Signal Transduction and Targeted Therapy [Link].

com/sigtrans

REVIEW ARTICLE OPEN

Targeting growth hormone function: strategies

and therapeutic applications
Man Lu1, Jack U. Flanagan2,3, Ries J. Langley 3,4
, Michael P. Hay 2,3
and Jo K. Perry 1,3

Human growth hormone (GH) is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has
pleiotropic effects across multiple physiological systems. GH is also expressed in extrapituitary tissues and has localized autocrine/
paracrine effects at these sites. In adults, hypersecretion of GH causes acromegaly, and strategies that block the release of GH or
that inhibit GH receptor (GHR) activation are the primary forms of medical therapy for this disease. Overproduction of GH has also
been linked to cancer and the microvascular complications that are associated with diabetes. However, studies to investigate the
therapeutic potential of GHR antagonism in these diseases have been limited, most likely due to difficulty in accessing therapeutic
tools to study the pharmacology of the receptor in vivo. This review will discuss current and emerging strategies for antagonizing
GH function and the potential disease indications.

Signal Transduction and Targeted Therapy (2019)4:3 ; [Link]

INTRODUCTION somatotroph cells also induces the release of GH from secretory

Human growth hormone (GH) is a peptide hormone that is secreted vesicles as a result of the influx of extracellular Ca2+.8 A complex
from the anterior pituitary. It has a central function of regulating series of short and long feedback loops negatively regulates GH
postnatal growth and metabolism and exhibits pleiotropic effects on secretion. Increased levels of GH and IGF1 in the circulation
various human tissues. Chronic hypersecretion of GH into the stimulate the release of somatostatin, which interacts with
circulation, usually from a GH-secreting pituitary adenoma, is somatostatin receptors and negatively regulates GH secretion
classically associated with acromegaly, a debilitating disease from the anterior pituitary.
characterized by excessive skeletal growth, soft tissue enlargement, GH secretion is also influenced by ghrelin, a GH secretagogue
insulin resistance, and cardiovascular and gastrointestinal morbid- that is produced primarily by the endocrine cells of the stomach,
ities.1 Increased GH levels have also been implicated in cancer and but also by the intestinal tract and hypothalamus.9 In addition,
diabetes.2–5 Pegvisomant, a GH analog, is the only clinically used secretion is regulated by thyroid hormones, leptin, androgens, and
antagonist of the GH receptor (GHR).6,7 However, other antagonists estrogen. Other key stimuli for secretion include nutrition,
are in clinical trials or preclinical development. This review will focus exercise, body composition, and the onset of deep sleep.10–13
on current strategies for antagonizing GH function and the related Distinct sex-specific secretion patterns are apparent.14,15
disease indications and will discuss considerations associated with Once released into the circulation, GH binds and activates the
an increasingly complex GH signal transduction network. Due to cell-surface GHR, as well as the related prolactin receptor in target
space limitations, reviews have been used in the place of original tissues such as liver, muscle, bone, and adipose tissue (Fig. 1). It is
articles in some instances. the key regulator of insulin-like growth factor 1 (IGF1), which is
secreted from target tissues, particularly the liver. Increased serum
GH and IGF1 produce feedback loops that lead to inhibition of
GH SECRETION AND PHYSIOLOGICAL FUNCTION GHRH, release of somatostatin, and consequently inhibition of GH
GH is released from the somatotroph cells of the anterior pituitary secretion from the pituitary. Whereas the endocrine system is the
in a pulsatile fashion. Release is primarily regulated by the main secretory pathway, GH is also expressed in many extra-
hypothalamic hormones, growth hormone-releasing hormone pituitary tissues in which it has autocrine and paracrine
(GHRH; positive regulation), and somatostatin (negative regula- effects.4,16,17
tion) (Fig. 1).8 GHRH is a peptide hormone that interacts with a G The primary function of GH is to promote postnatal longitudinal
protein-coupled receptor (GHRHR) in somatotroph cells to activate growth. It induces bone growth and is involved in the regulation
the cAMP signaling pathway, which leads to increased GH mRNA of lipid, carbohydrate, nitrogen, and mineral metabolism and
transcription and release. GHRH upregulates the pituitary-specific electrolyte balance. It increases lipolysis in adipocytes and
POU homeodomain transcription factor, Pit-1, which in turn, decreases body fat; it increases amino acid uptake and nitrogen
transcriptionally upregulates the GH1, GHRHR and Pit-1 genes retention in muscle and maintains muscle mass and strength.8,18
(auto-upregulation). Activation of GHRHR signaling in GH has effects on the immune system, cardiovascular system,

1
Liggins Institute, University of Auckland, Auckland, New Zealand; 2Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland, New
Zealand; 3Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand and 4Department of Molecular Medicine and Pathology, School of Medical Sciences,
University of Auckland, Auckland, New Zealand
Correspondence: Jo K. Perry ([Link]@[Link])

Received: 27 June 2018 Revised: 10 December 2018 Accepted: 12 December 2018

© The Author(s) 2019

 Targeting growth hormone function: strategies and therapeutic applications
Lu et al.
2
GHRH antagonists SSTN receptor ligands

GHRH SSTN
Nervous system

Cardiovascular Ghrelin Dopamine agonists

system GH

Digestive system
& metabolism
GH/IGF1
GH analogues
axis IGF1 Fusion proteins
Immune system GH GHR antagonists Anti-GHR antibody
Small molecule compound
Antisense oligo
Antagonists of downstream signaling
Muscular system

Autocrine/
Skeletal system
paracrine IGF1
actions
1234567890();,:

Fig. 1 Endocrine regulation of GH and therapeutic blockade. GH is secreted from the anterior pituitary under the control of hypothalamic
hormones, growth hormone releasing hormone (GHRH) and somatostatin (SSTN), and ghrelin, which is predominantly secreted in the
stomach. Endocrine secretion of GH impacts numerous physiological systems with wide-ranging effects in various tissues. GH is also
expressed in extrapituitary tissues in which it has localized autocrine/paracrine effects. Strategies to antagonize GH signaling are shown and
are described in detail below

