are threefold greater than IGF1, are minimally increased by GH22 and are significantly decreased
by prolonged fasting.
Following either local secretion or transport through
the circulation to target tissues, IGF1 and IGF2 bind to
the type 1 IGF1 receptor. IGF1 binds to the receptor with
sixfold to eightfold higher affinity than IGF2 and both
peptides have affinities that are more than 100-fold greater
than insulin23. Conversely, insulin has a much higher
affinity for its receptor. Following receptor activation,
the tyrosine kinase autophosphorylates tyrosine residues
that serve as important docking sites for the signalling
proteins SRC homology 2 domain-containing protein
(SHC) and insulin receptor substrate family 1 (IRS1)24.
Both of these signalling intermediates are important for
the activation of the phosphoinositide 3 kinase (PI3K)
and mitogen-activated protein (MAP) kinase pathways
that mediate the metabolic and growth promoting
actions of IGF1 and IGF2 (REF. 25).
IGF binding proteins
The concentrations of IGF1 and IGF2 in blood are also
determined indirectly by the levels of IGF binding proteins
(IGFBPs). IGFBP3 is the most abundant IGFBP in blood
and has the highest affinity for IGF1 and IGF2, therefore
it accounts for 75–80% of the total carrying capacity. The
IGF1–IGFBP3 complex binds to a third protein termed
acid labile subunit (ALS). This tripartite complex has a
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Pseudotumour cerebri
A condition in which there
is increased intracranial
pressure but no tumour.
Stat5b
A signalling protein that
following activation of a
growth hormone receptor
is phosphorylated and
translocated to the
nucleus where it induces
gene transcription.
HIV wasting
A syndrome in which patients
with HIV become severely
catabolic despite a normal
calorific intake.
half-life of 16 hours. By contrast, the half-life of free IGF1
is less than 15 minutes3. As the concentration of free IGF1
in normal subjects is less than 1% of the total IGF1 concentration, formation of this ternary complex results in
most of the IGF1 and IGF2 in blood being present in a
stable reservoir26. GH also stimulates IGFBP3 and ALS
secretion and this functions to further stabilize IGF1
levels27. During severe catabolism or conditions such as
diabetes, IGFBP3 undergoes proteolysis, resulting in a
lowering of the total IGF binding capacity28.
The second most abundant IGFBP is IGFBP2.
IGFBP2 does not bind to ALS and the IGF1–IGFBP2 or
IGF2–IGFBP2 complexes have much shorter half-lives
(~90 minutes). IGFBP2 in serum is unsaturated and
represents an excess reservoir of binding capacity3.
A third IGFBP, IGFBP1, accounts for only a small
percentage of the IGF carrying capacity. Like IGFBP2,
IGFBP1 is generally unsaturated and, therefore, represents a potential regulator of free IGF1 and IGF2.
IGFBP1 is suppressed by insulin and there is a fourfold
to fivefold increase in the fasting state29. Following feeding the decrease in IGFBP1 results in a rapid reduction
in the total IGF binding capacity making free IGF1 and
IGF2 more available to peripheral tissues.
IGFBP4, 5 and 6 are present in lower concentrations
and appear to be less important for regulating free IGF
concentrations in serum. IGFBPs are also synthesized by
peripheral tissues and in interstitial fluids there is usually
an excess of IGF binding capacity3. As the affinity of the
IGFBPs is higher than that of the IGF1 receptor, they
represent a potential reservoir of peptide that can bind
to cell surface receptors (FIG. 1).
In summary, IGF1 is regulated by multiple mechanisms that are known to regulate systemic growth. As
a general growth stimulant, IGF1 promotes multiple
metabolic actions that are required for growth, such as
protein synthesis, calcium accretion and fatty acid and
glucose transport30. Furthermore, as IGF1 receptors are
ubiquitously expressed, targeting IGF1 actions either by
reducing ligand concentration or by blocking IGF1 binding to the IGF1 receptor results in changes in multiple
tissues and limits the ability to target one specific cell
type or organ. Despite this limitation, it may be possible
to selectively target specific cell types by identifying
co-receptors that modify IGF1 action. Alternatively,
using drugs that target the IGF1 receptor in a setting
where other agents are used to achieve cell type specificity or in which blocking IGF1 action would provide an
additive effect on a particular cell-type that had been
targeted by an alternative therapy could be exploited.
Both of these approaches have been tested in cells in
culture or in experimental animal models31–35.
Activation of IGF1 receptor to treat dieases
The availability of recombinant human IGF1 has made
it possible to complete several clinical studies aiming to
determine whether an increase in the plasma concentrations of IGF1 results in stimulation of systemic growth,
reversal of catabolic states or enhancement of insulin
action. These studies were all based on a sound rationale
(detailed below), but their results have been variable.
nature reviews | drug discovery
Stimulation of statural growth. Patients with severe IGF1
deficiency have been treated with recombinant human
IGF1. The largest amount of clinical data has been gained
with children with short stature and mutations of the GH
receptor that resulted in resistance to GH, as manifested
by a failure to grow in response to GH therapy. Three
large clinical studies have shown that if IGF1 (80–120
µg per kg) is administered systemically twice a day by
subcutaneous injection, serum IGF1 concentrations
can be increased from low levels to levels that are 1.8
standard deviations above the mean for age36. Growth
rates during the first year of therapy have averaged 8–9
cm per year and between 6–7 cm per year in the second
year of therapy. This growth velocity can be maintained
for several years and these children generally achieve a
final adult height that is close to the lower limit of the
normal range. A few children have been able to achieve
their predicted final adult height but this is unusual. Side
effects have been minimal but have included oedema,
headaches, hypoglycaemia and pseudotumour cerebri37.
There is some disproportionate organ growth, with
splenic and tonsilar enlargement exceeding the increase
in the size of other organs. These changes revert to
normal when IGF1 is discontinued. IGF1 has also been
co-administered with IGFBP3. Treatment of children
with this complex results in more stable IGF1 levels
in serum. Growth rates that were attained during the
first year of therapy were equivalent to those obtained
using IGF1 alone36. Whether this will result in a reduced
side-effect profile has not been determined.
Other rare mutations that result in an alteration of
GH actions and dwarfism, such as signal transduction
and activator of transcription 5b (STAT5B) mutations,
IGF1 gene defects and IGF1 receptor mutations that
result in only partial loss of sensitivity to IGF1, represent reasonable targets for this therapy and studies to
prove that these patients will respond are ongoing38.
Currently a Phase II clinical trial is underway to determine whether short children (without known GH
receptor mutations) who have low IGF1 values and a
suboptimal response to GH therapy will benefit from
IGF1 therapy. Because IGF2 has a lower affinity for the
IGF1 receptor and because of uncertainty regarding its
safety, it has not been developed as a therapy for short
stature. In summary, IGF1 clearly has a role in treating
short children with severe IGF1 deficiency. The extent to
which children who are relatively resistant to GH but do
not have mutations in signalling proteins in the GH axis
will respond to IGF1 is currently being investigated.
Catabolic states. Several catabolic states result in relative
resistance to GH, which is mediated by increases in the
concentrations of cytokines, such as tumour necrosis
factor (TNF) and interleukin 1 (IL1), both of which
inhibit IGF1 synthesis and block its actions in tissues39.
GH resistance has been demonstrated in patients with
HIV wasting and various disorders related to inadequate
nutrient intake or absorption such as, cystic fibrosis,
coeliac disease and anorexia nervosa. IGF1 has been
administered for relatively short intervals (for example,
for less than 3 weeks) to these patients as well as to patients
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with burns and patients with closed head trauma, who
are severely catabolic. In general, these catabolic patients
respond to IGF1 with increases in protein synthesis
and a positive or overall anabolic response40. When the
IGF1–IGBP3 complex was administered to patients with
burns it led to an increase of protein synthesis41. IGF1 is a
potent growth factor for osteoblasts, and two studies, one
in elderly patients with hip fractures and one in younger
patients with anorexia nervosa, have been undertaken42,43.
The patients with anorexia received IGF1 alone, whereas
the hip fracture patients received IGF1–IGFBP3. Both
studies showed that the reduction in bone mineral density that is present in these two groups of patients can
be improved with IGF1 therapy. The effects that were
achieved with IGF1 were significant compared with
control groups that received a placebo, but they required
relatively high dosages. At present none of these small
studies has led to a large, randomized, controlled trial.
Studies have also been conducted in catabolic patients
with muscle wasting disease. One placebo-controlled
study in a small number of patients (n = 7) with myotonic
dystrophy gave positive results. The authors showed that
IGF1 given for 4 months stimulated protein synthesis and
inhibited protein breakdown. Muscle mass and strength
were also improved44. Two large randomized trials have
been performed in patients with amyotrophic lateral
sclerosis but they gave conflicting results45,46.
Haemoglobin A1C
A form of haemoglobin that
is sensitive to non-enzymatic
glycosylation, which therefore
reflects long-term changes
in blood glucose.
Arthralgias
Joint pains.
IGF1 in diabetes. The underlying rationale for using
IGF1 in patients with diabetes has a strong physiological
basis. IGF1 and insulin are ancestrally linked hormones
that diverged in evolution. Before that time, a single
IGF1/insulin precursor was used by organisms to link
nutrient intake and growth. When abundant food was
sensed the IGF1/insulin precursor was synthesized by
the olfactory apparatus, and it stimulated cells to use the
ingested nutrient for stimulation of protein synthesis
and tissue growth47. IGF1 synthesis remains linked to
nutrient intake and IGF1 has retained some insulin-like
properties such as stimulation of glucose transport into
skeletal muscle cells. Studies in humans have shown
that post-prandial glucose disposal is partly dependent upon IGF1 concentrations and that administering
IGF1 to patients with either severe insulin resistance
or type 2 diabetes results in improved post-prandial
glucose usage48. This occurs primarily at the level of
skeletal muscle as deletion of the IGF1 receptor in skeletal muscle in mice results in glucose intolerance and
impaired insulin action49 (FIG. 2).
Several observations suggest that IGF1 can enhance
insulin action in other tissues. This could occur either
by crosstalk between the insulin and the IGF1 signal transduction pathways, particularly in terms of
stimulating PI3K activation, which is a key enzyme for
regulating insulin-stimulated glucose transport or by
other, as yet undefined, mechanisms. IGF1 has 100times less affinity than insulin for binding to the insulin
receptor, so it is unlikely that the free IGF1 levels that
are required to stimulate insulin receptor activation are
ever reached. However, other mechanisms that provide
a basis for understanding how IGF1 might be of use in
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treating diabetes have been proposed. Administration
of IGF1 to mice lacking the IGF1 receptor in skeletal
muscle lowered their blood glucose, due to inhibition
of renal gluconeogenesis50. Other studies suggest that
IGF1 improves insulin sensitivity by inhibiting the
secretion of GH, which can function as an insulin
antagonist51.