neurogenesis and the central nervous system, and aging.3,19–21 As Once activated, GHR signal transduction is downregulated by
a consequence, abnormal GH secretion has the potential to suppressor of cytokine signaling proteins 1–3 (SOCS1–3); these
impact multiple tissues and organs. In particular, GH hypersecre- are negative regulators that facilitate the ubiquitination and
tion leads to gigantism in childhood and acromegaly in adults, degradation of the receptor. Downregulation of the receptor
whereas congenital disruption of GH signaling causes short also occurs through dephosphorylation by several protein
stature and in rare cases Laron syndrome. In adults, deficiency is tyrosine phosphatases and protein inhibitor of activated STATs
known as GH deficiency syndrome. (PIAS).2
Activation of the GHR and GHR-stimulated signal transduction
pathways has been comprehensively reviewed elsewhere, and we
GROWTH HORMONE RECEPTOR SIGNAL TRANSDUCTION refer the reader to recent reviews for a more detailed description
The GHR is a type I cytokine receptor that lacks intrinsic kinase of GHR-mediated signaling.2,3,18,22,26
activity and requires recruitment of the nonreceptor tyrosine In addition to activating the GHR, human GH can bind and
kinase, Janus kinase 2 (JAK2), for activation.2,3,22,23 Substantial activate a second cytokine receptor, the prolactin receptor.27
evidence also supports the concept that SRC family kinases, in The GHR also cross-talks and/or forms complexes with several
particular LYN, are recruited to the receptor. These kinases other growth factor and hormone receptors (Fig. 3). GH
participate in GHR signal transduction.2,3 A predimerized GHR increases the phosphorylation of the epidermal growth factor
homodimer interacts with the GH ligand through two binding receptor (EGFR) and promotes downstream ERK signaling.28–30 It
sites, which have different affinities for the receptor. Binding leads has been proposed that a GHR-JAK2-IGF1 receptor complex is
to a rotational change in the receptor transmembrane domain, formed, which is activated by GH stimulation and inhibited by a
which leads to transphosphorylation and activation of two JAK2 soluble IGF1 receptor extracellular domain fragment.31,32 The
molecules that are associated with the cytoplasmic domain of the androgen receptor also cross-talks with GH signaling at the level
receptor.24,25 Phosphorylated JAK2 then phosphorylates tyrosines of STAT5 and SOCS2 in prostate cancer cells.33 More recently it
in the cytoplasmic domain of GHR, and this facilitates recruitment has been demonstrated that EphA4, a member of the Eph family
of signaling molecules to the receptor. The primary signaling of receptor tyrosine kinases, may interact with the GHR.34 EphA4
pathway activated by GH is the JAK-STAT (signal transducer and knockout mice have dramatically reduced body size and
activator of transcription) pathway (Fig. 2). The STAT molecules impaired GHR signaling: they have normal levels of GH mRNA
that are activated by GH signaling are STAT1, 3, 5a, and 5b. Other expression in the pituitary but have reduced plasma IGF1 and
key signaling pathways that are utilized are the mitogen-activated reduced IGF1 mRNA expression in the liver. The authors
protein kinase (MAPK) and phosphatidylinositol 3-kinase/AKT/ demonstrated that EphA4 forms a complex with GHR and
mammalian target of rapamycin (PI3K/AKT/mTOR) pathways, as JAK2 and enhances IGF1 production in response to GH.34
well as SH2B1β, a scaffold protein that interacts with JAK2 and Furthermore, recent studies from Stuart Frank’s laboratory have
mediates GH-induced changes in the cytoskeleton.22 The GHR has shown that the GHR and prolactin receptor form complex
also been observed to rapidly translocate to the nucleus following heteromultimeric structures that may affect GH signal transduc-
activation, but its role there remains unclear. tion in some cell lines.35,36

Signal Transduction and Targeted Therapy (2019)4:3

 Targeting growth hormone function: strategies and therapeutic applications
Lu et al.
3

Ca2+ GH
Glucose

GHR

PLC JAK2 SRC

RAP JNK
DAG
FAK
PKC
IRS
RAS
?
RAF
STATs
PI3K
MEK

MAPK
AKT
mTOR
Igf1, Socs1-3, c-Fos,
GSK3 JunB, other genes

Fig. 2 GHR signal transduction. A predimerized GHR interacts with the GH ligand and activates the associated kinases, JAK2 and SRC. Key
signal transduction pathways activated by the GHR include the JAK-STAT, MEK/MAPK, PI3K/AKT/mTOR, and PLC/DAG/PKC pathways. The GHR
can also translocate to the nucleus (dotted line), but the function remains unclear. GHR growth hormone receptor, GH growth hormone, JAK2
janus kinase 2, SRC SRC proto-oncogene, STAT signal transducer and activator of transcription, MEK mitogen-activated protein kinase kinase,
MAPK mitogen-activated protein kinase, PI3K/AKT/mTOR phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin, GSK3 glycogen
synthase kinase 3, IRS insulin receptor substrate, PLC/DAG/PKC phospholipase C/diacylglycerol/protein kinase C, FAK focal adhesion kinase,
RAP rap guanine nucleotide exchanger

GH EXCESS: DISEASE INDICATIONS pegvisomant are described in more detail in the following
Acromegaly sections. Other strategies include dopamine agonists that bind
One of the most well-described diseases associated with excess to the dopamine receptors in the pituitary gland and block the
GH is acromegaly, a chronic disease that is generally caused by secretion of prolactin and GH. These agents may benefit patients
benign pituitary adenomas, with rare exceptions that include in whom hypersecretion of both prolactin and GH occurs.
secretion from tumors at other sites.37 Patients may exhibit clinical Radiotherapy is another therapeutic option but is reserved for
features, such as abnormal growth of the hands, feet and facial aggressive tumors that are not controlled by surgery or medical
features, and enlarged organs. Other pathologic features linked to treatment due to the high risk of hypopituitarism and other
effects of excessive GH may be observed, such as vertebral complications.37,41
deformities and abnormal calcium levels, increased risk of
cardiovascular disease, respiratory comorbidities, and glucose Cancer
intolerance.1,38,39 Hypersecretion of GH leads to elevated con- There is a growing body of evidence that implicates GH in
centrations of circulating IGF1 in acromegalic patients, and these multiple cancer types, particularly breast, colon and endometrial
two hormones may have different metabolic features and target cancer. Individuals with GH resistance, as seen in Laron syndrome,
tissue responses.40 a rare genetic condition resulting from an inactivating mutation in
Treatment options for acromegaly include surgery, medical the GHR, are protected from cancer and diabetes.44–46 Conversely,
therapy and radiotherapy. The aim of treatment is to reduce both patients with acromegaly have a higher risk of developing certain
GH and IGF-1 to within normal limits.37,40,41 The primary choice for cancers, although the extent of that risk remains a topic of debate
therapy is surgical removal of the tumor; however, there are some with conflicting observations.47,48 This is partly due to limitations
situations in which this may not achieve an optimal outcome, for in the ability to quantify the risk of cancer in patients with a rare
example in the case of larger tumors with significantly high levels disease and differences in the methodological approaches. Recent
of GH. Therefore, more than one intervention may be necessary to nationwide cohort studies in Italy and Denmark both found an
achieve symptom remission and GH/IGF1 normalization. Medical increased cancer risk in patients with acromegaly.48,49 This was
therapies are an important treatment option, particularly for supported by a meta-analysis of 23 studies, which observed a
patients who may not be suitable for surgery or those with slightly elevated overall risk of cancer in these patients.49
persistently high levels of GH/IGF1 following surgery. There are Such observations are supported by numerous in vitro and in vivo
three main types of medical therapy, including somatostatin studies that have demonstrated multiple effects on tumor develop-
receptor ligands (SRL), GHR antagonists and dopamine ago- ment.4,47,50,51 GH accelerates tumor progression through autocrine/
nizts42,43 (Table 1). The GHR antagonist pegvisomant is an analog paracrine effects on cancer cell behavior and neighboring cells
of GH that competes with GH for receptor binding and within the tumor microenvironment. These effects include promot-
consequently blocks GHR signal transduction. SRLs and ing cell survival/proliferation,52,53 migration/invasion,53,54 oncogenic

Signal Transduction and Targeted Therapy (2019)4:3

 Targeting growth hormone function: strategies and therapeutic applications
Lu et al.
4