Several clinical studies have been designed to test
the role of IGF1 in type 1 and type 2 diabetes. In type 1
diabetes, the mechanism of enhanced insulin sensitivity
is partly due to suppression of GH secretion, which
results in enhancement of insulin action as GH is a
direct antagonist of insulin in the liver52. Larger trials
of IGF1 administration to type 1 diabetics have shown
a consistent maintenance of reduced insulin requirements over 4–8-week periods and significant (~1%)
reductions in haemoglobin A1C53,54. Theoretically haemoglobin A1C could be lowered by more intensive
insulin administration, but none of these studies has
definitively proved that an independent mechanism
that accounts for IGF1’s glucose lowering effect exists.
However, the empiric fact remains that some patients
are easier to control with co-administration of IGF1
and insulin. This may be due in part to the fact that
increases in IGF1 are stable and are maintained for
several hours; this offers no advantage over long-acting
insulins, such as glargine insulin, which were not generally available at the time these trials were initiated.
Therefore, whether IGF1 administration offers any
advantage compared with long-acting insulin in type 1
diabetics has not been definitively proved.
Several large trials have been conducted in patients
with type 2 diabetes. When given as monotherapy
— without insulin or oral hypoglycaemic agents
— IGF1 reduced haemoglobin A1C by 1.2% in patients
with type 2 diabetes55, which is a clinically significant
improvement. In general, these were subjects who were
not well controlled as their mean haemoglobin A1C
was 8%. One study measured insulin sensitivity at the
end of a 6-week administration period and showed that
insulin sensitivity was enhanced 3.4-fold in patients
with type 2 diabetes38. Serum IGF1 concentrations that
were above the upper limit of normal had to be achieved
to obtain this degree of improvement in glycaemic
control. Administration of lower doses did not result
in significant improvement in haemoglobin A1C and
blood glucose levels56. Because of this relatively high
dosage requirement, side effects were frequent and were
similar to those that are seen in clinical conditions associated with excess GH secretion, for example, oedema,
arthralgias, headaches and myalgias. Occasionally, complications including Bell’s palsy, and pseudotumour
cerebri, tachycardia and hypoglycaemia have occured.
One trial included a group of type 2 diabetics who were
treated with the combination of insulin and IGF1. IGF1
improved haemoglobin A1C by an additional 0.7% compared with control subjects receiving insulin alone, suggesting that IGF1 enhanced insulin action, thus, leading
to a further improvement in the hyperglycaemic state57.
Administration of IGFBP3 with IGF1 appears to be
equally effective in terms of improving hyperglycaemia.
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GH
hormone
↑Gluconeogenesis
Liver
↓Gluconeogenesis
↑Lipolysis
Adipose
↓Lipolysis
Kidney
Pancreas
Insulin
↑Glucose
transport
IGF1
↓Gluconeogenesis
Muscle
Figure 2 | Growth hormone and IGF1 actions on glucose homeostasis. In addition
Naturegrowth
Reviews
| Drug1Discovery
to growth stimulation, growth hormone (GH) and insulin-like
factor
(IGF1)
have many important metabolic actions. GH acts directly on the liver to antagonize the
ability of insulin, which is secreted by the pancreas, to inhibit gluconeogenesis. GH
acts directly on fat cells to enhance lypolysis, which functions to elevate blood glucose,
again antagonizing the effects of insulin. IGF1 can directly lower blood glucose by
inhibiting renal gluconeogenesis. IGF1 can also act indirectly, through the IGF1
receptor in skeletal muscle, to enhance insulin action on glucose transport. IGF1
inhibits GH secretion by the pituitary gland, thus, IGF1 indirectly blocks the ability of
GH to antagonize insulin action; this indirect effect improves glucose homeostasis.
CA repeats
Cytosine–adenine repeats
that occur as polymorphisms
in genes.
Administration of this combination to 52 diabetics for 2
weeks resulted in decreases in fasting blood glucose of
35–40% with a marked reduction in insulin requirements averaging 66% (REF. 58). Therefore, IGF1 is a
potent insulin sensitizer, even when it’s given with its
binding protein. Whether administration of IGFBP3
with IGF1 will result in a reduction in side effects has
not yet been determined. No long-term Phase III trial
with IGF1 in type 2 diabetes has been completed.
Overproduction of IGF2 by several different types
of tumours has been shown to lead to hypoglycaemia59.
Normally, these forms of circulating IGF2 are precursor forms and have aberrant glycosylation patterns 22.
Despite the ability of IGF2 to lower blood glucose levels,
no human studies have determined whether IGF2 has
clinical use in type 2 diabetes.
Strategies to stimulate the IGF1 receptor by technologies other than by administering the ligand and,
therefore, enhance insulin sensitivity, are the subject of
ongoing experimental efforts but none has reached the
point of clinical testing. These include the development
of IGF1-like peptide agonists that have undergone structural modifications60–63. Another approach has been to
administer peptides or small molecules that inhibit IGF1
binding to IGFBPs and therefore increase free IGF1 levels,
which results in enhanced insulin action64–66.
nature reviews | drug discovery
Optimization of insulin sensitivity. A large body of
literature supports the concept that increased insulin
resistance, even when normal or mildly elevated glucose concentrations are present, results in increased
cardiovascular risk67. As IGF1 lowers insulin resistance
in type 2 diabetes, it has been proposed that low serum
IGF1 concentrations could contribute to the increased
insulin resistance that is noted in certain clinical conditions such as cardiovascular disease. Epidemiological
studies of individuals between the ages of 40 and 70
years support this concept. Individuals with IGF1 levels
in the lower quartile of the normal range and IGFBP3
in the highest quartile (therefore with the lowest free
IGF1 concentrations) had a 4.23-fold increase in risk of
developing cardiovascular disease over a 7-year period68.
By contrast, individuals with IGF1 in the highest quartile
and IGFBP3 in the lowest quartile had a reduced risk.
The relative risk was calculated such that for each 40
ng per ml decrease in serum IGF1, there was a twofold
increase in the risk of developing coronary artery disease. Epidemiological studies have shown that a subset
of the Dutch/Caucasian population (11% of the population) have a polymorphism in the number of CA repeats
near the promoter region of the IGF1 gene69. They are
termed non-carriers of the two most common genotypes.
Interestingly, these non-carriers have a 32% reduction in
serum IGF1 concentrations, their birth length is lower
than unaffected siblings and their final adult height is
3.2 cm less than the mean for the general population. It
has been presumed that these individuals have to secrete
more GH to maintain a normal IGF1 and that this GH
hypersecretion worsens the insulin resistance. Consistent
with this hypothesis is the observation that in a group of
these individuals over the age of 60 the risk of developing
type 2 diabetes was increased 2.2-fold and their risk of
myocardial infarction was increased 3.4-fold69. Whether
these individuals will benefit from a normalization of
IGF1 has not yet been determined.
Inhibition of IGF1 to modify disease activity
IGF1 and atherosclerosis. As outlined in the previous
section, a reduction in systemic IGF1 concentration due
to gene polymorphisms or other variables may worsen
insulin insensitivity, which is clearly a risk factor for the
development of atherosclerosis. Despite the known effect
of circulating IGF1 on insulin sensitivity, IGF1 that is
synthesized locally in blood vessels can function in an
autocrine or paracrine manner to stimulate the progression of atherosclerotic lesions (FIG. 3). Evidence obtained
from animal models shows that IGF1 could be involved
in stimulating atherogenesis70,71. IGF1 receptors are
abundant in vascular smooth muscle cells (SMCs) and
factors that stimulate atherosclerosis, such as angiotensin
II, upregulate IGF1 receptor expression72. Activated
macrophages that are deposited in blood vessels have
increased expression of IGF1 (REF.73). Vascular injury that
is induced by balloon denudation or hypercholesterolaemia increases IGF1 synthesis. IGF1 then acts to stimulate
SMC division and migration leading to an acceleration
of atherosclerosis70,73. In hypertensive animals there is
increased IGF1 mRNA and protein expression74. A variety
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Blood flow
Monocyte
Activated
monocyte
ECM
synthesis
IGF1
release
SMC
SMC proliferation
Migration of
activated SMC
Figure 3 | IGF1 and atherosclerosis. Insulin-like growth factor 1 (IGF1) is synthesized and released by activated
monocytes when they penetrate the vascular wall and are activated by various stimuli, including
oxidized
low-density
Nature Reviews
| Drug
Discovery
lipoprotein and advanced end glycosylation products (proteins that are abnormally glycosylated as a result of the high
glucose concentrations that are present in diabetes). IGF1 that is secreted by monocytes can act directly on smooth
muscle cells (SMCs) to stimulate their migration into the neointimal space or their proliferation. IGF1 can also stimulate
extracellular matrix (ECM) synthesis. This expansion of the neointima leads to an enlargement of the developing
atherosclerotic plaque, resulting in blood flow restriction.
Cyclin dependent kinase‑4
Following cyclin C1 binding,
CDK4 phosphorylates critical
substrates for cell progression
through the cell cycle.
Cyclin E
A member of the cyclin family
that binds to CDK1 and that
is required for G1to S phase
transition.
of techniques have been used to block IGF1 action in
animal models of atherosclerosis and this strategy successfully blocks lesion progression. In one approach,
investigators used a protease resistant form of an IGFBP,
IGFBP4, which has been shown to inhibit IGF1 actions75.
Overexpression of this mutant IGFBP in mouse SMCs led
to a decrease in the number of SMCs in blood vessels75.
Inhibitors of IGF1 synthesis, such as octreotide, prevent
vascular SMC proliferation and neointimal proliferation
in experimental animal models76. A stable decapeptide
analogue of IGF1 that inhibits IGF1 receptor activation
was shown to inhibit vascular SMC DNA synthesis after
rat carotid balloon injury77. Therefore, although inhibiting IGF1 receptor activation has been proposed as a
strategy for inhibiting atherosclerosis, the IGF1 receptor
is expressed ubiquitously and it is possible that global
inhibition of IGF1 actions in non-vascular tissue could
have deleterious effects.
To circumvent the problem of inhibiting IGF1 receptor function ubiquitously investigators have searched
for co-receptors that may be activated together with
the IGF1 receptor during vascular injury. One such
receptor is the αVβ3 integrin. As SMCs require attachment to the substratum through integrins in order to
respond to IGF1, it has been proposed that by inhibiting ligand occupancy of the αVβ3 integrin may inhibit
IGF1 actions selectively in cell types that express αVβ3.