GH GH GH GH GH GH
EphA4

PRLR GHR EGFR IGFR

GHR-PRLR

JAK2 SRC JAK2

JAK2 JAK2 SRC JAK2 SRC JAK2

AR
STATs PI3K

MEK
AKT

mTOR MAPK

Fig. 3 GHR crosstalk. In addition to the GHR, GH can bind and activate the PRLR, and the GHR can form heteromultimers with PRLR.
Furthermore, GHR cross-talks and/or forms complexes with several other growth factor and hormone receptors, such as EphA4, EGFR, and
IGF1R, which enhances the stimulation of downstream signaling pathways. GHR growth hormone receptor, GH growth hormone, JAK2 janus
kinase 2, STAT signal transducer and activator of transcription, MEK mitogen-activated protein kinase kinase, MAPK mitogen-activated protein
kinase, PI3K/AKT/mTOR phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin, PRLR prolactin receptor, EGFR epidermal growth
factor receptor, IGF1R insulin-like growth factor 1 receptor, AR androgen receptor

transformation,55,56 and epithelial-to-mesenchymal transition,54,57,58 radioresistance, and GHR antagonism/suppression may be bene-
as well as promoting tumor angiogenesis59 and lymphangiogen- ficial when combined with radiotherapy and certain chemother-
esis60 and enhancing a cancer stem cell-like phenotype.57,61 These apeutic drugs.47,75–77 Recently, we reported that GH promotes
effects have been observed in multiple tumor types, including radioresistance in cancer cell lines78 and that pegvisomant sup-
breast, endometrial, and hepatocellular carcinomas, and lung cancer, presses endometrial tumor regrowth following radiotherapy in a
melanoma, prostate cancer, and colon cancer.17,47,57,61–63 The effects xenograft model, which highlights the potential utility of this
are mediated through altered transcription of numerous genes that combinational approach and identifies GHR antagonism as a
are associated with various aspects of cancer progression. A recent potential molecularly targeted radiosensitizing strategy.76 This
study demonstrated that disrupted GH signaling is associated with finding is of interest because for many common cancers, adding
elevated p53 in colon tissue in humans and mice and that GH may molecularly targeted agents to radiotherapy can increase pre-
act as a tumor promoter by suppressing p53, PTEN, and APC levels.64 clinical cure rates,79–81 and currently the only targeted agent
In addition, GH regulates the function of other receptors that clinically approved for this application is the EGFR antagonist,
promote cancer progression.65,66 cetuximab.
Single-nucleotide polymorphisms in GH-related genes are
associated with the risk of developing osteosarcoma, breast, and Diabetes mellitus
colon cancer.67–69 Recently, a P495T variant of the GHR that is Diabetes mellitus is a chronic metabolic disorder that is
associated with increased incidence of lung cancer in various characterized by elevated blood glucose caused by deficiency
ethnic groups was shown to prolong GH signaling, which leads to or resistance to insulin. Glucose homeostasis is primarily
increased expression of genes associated with tumor proliferation regulated by insulin, which lowers blood glucose by increasing
and epithelial-to-mesenchymal transition.70 The amino acid the uptake into cells and increasing its utilization and storage as
change at position 495 impairs SOCS2 binding and leads to a fat and glycogen in peripheral tissues. Insulin also decreases
reduced downregulation of the receptor. gluconeogenesis (synthesis of glucose from noncarbohydrate
Such studies support the rationale for testing GHR antagonism carbon substrates) and glycogenolysis (breakdown of glycogen).
in cancer, but only a small number of preclinical studies have used GH has well-described diabetogenic actions. In particular, GH
pegvisomant in an oncology setting. Single agent growth- opposes the actions of insulin: it increases glucose production
inhibitory effects have been reported in breast, colon, and through gluconeogenesis and glycogenolysis in the liver and
meningioma tumor xenografts, which suggests that GHR antag- kidney, suppresses glucose uptake in adipose tissues, and is
onism as a monotherapy may have efficacy in some tumor lipolytic. In healthy adults and adolescents during puberty,
types.71–74 However, it is clear from these studies that not all increased GH levels impair glucose tolerance and induce insulin
tumor types tested were responsive, and currently the field is resistance.82,83 Conversely, adults with Laron syndrome have
lacking diagnostic biomarkers capable of predicting response. reduced circulating IGF1 and increased insulin sensitivity.45,46,84
As with many targeted therapies, improved anticancer This is supported by studies in mice85 and dogs.86 Blocking the
responses may be observed with combination therapeutic effects of GH in patients with acromegaly improves diabetes and
approaches. In this regard, GH promotes chemo- and glucose metabolism. However, a one-month treatment with a

Signal Transduction and Targeted Therapy (2019)4:3

 Targeting growth hormone function: strategies and therapeutic applications
Lu et al.
5
retinopathy compared to T2D patients with nonproliferative
Table 1. GH signaling inhibitors
retinopathy or with no evidence of this complication.97
Strategy/drug name Target Company An increased prevalence of proliferative retinopathy is also
observed in patients with acromegaly.98 Whether GHR-targeted
SSTN receptor ligands strategies will be an effective treatment for retinopathy is still a
Octreotide LAR42,43 GH secretion Novartis; clinical use matter of debate: a small clinical study using the GHR antagonist,
Lanreotide autogel42,43 GH secretion Ipsen; clinical use
pegvisomant, did not observe regression of proliferative diabetic
retinopathy. However, it has been suggested that this may have
Pasireotide LAR42,43 GH secretion Novartis; clinical use been due to insufficient suppression of IGF1.99,100
Octreolin42,43 GH secretion Chiasma; clinical In diabetic nephropathy, excess GH stimulates glomerular
development growth, affects the structure and function of the kidney, and is
Intravail Octreotide GH secretion Aegis; clinical use associated with glomerular podocyte dysfunction.89,101–103
ProTek42,43
Somatoprim (DG3173)42,43 GH secretion Aspireo; clinical Longevity
development The GH/IGF1 axis has an intriguing association with longevity in
Dopamine agonist animals. Numerous studies, particularly in rodents, indicate that
Cabergoline42,43 PRL/GH Par Pharmaceutical; clinical suppression of the GH/IGF1 axis has multiple benefits in terms of
secretion use aging. Disruption of GH and IGF1 signaling extends lifespan,
GHRH antagonists111 GH secretion Preclinical development
enhances insulin sensitivity, decreases DNA and protein oxidation
in the liver, reduces cancer incidence and may reduce age-related
GH analogs
inflammation.20,104–108 GHR dysfunction clearly protects indivi-
Pegvisomant/B20366,114 GHR Pfizer; clinical use duals with Laron Syndrome against aging-related diseases such as
GH-G120R118 GHR/PRLR cancer and diabetes, but it is unclear whether GH/IGF1 deficiency
Fusion proteins increases human lifespan, although a handful of studies have
Antagonist–GHBP GHR Asterion Ltd.; clinical indicated that attenuated GH/IGF1 function is associated with
fusion128 development human longevity.109,110
Antisense oligonucleotide
ATL1103 (Atesidorsen)132 GHR Antisense Therapeutics STRATEGIES THAT TARGET GHR SIGNALING
Ltd.; clinical development The most successful strategy to date for directly inhibiting GHR
Anti-GHR antibody function has undoubtedly been peptide receptor antagonists,
Anti-GHRcyt-mAb133,137 GHR exemplified by the clinically used GHR antagonist pegvisomant
GF185136 GHR (see below). However, therapeutic options to target the GHR are
RN172135 GHR Pfizer; preclinical
still limited, and pegvisomant can be difficult for researchers to
access. Given the growing body of evidence that has suggested a
CG-86134 Ghr (porcine)
role for this receptor in cancer and other diseases, there is
Small molecule compound certainly room for the development of alternative targeted
BVT-A138 Unknown therapeutics and several approaches are in preclinical and clinical
GH signaling pathway inhibitors development (Figs. 1 and 4, Table 1).
JAK-STAT, MAPK, PI3K/AKT/ Inhibitory strategies broadly fall into three categories: those that
mTOR140–144 inhibit inhibition of GH secretion from the pituitary (pre-receptor),
those that directly inhibit the GHR, and drugs which inhibit
GHR growth hormone receptor, SSTN somatostatin, PRLR prolactin receptor, downstream components of GHR signaling pathways (post-
PRL prolactin, JAK-2 Janus kinase 2, STAT signal transducer and activator of receptor).
transcription, MAPK mitogen-activated protein kinase, PI3K/AKT/mTOR
phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin
Inhibitors of GH secretion (pre-receptor)
Inhibitors of GH secretion include SRLs, dopamine agonizts and
GHRH antagonists.42,43,111 SRLs bind to the somatostatin receptors
that are present in the tumor and suppress the secretion of GH
GHR antagonist had no effect on insulin sensitivity in insulin- from the pituitary. These inhibitors include the first-generation
resistant nondiabetic men.87 SRLs, octreotide and lanreotide, and the second-generation SRLs,
In addition to systemic effects on glucose metabolism and pasireotide, octreolin, and somatoprim (Table 1). Currently, SRLs
insulin sensitivity, GH may contribute to diabetes-associated are used to treat acromegaly and neuroendocrine tumors. Other
complications, such as diabetic retinopathy and diabetic renal applications include diabetes, obesity and cancer.112 SRLs also
disease, through localized expression and autocrine/paracrine have direct anticancer activity through their actions on tumor cells
effects in tissues,88–93 although published research in these areas that express somatostatin receptors, but it is unclear whether they
is limited. Diabetic retinopathy is one of the most frequent suppress tumoral (autocrine/paracrine) secretion of GH.
complications of diabetes and is a leading cause of blindness. The Peptide GHRH analog antagonists have been developed in
proliferative form is a more advanced stage of the disease and is several labs. In particular, studies by Schally et al.111 have led to a
characterized by retinal neovascularization. Extrapituitary expres- series of well-characterized inhibitors.113 GHRH and GHRH
sion of GH has been detected in the human retina and vitreous receptors are expressed in many cancer cells and tumor tissues.
fluid,94 and GH has been demonstrated to directly stimulate the Antagonists for GHRH inhibit the proliferation of a wide range of
proliferation of human retinal microvascular endothelial cells cancer cell lines in vitro and inhibit xenograft tumor growth, which
in vitro.95 In vivo, ischemia-induced retinal neovascularization was demonstrates their potential clinical utility.111 Similar to SRLs,
inhibited in transgenic mice expressing a GH antagonist gene.96 GHRH antagonists inhibit endocrine secretion of GH from the
Increased serum levels of GH and IGF1 have been observed in anterior pituitary to varying extents. However, the main action of
type 2 diabetes mellitus (T2D) patients with proliferative diabetic these antagonists is through direct inhibition of GHRH receptors in