Ligand occupancy of αVβ3 integrin leads to the ability of
SMCs to recruit the signalling protein SHC to the plasma
membrane78. As SHC activation is required for IGF1 to
stimulate SMC migration and division, blocking ligand
occupancy of αVβ3 prevents the recruitment of SHC
to the membrane and, therefore, results in an inability
to facilitate SHC responsiveness to IGF1 (REF. 79). αVβ3
antagonists that block IGF1-stimulated SHC activation
block IGF1 stimulated cell growth. An in vivo study
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in pigs using antagonists that block ligand occupancy
of αVβ3 showed that IGF1 signalling was inhibited
and atherosclerotic lesion progression was blocked80.
Atherosclerotic lesion size was reduced by 48% following
a 3-week infusion of αVβ3 antagonists, suggesting that
by blocking IGF1 action in this cell type the proliferative
phase of atherosclerosis could be inhibited.
IGF1 and cancer therapy. Because of its role as a generalized systemic growth factor and because many tumour
cell types possess IGF1 receptors, targeting IGF1 has
been extensively studied in the context of cancer
research. Early experimental findings showed that breast
cancer cells expressing IGF1 receptors were responsive to
this growth factor81. Furthermore, overexpression of the
IGF1 receptor in various cell types results in acquisition
of the transformed phenotype82 (FIG. 4). This has been
observed in cells grown in agar and in cells transplanted
into experimental animals82,83. These types of experiments have shown that when human tumour cell types
with increased expression of IGF1 receptors were transplanted into nude mice they were often tumorogenic84.
Deletion of the IGF1 receptor in several tumour cell
models showed that other growth factors, such as PDGF,
were incapable of transformation without IGF1 receptor expression85. These observations have been extended
to tumorogenic viruses such as SV40. Therefore, it has
been proposed that IGF1 has a critical role in allowing
tumour cells to maintain the malignant phenotype and
respond inappropriately to viruses or peptide growth
factors that have transforming activity. IGF1 induces
cell-cycle regulatory changes that may be important for
acquisition of the malignant phenotype. Specifically it
increases cyclin D1 and cyclin-dependent kinase 4 (CDK4)
gene expression leading to retinoblastoma (RB) phosphorylation and activation of cyclin E86. In addition, it
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Wilms’ tumour
Also termed nephroblastoma.
A tumour of kidney origin
usually occurring in young
children.
Hypoxia inducible factor 1
(HIF1). A transcription factor
that is expressed in response
to low oxygen.
downregulates the transcriptional inhibitor, p27/KIP1
leading to CDK4 activation87. In addition, phosphatases,
such as PTEN, that have been shown to be dysregulated
in cancer are important for restraining IGF1-mediated
cell-cycle progression88.
Studies that are more directly linked to human malignancy have shown that there is increased expression of
IGF1 or the IGF1 receptor in breast, lung, thyroid, gastro­
intestinal tract, prostate, glioblastoma, neuroblastoma,
meningioma and rhabdomyosarcoma89. Epidemiological
studies have shown that subjects with serum IGF1 levels
in the upper quartile of the normal range compared
with subjects who have values in the lower quartile of
the normal range are at increased risk of pre-menopausal
breast cancer and other cancers, such as prostate, lung,
colorectal, endometrial and bladder90–95.
Subjects with a loss of imprinting of the IGF2 gene
have been shown to be at increased risk for adenomatous polyp formation and early cervical squamous cell
changes that are considered pre-malignant96. Loss of
IGF2 imprinting has been noted in subjects who developed Wilms’ tumour and neuroblastoma97. IGF2 has also
been implicated in accelerating tumour metastasis.
Overexpression of IGF2 in the primary tumour has
been shown to be predictive of colorectal metastases98
and overexpression of the IGF1 receptor has been
noted in highly metastasizing synovial carcinomas and
melanomas99–100. Furthermore, IGF2 overexpression has
been used to predict metastasis from adrenal cortical
carcinomas101.
Potential mechanisms that alter IGF1 synthesis or action
in tumours. In addition to direct effects on growth and/
or metastases of tumour cells, the IGF1 axis is implicated
Tumour
Mitosis of
tumour cells
IGF1
Stromal cells
IGF1
receptor
Endocrine
secreted IGF1
Migration
and metastasis
Blood vessel
Endothelial
break
Figure 4 | IGF1 actions and mechanisms of tumour development. Insulin-like
growth factor 1 (IGF1) concentrations in the tumour microenvironment can be altered
Nature Reviews | Drug Discovery
by several factors. Tumours have increased numbers of blood
vessels, which provide an
abundant source of IGF1. IGF1 can be synthesized by stromal cells that are adjacent to
the cancer cells and contained within the tumour mass. The tumour itself can at times
synthesize excess IGF1. IGF1 can act directly on cancer cells that possess IGF receptors
to stimulate tumour cell growth. Likewise, tumour cell migration and metastasis can be
stimulated. IGF1 can alter metastases by changing the ability of tumour cells to
penetrate the vascular wall or by stimulating the production of extracellular matrix to
form a nidus for attachment of the metastizing tumour cells.