Signal Transduction and Targeted Therapy (2019)4:3

 Targeting growth hormone function: strategies and therapeutic applications
Lu et al.
6

Small molecule compound Anti-GHR antibody

B2036/pegvisomant
GHBP-GHR GH
antagonist
fusion protein
GHR

Signalling Blocked

ATL1103, Antisense RNA

Degraded
GHR mRNA
GHR gene

Fig. 4 Strategies targeting the GHR One protein-derived GHR antagonist is clinically approved (pegvisomant), and several other GHR-targeted
approaches are in development. These include an antagonist-GHBP fusion protein and anti-GHR antibodies, which inhibit the activation of
GHR and block downstream signaling. Another approach is atesidorsen (ATL1103), an antisense oligonucleotide (ASO), that binds and induces
the degradation of GHR mRNA. Small molecule compounds may also have applications; however, there are currently limited reports in this
area

tumor tissues. Potential applications besides oncology include affinity for the receptor somewhat. Because pegvisomant targets
acromegaly, diabetic retinopathy, and nephropathy.111 the GHR instead of GH, it results in reduced IGF1 and enhanced
GH levels through the negative-feedback loop. Therefore,
GHR antagonists measurement of GH is not useful to monitor treatment of
Pegvisomant. Pegvisomant is a chemically modified (PEGylated) acromegaly with pegvisomant: instead IGF1 is determined as a
analog of GH that was discovered in John Kopchick’s lab and surrogate biomarker.120,121 In addition, pegvisomant treatment
developed by Pfizer. It is the only clinically approved GHR decreases the insulin and glucose concentrations.122
antagonist and has been approved by the FDA for the treatment Pegvisomant is highly efficacious with only mild-side effects.
of acromegaly [reviewed in ref. 6,114,115]. The first reported GHR One concern was potential adenoma growth caused by the
antagonist was a bovine GH protein that was mutated with three increased levels of circulating GH. From the clinical trials
amino acid substitutions located in helix 3, which resulted in a conducted so far, changes in the tumor size or recurrence were
dwarf phenotype in transgenic mice.6,116,117 A similar result was infrequent, but further assessment needs to be carried out. An
observed with a single amino acid substitution of glycine to evaluation of pegvisomant as long-term monotherapy in acrome-
arginine at position 120 on helix 3 of human GH (G120R).118 galic patients from the global safety surveillance study ACROS-
Pegvisomant contains a G120K mutation (substitution to a lysine TUDY reported increases or increases/decreases in the tumor sizes
also allows PEGylation at this site). Eight more mutations (H18D, in 12 of 542 subjects (2.2%).7 Another study reviewed the efficacy
H21N, R167N, K168A, D171S, K172R, E174S, and I179T) were of pegvisomant as a monotherapy for acromegaly over a 10-year
introduced at binding site 1 on the molecule to prevent period, and showed 6 of 64 (9.4%) cases with tumor growth.123
PEGylation and to increase the affinity for the receptor at this Pegvisomant has also been evaluated in a combination therapy
site.6 This antagonist, which is the protein component of with SRL, particularly with respect to normalizing the IGF1
pegvisomant, is known as B2036. The half-life of native GH (as concentration in acromegalic patients who have failed SRL
well as B2036) in the circulation is short, which limits its in vivo monotherapy. The outcome of a 42-week study of active
efficacy. To reduce clearance and increase the serum half-life, acromegalic patients demonstrated that the combined therapy
polyethylene glycol-5000 (PEG5000) was conjugated to the was effective in normalizing the levels of IGF1 and that there was
molecule.119 PEGylation extends the serum half-life, delays renal no indication of tumor growth.124 However, an analysis of 62 SRL-
clearance, and reduces the immunogenicity of pegvisomant resistant acromegalic patients indicated better IGF1 normalization
(B2036-PEG). B2036 competes with GH in vitro on the basis of with pegvisomant monotherapy compared to combined pegvi-
an increased affinity for the GHR. However, PEGylation reduces the somant/SRL treatment.125 Although pegvisomant is well tolerated