nature reviews | drug discovery
in angiogenesis. IGF1 has been shown to synergize with
hypoxia inducible factor 1 (HIF1) in promoting tumour
cell replication102,103. IGF1 also functions with hypoxia
to mediate metastases of transplanted tumours, and
hypoxia plus IGF1 can modulate the expression of
vascular endothelial growth factor (VEGF), a potent
inducer of tumour angiogenesis104,105. IGF1 has been
shown to enhance expression of matrix metalloproteases
(MMPs), such as MMP2 and MMP9 that are important
in tumour invasion and metastases106,107. Tumours that
are transplanted into experimental animal models that
had reduced serum IGF1 levels have been shown to
have reduced metastatic potential. Animals with a 75%
reduction in serum IGF1 levels following deletion of
IGF1 synthesis in the liver showed minimal metastases
of cecal carcinoma compared with mice that had normal serum IGF1 levels108. Moreover, nutrient deprivation, which has been shown to reduce IGF1 synthesis,
reduced the metastatic potential of colon carcinoma109.
Overexpression of a soluble form of the IGF1 receptor that prevents IGF1 from binding to its receptor
decreased the metastatic potential of a lung carcinoma
cell line110. In an animal model that develops early stages
of adenocarcinoma of the prostate, overexpression of
the IGF1 receptor within the basal epithelial layers led
to a spontaneous, stepwise progression of prostate carcinoma111. Mice expressing a constitutively active form
of the IGF1 receptor developed salivary and mammary
adenocarcinomas112.
One of the major actions of IGF1 in both normal
and tumour cell types is to inhibit apoptosis. As cancer
therapies, for example, radiation and chemotherapy,
often induce apoptosis, it is predicted that IGF1 should
confer radioresistance113,114 and resistance to induction of apoptosis that occurs in tumour cells following
exposure to chemotherapeutic agents. This is indeed
the case: the addition of IGF1 rescues breast cancer cells
from doxorubicin-induced apoptosis 115,116. Similarly,
IGF1 upregulation was found to induce resistance to
cytosine arabinoside (Ara-C) in leukaemia117. Cells that
overexpress IGF1 are relatively resistant to both of these
treatments and IGF1 receptor transfection prevents
apoptosis after radiation damage. Thus, treatment with
agents that block IGF1 actions when combined with
these other therapeutic approaches may enhance the
efficacy of these treatment modalities.
Factors that change the equilibrium between extracellular concentrations of IGF1 or IGF2 and the IGF1
receptor have been shown to alter tumour cell growth.
Some tumour cell types in prostate or colon carcinomas,
for example, have increased IGF1 receptor expression118–
121
, and the affinity of IGF1 receptors for IGF1 is altered
in some tumour cell types, such as breast carcinoma.
Altered glycosylation of the IGF1 receptor-α subunit,
which results in equal affinity of this form of the receptor for IGF1 and IGF2 (ref. 122), has been reported in
gliomas. Altered glycosylation of the β-chain of the
IGF1 receptor has also been reported 123. Leukaemia
cells expressing this form of the β-subunit were
shown to respond to low concentrations of IGF1 with
increased growth and receptor autophosphorylation124.
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REVIEWS
An alternative form of the insulin receptor that is
expressed in normal fetal, but not adult, tissues can bind
to IGF1 and IGF2 with higher affinity due to alternative splicing; this form of the insulin receptor has been
found in breast, colon and lung carcinoma, resulting in
an enhanced mitogenic response to IGF2 (REF.125,126).
As there is three times as much IGF2 in serum compared with IGF1, this may be an important tumorogenic
mechanism.
A change in the extracellular concentrations of IGFBPs
can alter the ligand–receptor equilibrium. Many
tumours synthesize IGFBPs. This is believed to keep
tumour growth in check as, generally, when the IGFBPs
are present in high concentrations in extracellular fluids
they can inhibit IGF1 and IGF2 actions127. Some tumour
cell types such as non-small cell cancer and gastric adeno­
carcinoma have been reported to synthesize less IGFBP
following malignant transformation128,129. Under these
conditions it is reasonable to postulate that the amount
of free IGF1 may increase even if there is no change in
IGF1 synthesis. Furthermore, animal experiments have
shown that administration of IGFBPs can attenuate
IGF1 action and reduce tumour cell growth. Cleavage
of IGFBPs by proteases can result in an increased release
of free IGF1 to receptors and several proteases that have
been shown to be secreted by tumour cell types cleave
IGFBP3 (ref. 130). Therefore, IGF1 release from IGFBPs
has been proposed as a mechanism for altering cancer
cell growth131–133.
The altered expression of tumour suppressor genes
alters the growth of many cancers. Two tumour suppressor genes, p53 and Wilms’ tumour protein (WT1)
have been shown to alter IGF1 expression or function.
Overexpression of p53 mutants (a mutation that occurs
frequently in cancer) can result in reduced IGF1 receptor ubiquitination, thus reducing the rate of degradation
of the IGF1 receptor134. IGF1 itself can increase murine
double minute 2 (MDM2) expression which leads to p53
degradation. WT1 normally regulates the expression of
the IGF1 receptor and IGF2 synthesis; however, when
mutations are present (as occur in Wilms’ tumour) this
repression is lost135.
In summary, multiple mechanisms have been shown
to modulate tumour cell responsiveness to IGF1 and
IGF2. These include increases in IGF1 or IGF2 synthesis,
increased IGF1 receptor expression, release of proteases
that cleave IGFBPs and mutations that alter the function of tumour suppression genes. Strategies to determine which of these changes have occurred in a specific
tumour type are likely to lead to rational strategies that
target IGF1 actions with greater specificity.