Signal Transduction and Targeted Therapy (2019)4:3

 Targeting growth hormone function: strategies and therapeutic applications
Lu et al.
7
and highly effective, some limitations need to be considered. antibody (GF185) that targets the human GHR, which acts as a full
Pegvisomant is more costly than SRL, and daily injection is competitor for GH binding and also inhibits GHR signaling. Lan
required. Treatment side-effects include elevated aminotransfer- et al.134 have generated an anti-idiotypic antibody (CG-86) which
ase levels and injection site reactions (lipohypertrophy). mimics an epitope on porcine GH and investigated the inhibitory
As described above, a small number of preclinical studies have effects on GH signaling and cell proliferation, which demonstrated
demonstrated efficacy for pegvisomant in certain tumor mod- the potential utility of this approach for generating GH
els.71–73,76 One obstacle to preclinical use in animal models is the antagonists. More recently Pfizer has reported development of a
species specificity of the drug. Both human GH and the protein humanized GHR monoclonal antagonist antibody (RN172), which
component of pegvisomant (B2036) can bind the human and blocked GH signaling in vitro and reduced IGF1 production in
mouse GHR, but pegylation significantly reduces the affinity for monkeys following a single-intravenous injection.135
the mouse GHR. Consequently, much higher concentrations of
pegvisomant are necessary to reduce serum IGF1 in mice.47 In Small molecules. The only small molecule GHR antagonist that
addition, rodent GH does not activate the human or primate GHR, has been reported is an orally available compound BVT-A (N-[5-
so the use of pegvisomant in animal models of disease does not (aminosulfonyl)-2-methylphenyl]-5-bromo-2-furamide). In two stu-
address the effect of the blockade of systemic GH. Therefore, dies, BVT-A suppressed GH induction of IGF1 expression in
although early animal studies have been promising, these hepatocytes in vitro and reduced GH stimulation of
limitations combine to reduce the potential of these in vivo IGF1 secretion and body weight in hypophysectomized rats.138,139
studies to support clinical translation. However, it is unclear where in the GH signaling pathway this
compound acts, and no subsequent activity has been reported in
Antagonist–GHBP fusion proteins. An alternative approach that is this area since the original publication.
used to generate long-acting forms of protein therapeutics
involves generating larger chimeric proteins that avoid kidney Inhibitors of GH signal transduction pathways (post-receptor)
filtration. Richard Ross and colleagues from Asterion Ltd. have Given that GH activates JAK-STAT, PI3K/AKT/mTOR and MAPK
developed fusion proteins composed of the GH ligand or a GHR signaling, agents which target components of these signaling
antagonist fused to GH-binding protein (GHBP), the extracellular pathways would be expected to modulate pathway-specific GH
domain of the GHR, which is proteolytically cleaved from the effects. However, targeting GH signal transduction pathways will
receptor and exists in the circulation (Fig. 4). The fusion of GH to unlikely be specific to GH signaling because other receptors and
its natural binding protein decreases its immunogenicity and cell signaling pathways can also utilize the same signaling
prolongs its half-life in the circulation.126 Initially, a GH–GHBP pathways as GH. The potential for small molecules to inhibit
fusion protein agonist was generated for the treatment of GH these pathways and non-selectively inhibit GHR signaling needs to
deficiency.127 This chimeric protein was found to exist in solution be considered in small molecule discovery studies. A detailed
as both a monomer and a dimer. In the dimer form, the GH description of therapeutic drugs that target molecules in the GHR
portion of one molecule bound to the receptor portion of another signal transduction pathways is beyond the scope of the current
molecule in a head-to-tail reciprocal dimer. More recently review, and we refer the reader to recent reviews.140–144
Wilkinson et al. demonstrated that fusion of GHBP to a GHR
antagonist protein similar to B2036 significantly reduced IGF1 by
14% after a single subcutaneous injection in rabbits and may be TARGETING AUTOCRINE/PARACRINE, AND SYSTEMIC
useful for treating acromegaly.128 Introduction of a W104A FUNCTIONS: THERAPEUTIC CONSIDERATIONS
mutation in the fused GHBP prevented intra- and inter- GHR antagonism suppresses the endocrine, autocrine, and
molecular binding. Three chimeric GHR antagonists were gener- paracrine functions of GH, and this is an important consideration
ated with extended in vivo clearance times; the terminal half-life that has particular relevance for cancer on the basis that both
of the fusion proteins was greater than 20 h in rats.128 systemic and tumor-derived GH contribute to cancer progres-
sion.4,47,50 Furthermore, it is quite clear from earlier studies by
Antisense oligonucleotides. Advances in antisense therapy have Lobie and colleagues that GH has differential effects depending
led to development of novel GHR antagonists (Fig. 4). Antisense on whether the source of GH is pulsatile secretion from the
oligonucleotides (ASOs) are short single-stranded DNA or RNA pituitary or secretion from cancer cells or other cells in the tumor
molecules (or chemical analogs) that bind and induce the microenvironment. For example, in breast cancer, autocrine
degradation of target RNAs.129 Early studies reported an inhibitory expression of GH from the tumor cells promotes a more
effect of GHR-targeted antisense oligonucleotides on GHR aggressive cellular phenotype, compared to exogenously added
expression and IGF1 production in mice.130,131 Antisense Ther- GH, which mimics endocrine secretion.52,54,145,146 This phenom-
apeutics Ltd. is developing an antisense oligonucleotide drug, enon may not be limited to cancer. For example, autocrine/
ATL1103 (now atesidorsen). Atesidorsen is a 20-mer ASO that has paracrine actions may also be important in conditions such as
been modified to enhance its stability and circulating half-life. In diabetic retinopathy because GH expression occurs in ocular
Phase II outcomes, twice-weekly treatment with 200 mg atesidor- tissues.88 Notably, antagonism of GH signaling has the added
sen was well tolerated and decreased the serum IGF1 concentra- benefit of suppressing the IGF1-mediated effects, which con-
tion by 27.8% at week 14 and 18.7% at week 21 in acromegalic tribute to the etiology of several disease indications in a manner
patients.132 In addition, interim analysis from a small higher dose similar to that described above.
study using twice-weekly 300 mg atesidorsen for 13 weeks As with any therapeutic agents, the potential for side effects
demonstrated results consistent with the Phase II trial outcomes associated with suppression of GH should be considered. Apart
(Antisense Therapeutic Ltd.). from the known side effects associated with pegvisomant, which
are described above, potential adverse effects may be extra-
Anti-GHR antibodies. GHR antibodies that inhibit GHR-mediated polated from adult GH deficiency (AGHD). The clinical features of
signal transduction have been reported.133–136 Stuart Frank’s lab AGHD includes abnormal body composition, decreased cardiac
has developed an inhibitory conformation-sensitive monoclonal capacity, increased risk of fracture, insulin resistance, and
antibody (Anti-GHRcyt-mAb) that targets the extracellular domain decreased quality of life.147–150 The abnormal body composition
of the rabbit GHR. Anti-GHRcyt-mAb effectively inhibits activation is characterized by increased adipose tissue mass, decreased lean
and downstream signal transduction of the rabbit and human body mass, decreased muscle mass and strength.148,149 Cardiac
GHR.133,137 Similarly, Sun et al.136 have reported a monoclonal changes, such as reduced aortic area and left ventricular mass