Targeting the IGF system for cancer therapy. Several
strategies have been outlined by which the IGF1 system
might be targeted as a form of cancer therapy. These
include reduction in the number of IGF1 receptors by
antisense oligonucleotides or short-interfering RNA
(siRNA), inhibition of IGF1 receptor function by
inhibiting IGF1 binding using monoclonal antibodies
or by using tyrosine kinase inhibitors that inhibit the
828 | o ctober 2007 | volume 6
enzymatic activity of the receptor. Last, overexpression
of inhibitory forms of IGFBPs has also been proposed
as a potential therapeutic strategy. A list of studies that
have used these approaches in animal models is shown
in Tables 1, table 2.
Numerous studies have used monoclonal antibodies to target the IGF1 receptor (Table 1). Most of these
antibodies have a high affinity for the hormone binding domain of the receptor and function by directly
inhibiting IGF1 or IGF2 binding. However, in some
of these studies the antibodies have also been shown
to reduce the number of IGF1 receptors by enhancing the rate of receptor internalization. Most of these
model systems used immunocompromised mice and
human tumour cell lines to establish xenografts. The
antibody was then injected over several weeks. The
parameters that have been analysed include tumour
size, cell growth, apoptosis, metastases and mouse
survival. A wide range of tumour cell types have been
used. The initial studies136–139 were conducted using
mouse monoclonal antibodies, but more recently either
humanized140 or fully human141 antibodies have been
prepared and tested. In some experiments, the authors
analysed whether administration of the antibody
enhanced the effect of radiation142 or an established
chemotherapeutic approach143,144, confirming the idea
that inhibition of IGF1 actions enhances the effects
of established antitumour therapies145. One group of
investigators developed a bispecific antibody by combining two previously identified antibodies, one against
the IGF1 receptor and one against the EGF receptor,
into a single antibody. This bispecific antibody bound
both targets simultaneously and prevented IGF1 and
EGF from binding to their receptors146. This antibody
has in vivo tumour activity; specifically it was shown
to inhibit the growth of BXPC3 or HD29 tumour cells
that were injected into mice141.
In summary, multiple antibodies directed against the
human IGF receptor have potent activity in xenograft
models. Many of the antibodies are currently in Phase I
trials and the results of single-dose escalation studies,
as well as those from studies that combine chemotherapeutic agents, are eagerly awaited. No Phase II human
studies have been reported with any of these antibodies,
therefore, their degree of antitumour activity in human
cancers remains to be determined.
Tyrosine kinase inhibitors. The development of smallmolecule inhibitors of the IGF1 receptor tyrosine kinase
has been a major challenge owing to cross-reactivity
with insulin receptors. The inhibitors that have been
developed and tested in animal models so far are shown
in table 2. As for the monoclonal antibodies, these
studies have used immunocompromised mice and
human tumour xenografts to assess efficacy. In general,
changes in tumour growth have been the primary end
point, although changes in animal survival and the ability to enhance the effects of chemotherapeutic agents
have also been studied147–150. Most of these compounds
have been designed to compete for the ATP binding
site on the tyrosine kinase. However, one compound
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Table 1 | Anti-IGF1 receptor antibody efficacy in animal studies
Antibody Name Species
Tumour cell type
Model
Comment
αIR3
Mouse
Breast cancer
Athymic mice
Decreased tumour size
Refs
136
αIR3
Mouse
Rhabdomysarcoma
Athymic mice
Decreased tumour size
137
αIR3
Mouse
Ewing sarcoma
Athymic mice
Decreased tumour size
138
αIR3
Mouse
Non-small-cell
lung cancer
Athymic mice
Decreased tumour size
139
SCFV/FC
Mouse/human
chimera
Breast cancer
Athymic mice
Decreased tumour size
164
SCFV/FC
Mouse/human
chimera
Breast cancer
Athymic mice
IGF1 receptor
downregulation
165
SCF/FC
Mouse/human
chimera
Breast cancer
Athymic mice
Decreased tumour size, enhanced effect
combined with tamoxifen
143
EM/164
Mouse
Pancreatic
Athymic mice
Decreased tumour growth
166
A‑12
Fully humanized
Breast cancer
Athymic mice
Decreased tumour size, apoptosis
167
Bispecific
Humanized anti-IGF1
and EGF receptor
Pancreatic/colon
Athymic mice
Induced receptor down regulation,
inhibited tumour growth
141
A‑12
Fully humanized
Prostate cancer
Athymic mice
Decreased tumour size, apoptosis
168
19D12
Fully humanized
Ovarian cancer
Athymic mice
Decreased tumour size
169
H7C10
Humanized
Non-small-cell lung cancer
Athymic mice
Decreased tumour size, prolonged lifespan
140
CP751‑871
Fully humanized
Breast cancer
Athymic mice
IGF1 receptor downregulation, decreased
tumour size
170
KM1468
Mouse (Anti-IGF2)
Colon cancer
Athymic mice
Blocked colon cancer metastases
171
SCFV/FC
Mouse/human
chimera
Breast cancer
Athymic mice
Downregulated IGF1 and insulin receptors
172
A‑12
Fully humanized
Prostate cancer
Athymic mice
Augmented doxytaxel-induced inhibition
of tumour growth
144
A‑12
Fully humanized
Non-small-cell lung cancer
Athymic mice
Enhanced radiation-induced tumour cell
apoptosis
142
A‑12
Fully humanized
Multiple myeloma
SCID mice
Decreased tumour growth and
vascularization
163
EGF, epidermal growth factor; IGF, insulin-like growth factor; SCID, severe combined immunodeficiency.
that does not compete for this site has been tested151,152.