Signal Transduction and Targeted Therapy (2019)4:3

 Targeting growth hormone function: strategies and therapeutic applications
Lu et al.
8
index, are also reported in adult-onset GH deficiency.151 A study of 8. Bonert, V. S. & Melmed, S. in The Pituitary: Fourth Edition 85–127. [Link]
adults with isolated GH deficiency (i.e., AGHD that does not 10.1016/B978-0-12-804169-7.00004-0 (2017).
involve abnormalities in other pituitary hormones) reported 9. Okada, S. & Kopchick, J. J. Biological effects of growth hormone and its
decreased total IgG levels but no increased risk of infectious antagonist. Trends Mol. Med. 7, 126–132 (2001).
10. Frenette, E., Lui, A. & Cao, M. Neurohormones and sleep. Vitam. Horm. 89, 1–17
disease in the subjects.152 In addition, abnormal vascular and
(2012).
neural retinal morphology was observed in adults with isolated 11. Berryman, D. E. & List, E. O. Growth hormone’s effect on adipose tissue: quality
GH deficiency.153 It was demonstrated that anaerobic capacity was versus quantity. Int. J. Mol. Sci. 18, 10.3390/ijms18081621 (2017).
impaired in GH-deficient adults, and this decreases exercise 12. Ho, K. Y. et al. Fasting enhances growth hormone secretion and amplifies the
tolerance and quality of life.154 Skin and sleep changes were also complex rhythms of growth hormone secretion in man. J. Clin. Invest. 81,
reported in GH-deficient adults.148,155 968–975 (1988).
13. Gunawardane, K., Krarup Hansen, T., Sandahl Christiansen, J. & Lunde Jorgensen,
J. O. Normal Physiology of Growth Hormone in Adults. Endotext [Internet]
CONCLUSION ([Link], Inc., South Dartmouth (MA), 2000). [Link]
books/NBK279056/.
Suppression of the GH/IGF1 axis is a key medical therapy that is
14. Vijayakumar, A., Novosyadlyy, R., Wu, Y. J., Yakar, S. & LeRoith, D. Biological effects
indicated for acromegaly and may also be useful in other diseases of growth hormone on carbohydrate and lipid metabolism. Growth Horm. IGF Res.
such as cancer. Currently, pegvisomant is the only clinically used 20, 1–7 (2010).
GHR inhibitor. However, a small number of GHR antagonists are in 15. Jaffe, C. A. et al. Regulatory mechanisms of growth hormone secretion are
clinical trials or preclinical development, and we anticipate that sexually dimorphic. J. Clin. Invest. 102, 153–164 (1998).
these will eventually expand the options available for clinical and 16. Harvey, S. Extrapituitary growth hormone. Endocrine 38, 335–359 (2010).
research applications. 17. Perry, J. K., Liu, D. X., Wu, Z. S., Zhu, T. & Lobie, P. E. Growth hormone and cancer:
Clearly, the most successful strategy for targeting GHR an update on progress. Curr. Opin. Endocrinol. Diabetes Obes. 20, 307–313
signaling to date has involved protein-based therapeutics. (2013).
18. Troike, K. M. et al. Impact of growth hormone on regulation of adipose tissue.
However, other strategies are showing promise, particularly
Compr. Physiol. 7, 819–840 (2017).
antisense oligo and antibody-based approaches. One avenue 19. Waters, M. J. & Blackmore, D. G. Growth hormone (GH), brain development and
that has been underexplored is the development of small neural stem cells. Pediatr. Endocrinol. Rev. 9, 549–553 (2011).
molecule therapeutic agents to target the receptor. The GHR is a 20. Gesing, A. et al. A long-lived mouse lacking both growth hormone and growth
challenging target in this regard in that it lacks a kinase domain hormone receptor: a new animal model for aging studies. J. Gerontol. Ser. A Biol.
and the ligand binding surface involves a large, relatively Sci. Med. Sci. 72, 1054–1061 (2017).
featureless protein-protein interface. Identification of inhibitors 21. Bartke, A., List, E. O. & Kopchick, J. J. The somatotropic axis and aging: Benefits of
of protein-protein interactions has been a major challenge in endocrine defects. Growth Horm. IGF Res. 27, 41–45 (2016).
drug discovery, yet screening strategies, including high- 22. Carter-Su, C., Schwartz, J. & Argetsinger, L. S. Growth hormone signaling path-
ways. Growth Horm. IGF Res. 28, 11–15 (2016).
throughput screening and fragment-based drug design, are
23. Zhu, T., Goh, E. L. K., Graichen, R., Ling, L. & Lobie, P. E. Signal transduction via
able to identify compounds suitable for drug develop- the growth hormone receptor. Cell. Signal. 13, 599–616 (2001).
ment.156,157 Recent successes with such strategies have resulted 24. Waters, M. J. & Brooks, A. J. JAK2 activation by growth hormone and other
in high impact therapies including agents that block the p53- cytokines. Biochem. J. 466, 1–11 (2015).
MDM protein interaction and the formation of antiapoptotic 25. Brooks, A. J. et al. Mechanism of activation of protein kinase JAK2 by the growth
complexes by the Bcl2 protein with Navitoclax and Veneto- hormone receptor. Science 344, 1249783 (2014).
clax.157 Conceivable mechanisms for on-target GHR inhibition 26. Ceseña, T. I. et al. Multiple mechanisms of growth hormone-regulated gene
involve disruption of the formation of the signaling complex. transcription. Mol. Genet. Metab. 90, 126–133.
Indeed, this type of inhibitory mechanism was described for 27. Goffin, V., Shiverick, K. T., Kelly, P. A. & Martial, J. A. Sequence-function rela-
tionships within the expanding family of prolactin, growth hormone, placental
blocking the interaction between another cytokine receptor, the
lactogen, and related proteins in mammals. Endocr. Rev. 17, 385–410.
interleukin-2 receptor, and its ligand.158 Recent advances in our 28. Li, X., Huang, Y., Jiang, J. & Frank, S. J. Synergy in ERK activation by cytokine receptors
understanding of GHR activation24 should contribute to the and tyrosine kinase growth factor receptors. Cell. Signal. 23, 417–424 (2011).
development of small molecule-based targeting strategies. 29. Huang, Y., Kim, S. O., Jiang, J. & Frank, S. J. Growth hormone-induced phos-
phorylation of epidermal growth factor (EGF) receptor in 3T3-F442A cells:
modulation of EGF-induced trafficking and signaling. J. Biol. Chem. 278,
ADDITIONAL INFORMATION 18902–18913 (2003).
Conflict of interest: The authors declare that they have no conflict of interest. 30. Yamauchi, T. et al. Tyrosine phosphorylation of the EGF receptor by the kinase
Jak2 is induced by growth hormone. Nature 390, 91 (1997).
31. Gan, Y. et al. Human GH receptor-IGF-1 receptor interaction: implications for GH
REFERENCES signaling. Mol. Endocrinol. 28, 1841–1854 (2014).
32. Huang, Y., Kim, S.-O., Yang, N., Jiang, J. & Frank, S. J. Physical and functional
1. Melmed, S. Acromegaly pathogenesis and treatment. J. Clin. Invest. 119,
interaction of growth hormone and insulin-like growth factor-I signaling ele-
3189–3202 (2009).
ments. Mol. Endocrinol. 18, 1471–1485 (2004).
2. Dehkhoda, F., Lee, C. M. M., Medina, J. & Brooks, A. J. The growth hormone
33. Iglesias-Gato, D. et al. SOCS2 mediates the cross talk between androgen
receptor: mechanism of receptor activation, cell signaling, and physiological
and growth hormone signaling in prostate cancer. Carcinogenesis 35, 24–33
aspects. Front. Endocrinol. 9, 35 (2018).
(2014).
3. Brooks, A. J. & Waters, M. J. The growth hormone receptor: mechanism of
34. Jing, X. et al. Crosstalk of humoral and cell–cell contact-mediated signals in
activation and clinical implications. Nat. Rev. Endocrinol. 6, 515–525 (2010).
postnatal body growth. Cell Rep. 2, 652–665 (2012).
4. Perry, J. K., Emerald, B. S., Mertani, H. C. & Lobie, P. E. The oncogenic potential of
35. Liu, Y. et al. GHR/PRLR heteromultimer is composed of GHR homodimers and
growth hormone. Growth Horm. IGF Res. 16, 277–289 (2006).
PRLR homodimers. Mol. Endocrinol. 30, 504–517 (2016).
5. Thankamony, G. A., Dunger, D. B. & Acerini, C. L. Pegvisomant: current and
36. Xu, J. et al. The role of prolactin receptor in GH signaling in breast cancer cells.
potential novel therapeutic applications. Expert. Opin. Biol. Ther. 9, 1553–1563
Mol. Endocrinol. 27, 266–279 (2013).
(2009).
37. Dineen, R., Stewart, P. M. & Sherlock, M. Acromegaly—diagnosis and clinical
6. Kopchick, J. J., Parkinson, C., Stevens, E. C. & Trainer, P. J. Growth hormone
management. QJM 110, 411–420 (2016).
receptor antagonists: discovery, development, and use in patients with acro-
38. Pivonello, R. et al. Complications of acromegaly: cardiovascular, respiratory and
megaly. Endocr. Rev. 23, 623–646 (2002).
metabolic comorbidities. Pituitary 20, 46–62 (2017).
7. Freda, P. et al. Long-term treatment with pegvisomant as monotherapy in
39. Lombardi, G. et al. The cardiovascular system in growth hormone excess and
patients with acromegaly: experience from acrostudy. Endocr. Pract. 21, 264–274
growth hormone deficiency. J. Endocrinol. Invest. 35, 1021–1029 (2012).
(2015).