Some of the ATP binding site inhibitors have activity
against the insulin receptor, as demonstrated by the
increase in blood glucose levels after a single injection151. None of these small molecule inhibitors has
entered clinical trials.
Another approach has been to use antisense RNA
or siRNAs to inhibit tumour growth153. To date these
targeting strategies have used cells in culture and have
not been broadly applied to in vivo models of tumour
activity. In general, these strategies have been effective in downregulating the number of IGF receptors
and, thereby, have increased the susceptibility of these
tumour cells to chemotherapeutic agents154. Likewise,
increased cell death has been demonstrated with these
approaches and this response did not require the coadministration of other cytotoxic agents. In a pilot study
with patients who had gliomas using an IGF1 receptor
antisense oligonucleotide showed clinical or radiological improvement in 8 out of 12 patients. Two patients
were classified as complete responders and four of them
as partial responders155.
nature reviews | drug discovery
Challenges and opportunities for IGF1 therapies
There are several challenges and opportunities for using
IGF1 as an anabolic agent. Recent molecular studies have
precisely defined the pathways that are used to augment
protein synthesis in response to IGF1. These pathways
have both positive and negative regulatory elements156.
How these elements are altered and function in conjunction with other important pathways, such as the pathways
that mediate the direct effects of leucine on protein synthesis, or in conjunction with pathways that are stimulated
by other hormones and growth factors, such as oestrogens,
androgens or transforming growth factor-β (TGFβ), will
provide important information for designing future studies and for the development of therapies to assess clinical
responses157–159. As the defects that occur in these signalling pathways in catabolic states become better defined, it
will be possible to plan rational uses for the stimulation
of the IGF1 pathway; this information should prevent
significant off-target effects. Similarly, the ability to target
IGF1 to particular tissue compartments or cell types, such
as the gastrointestinal epithelium in short bowel disorders,
has not been exploited and such local targeting could take
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Table 2 | IGF1 receptor tyrosine kinase inhibitor efficacy in animal studies
Compound
Tumour Type
Model
Comment
Refs
NVP-AEW541‑A
Fibrosarcoma
Athymic mice
Inhibited tumour growth
173
BMS‑536,924
Salivary Gland
Athymic mice
Inhibited tumour growth
174
BMS‑554,417
Salivary gland
Athymic mice
Inhibited tumour growth
175
Cyclolignan
Uveal melanoma
Athymic mice
Inhibited tumour growth
151
TAE226
Glioma
Athymic mice
Inhibited tumour growth, increased survival
176
NVP-AEW541
Neuroblastoma
SCID mice
Inhibited tumour invasiveness
177
Cyclolignan
Myeloma cells
Syngeneic mice
Inhibited tumour growth, increased survival
152
NVPADW742
Myeloma cells
SCID mice
Inhibited tumour growth, metastases and increased
survival
178
NVPAEW541
Ewing sarcoma
Athymic mice
Inhibited tumour growth and angiogenesis
179
PQ401
Breast cancer
Syngeneic mice
Inhibited tumour growth
180
NVP-AEW541
Ewing sarcoma
Athymic mice
Combined with vitronectin inhibited tumour growth
147
SCID, severe combined immunodeficiency.
advantage of IGF1’s known anabolic properties while
minimizing off-target effects — high concentrations of
peptide outside the local gastrointestinal epithelial area
would not be required to achieve the desired therapeutic
response. Likewise, in patients with burns it may be possible to apply IGF1 locally to improve tissue healing without
requiring high blood concentrations and systemic administration. Co-administration of IGF1 and IGFBP3 may
also obviate the side effects associated with high systemic
plasma IGF1 levels but allow sufficient IGF1 to equilibrate
with the extravascular space to achieve a therapeutically
useful effect160. Several small Phase II studies have been
completed using this combination and the results suggest
that in catabolic states, such as myotonic dystrophy, there
may be efficacy160.
Inhibition of the IGF1 axis may also be helpful in
modifying the activity of a number of disease states.
Because of its potent anti-apoptotic activity, inhibiting
IGF1 signalling is a major therapeutic goal in cancer
research161,162. Recent studies that have combined the
use of local radiotherapy and/or chemotherapy with
IGF1 inhibitors to take advantage of the fact that IGF1
can antagonize the pro-apoptotic effects of these treatments142,145,163. This appears to be a particularly promising
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Competing interests statement
The authors declare no competing financial interests.
DATABASES
OMIM:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
Amyotrophic lateral sclerosis | anorexia nervosa |
Bell’s palsy | coeliac disease | cystic fibrosis |
myotonic dystrophy
UniProtKB: http://ca.expasy.org/sprot
IGF1 | IGF2 | proinsulin | somatotropin
FURTHER INFORMATION
Clemmons’ laboratory homepage:
http://www.med.unc.edu/wrkunits/2depts/medicine/
endocrin/research/ClemmonsMaile/ClemmonsLab.htm
All links are active in the online pdf
volume 6 | o ctober 2007 | 833
© 2007 Nature Publishing Group