Signal Transduction and Targeted Therapy (2019)4:3

 Targeting growth hormone function: strategies and therapeutic applications
Lu et al.
9
40. Melmed, S. et al. Guidelines for acromegaly management: an update. J. Clin. 70. Chhabra, Y. et al. A growth hormone receptor SNP promotes lung
Endocrinol. Metab. 94, 1509–1517 (2009). cancer by impairment of SOCS2-mediated degradation. Oncogene 37, 489–501
41. Giustina, A. et al. Expert consensus document: a consensus on the medical (2018).
treatment of acromegaly. Nat. Rev. 10, 243–248 (2014). 71. Divisova, J. et al. The growth hormone receptor antagonist pegvisomant blocks
42. Melmed, S. New therapeutic agents for acromegaly. Nat. Rev. 12, 90–98 (2016). both mammary gland development and MCF-7 breast cancer xenograft growth.
43. Maffezzoni, F., Frara, S., Doga, M., Mazziotti, G. & Giustina, A. New medical Breast Cancer Res. Treat. 98, 315–327 (2006).
therapies of acromegaly. Growth Horm. IGF Res. 30–31, 58–63 (2016). 72. Dagnaes-Hansen, F., Duan, H., Rasmussen, L. M., Friend, K. E. & Flyvbjerg, A.
44. Laron, Z., Kauli, R., Lapkina, L. & Werner, H. IGF-I deficiency, longevity and cancer Growth hormone receptor antagonist administration inhibits growth of human
protection of patients with Laron syndrome. Mutat. [Link]. Mutat. Res. 772, colorectal carcinoma in nude mice. Anticancer Res. 24, 3735–3742 (2004).
123–133 (2017). 73. McCutcheon, I. E. et al. Antitumor activity of the growth hormone receptor
45. Guevara-Aguirre, J. et al. Growth hormone receptor deficiency is associated with antagonist pegvisomant against human meningiomas in nude mice. J. Neuro-
a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci. surg. 94, 487–492 (2001).
Transl. Med. 3, 70ra13 (2011). 74. Friend, K. E. Cancer and the potential place for growth hormone receptor
46. Steuerman, R., Shevah, O. & Laron, Z. Congenital IGF1 deficiency tends to confer antagonist therapy. Growth Horm. IGF Res. Suppl A, 121–123 (2001).
protection against post-natal development of malignancies. Eur. J. Endocrinol. 75. Basu, R., Baumgaertel, N., Wu, S. & Kopchick, J. J. Growth hormone receptor
164, 485–489 (2011). knockdown sensitizes human melanoma cells to chemotherapy by attenuating
47. Perry, J. K., Wu, Z. S., Mertani, H. C., Zhu, T. & Lobie, P. E. Tumour-derived human expression of ABC drug efflux pumps. Horm. Cancer 8, 143–156 (2017).
growth hormone as a therapeutic target in oncology. Trends Endocrinol. Metab. 76. Evans, A., Jamieson, S. M. F., Liu, D. X., Wilson, W. R. & Perry, J. K. Growth
28, 587–596 (2017). hormone receptor antagonism suppresses tumour regrowth after radiotherapy
48. Terzolo, M. et al. Acromegaly is associated with increased cancer risk: a survey in in an endometrial cancer xenograft model. Cancer Lett. 379, 117–123 (2016).
Italy. Endocr. Relat. Cancer 24, 495–504 (2017). 77. Minoia, M. et al. Growth hormone receptor blockade inhibits growth hormone-
49. Dal, J. et al. Cancer Incidence in patients with acromegaly: a cohort study and induced chemoresistance by restoring cytotoxic-induced apoptosis in breast
meta-analysis of the literature. J. Clin. Endocrinol. Metab. 103, 2182–2188 (2018). cancer cells independently of estrogen receptor expression. J. Clin. Endocrinol.
50. Harvey, S., Martínez-Moreno, C. G., Luna, M. & Arámburo, C. Autocrine/paracrine Metab. 97, E907–E916 (2012).
roles of extrapituitary growth hormone and prolactin in health and disease: an 78. Bougen, N. M. et al. Autocrine human GH promotes radioresistance in mammary
overview. Gen. Comp. Endocrinol. 220, 103–111 (2015). and endometrial carcinoma cells. Endocr. Relat. Cancer 19, 625–644 (2012).
51. Chhabra, Y., Waters, M. J. & Brooks, A. J. Role of the growth hormone – IGF-1 axis 79. Harrington, K. J. et al. Guidelines for preclinical and early phase clinical
in cancer. Expert Rev Endocrinol Metab. 6, 71–84 (2011). assessment of novel radiosensitisers. Br. J. Cancer 105, 628–639 (2011).
52. Kaulsay, K. K. et al. Autocrine stimulation of human mammary carcinoma cell 80. Lawrence, Y. R. et al. NCI-RTOG translational program strategic guidelines for the
proliferation by human growth hormone. Exp. Cell Res. 250, 35–50 (1999). early-stage development of radiosensitizers. J. Natl. Cancer Inst. 105, 11–24
53. Pandey, V. et al. Autocrine human growth hormone stimulates oncogenicity of (2013).
endometrial carcinoma cells. Endocrinology 149, 3909–3919 (2008). 81. Sharma, R. A. et al. Clinical development of new drug-radiotherapy combina-
54. Mukhina, S. et al. Phenotypic conversion of human mammary carcinoma cells by tions. Nat. Rev. Clin. Oncol. 13, 627–642 (2016).
autocrine human growth hormone. Proc. Natl Acad. Sci. 101, 15166–15171 82. Hannon, T. S., Janosky, J. & Arslanian, S. A. Longitudinal study of physiologic
(2004). insulin resistance and metabolic changes of puberty. Pediatr. Res. 60, 759–763
55. Zhu, T. et al. Oncogenic transformation of human mammary epithelial cells by (2006).
autocrine human growth hormone. Cancer Res. 65, 317–324 (2005). 83. Nellemann, B. et al. Growth hormone-induced insulin resistance in human
56. Ogawa, Y., Watanabe, M. & Tominaga, T. Prognostic factors of craniophar- subjects involves reduced pyruvate dehydrogenase activity. Acta Physiol. 210,
yngioma with special reference to autocrine/paracrine signaling: under- 392–402 (2014).
estimated implication of growth hormone receptor. Acta Neurochir. 157, 84. Guevara-Aguirre, J. et al. GH receptor deficiency in Ecuadorian adults is asso-
1731–1740 (2015). ciated with obesity and enhanced insulin sensitivity. J. Clin. Endocrinol. Metab.
57. Wang, J. J. et al. Autocrine hGH stimulates oncogenicity, 100, 2589–2596 (2015).
epithelial–mesenchymal transition and cancer stem cell-like behavior in human 85. Boparai, R. K., Arum, O., Khardori, R. & Bartke, A. Glucose homeostasis and insulin
colorectal carcinoma. Oncotarget 8, 103900–103918 (2017). sensitivity in growth hormone-transgenic mice: a cross-sectional analysis. Biol.
58. Basu, R., Wu, S. & Kopchick, J. J. Targeting growth hormone receptor in human Chem. 391, 1149–1155 (2010).
melanoma cells attenuates tumor progression and epithelial mesenchymal 86. Strage, E. M. et al. Relationship among insulin resistance, growth hormone, and
transition via suppression of multiple oncogenic pathways. Oncotarget 8, insulin-like growth factor I concentrations in diestrous Swedish Elkhounds. J.
21579–21598 (2017). Vet. Intern. Med. 28, 419–428 (2014).
59. Brunet-Dunand, S. E. et al. Autocrine human growth hormone promotes tumor 87. Lee, A. P., Mulligan, K., Schambelan, M., Murphy, E. J. & Weiss, E. J. Growth
angiogenesis in mammary carcinoma. Endocrinology 150, 1341–1352 (2009). hormone receptor antagonism with pegvisomant in insulin resistant non-
60. Banziger-Tobler, N. E., Halin, C., Kajiya, K. & Detmar, M. Growth hormone pro- diabetic men: a phase II pilot study. F1000Research 6, 614 (2017).
motes lymphangiogenesis. Am. J. Pathol. 173, 586–597 (2008). 88. Harvey, S. & Martinez-Moreno, C. G. Growth hormone and ocular dysfunction:
61. Chen, Y. J. et al. Autocrine human growth hormone promotes invasive and endocrine, paracrine or autocrine etiologies? Growth Horm. IGF Res. 29, 28–32
cancer stem cell-like behavior of hepatocellular carcinoma cells by STAT3 (2016).
dependent inhibition of CLAUDIN-1 expression. Int. J. Mol. Sci. 18, E1274 (2017). 89. Mukhi, D., Nishad, R., Menon, R. K. & Pasupulati, A. K. Novel actions of growth
62. Chhabra, Y., Waters, M. J. & Brooks, A. J. Role of the growth hormone–IGF-1 axis hormone in podocytes: Implications for diabetic nephropathy. Front. Med. 4, 102
in cancer. Expert Rev. Endocrinol. Metab. 6, 71–84 (2011). (2017).
63. Brittain, A. L., Basu, R., Qian, Y. & Kopchick, J. J. Growth hormone and the 90. Kamenicky, P., Mazziotti, G., Lombes, M., Giustina, A. & Chanson, P. Growth
epithelial-to-mesenchymal transition. J. Clin. Endocrinol. Metab. 102, 3662–3673 hormone, insulin-like growth factor-1, and the kidney: pathophysiological and
(2017). clinical implications. Endocr. Rev. 35, 234–281 (2014).
64. Chesnokova, V. et al. Growth hormone is permissive for neoplastic colon 91. Holly, J. M., Amiel, S. A., Sandhu, R. R., Rees, L. H. & Wass, J. A. The role of growth
growth. Proc. Natl Acad. Sci. 113, E3250–E3259 (2016). hormone in diabetes mellitus. J. Endocrinol. 118, 353–364 (1988).
65. Gonzalez, L. et al. Attenuation of epidermal growth factor (EGF) signaling by 92. Pasupulati, A. K. & Menon, R. K. Growth hormone and chronic kidney disease.
growth hormone (GH). J. Endocrinol. 233, 175–186 (2017). Curr. Opin. Nephrol. Hypertens. 28, 10–15 (2018).
66. Recouvreux, M. V. et al. Androgen receptor regulation of local growth hormone 93. Bermea, K. C., Rodríguez-García, A., Tsin, A. & Barrera-Saldaña, H. A. Somato-
in prostate cancer cells. Endocrinology 158, 2255–2268 (2017). lactogens and diabetic retinopathy. Growth Horm. IGF Res. 41, 42–47
67. Wagner, K., Hemminki, K. & Försti, A. The GH1/IGF-1 axis polymorphisms and (2018).
their impact on breast cancer development. Breast Cancer Res. Treat. 104, 94. Harvey, S., Parker, E., Macdonald, I. & Sanders, E. J. Growth hormone is present in
233–248 (2007). the human retina and vitreous fluid. Neurosci. Lett. 455, 199–202 (2009).
68. Le Marchand, L. et al. Association of a common polymorphism in the 95. Rymaszewski, Z., Cohen, R. M. & Chomczynski, P. Human growth hormone sti-
human GH1 gene with colorectal neoplasia. J. Natl. Cancer Inst. 94, 454–460 mulates proliferation of human retinal microvascular endothelial cells in vitro.
(2002). Proc. Natl Acad. Sci. USA 88, 617–621 (1991).
69. Shi, J., Tong, J. H. & Cai, S. GH1 T1663A polymorphism and cancer risk: a meta- 96. Smith, L. E. Essential role of growth hormone in ischemia-induced retinal neo-
analysis of case–control studies. Tumor Biol. 35, 4529–4538 (2014). vascularization. Science 276, 1706–1709 (1997).

Signal Transduction and Targeted Therapy (2019)4:3

 Targeting growth hormone function: strategies and therapeutic applications
Lu et al.
10
97. Zhang, J. et al. Correlation of retinopathy with serum levels of growth hormones 126. Cawley, P., Wilkinson, I. & Ross, R. J. Developing long‐acting growth hormone
and insulin-like growth factor-1 in patients with diabetic retinopathy. Int. J. Clin. formulations. Clin. Endocrinol. 79, 305–309 (2013).
Exp. Med. 10, 1325–1329 (2017). 127. Wilkinson, I. R. et al. A ligand-receptor fusion of growth hormone forms a dimer
98. Wu, T. E. & Chen, H. S. Increased prevalence of proliferative retinopathy in and is a potent long-acting agonist. Nat. Med. 13, 1108–1113 (2007).
patients with acromegaly. J. Chin. Med. Assoc. 81, 230–235 (2018). 128. Wilkinson, I. R. et al. A long-acting GH receptor antagonist through fusion to GH
99. Growth Hormone Antagonist for Proliferative Diabetic Retinopathy Study Group. binding protein. Sci. Rep. 6, 35072 (2016).
The effect of a growth hormone receptor antagonist drug on proliferative 129. Crooke, S. T. Molecular mechanisms of antisense oligonucleotides. Nucleic Acid.
diabetic retinopathy. Ophthalmology 108, 2266–2272 (2001). Ther. 27, 70–77 (2017).
100. Chantelau, E. Effect of a growth hormone receptor antagonist on proliferative 130. Tachas, G. et al. A GH receptor antisense oligonucleotide inhibits hepatic GH
diabetic retinopathy. Ophthalmology 109, 2187–2188 (2002). receptor expression, IGF-I production and body weight gain in normal mice. J.
101. Blutke, A., Schneider, M. R., Wolf, E. & Wanke, R. Growth hormone (GH)-trans- Endocrinol. 189, 147–154 (2006).
genic insulin-like growth factor 1 (IGF1)-deficient mice allow dissociation of 131. Wilkinson-Berka, J. L. et al. An antisense oligonucleotide targeting the growth
excess GH and IGF1 effects on glomerular and tubular growth. Physiol. Rep. 4, hormone receptor inhibits neovascularization in a mouse model of retinopathy.
10.14814/phy2.12709 (2016). Mol. Vis. 13, 1529–1538 (2007).
102. Grunenwald, S., Tack, I., Chauveau, D., Bennet, A. & Caron, P. Impact of growth 132. Trainer, P. J. et al. A randomised, open-label, parallel group phase 2 study of
hormone hypersecretion on the adult human kidney. Ann. Endocrinol. 72, antisense oligonucleotide therapy in acromegaly. Eur. J. Endocrinol. 179, 97–108
485–495 (2011). (2018).
103. Kumar, P. A. et al. Growth hormone (GH)-dependent expression of a natural 133. Jiang, J. et al. A conformationally sensitive growth hormone receptor antibody:
antisense transcript induces zinc finger E-box-binding homeobox 2 (ZEB2) impact on GH signaling and GHR proteolysis. Mol. Endocrinol. 18, 2981–2996
in the glomerular podocyte: a novel action of GH with implications for (2004).
the pathogenesis of diabetic nephropathy. J. Biol. Chem. 285, 31148–31156 134. Lan, H., Zheng, X., Khan, M. A. & Li, S. Anti-idiotypic antibody: a new strategy for
(2010). the development of a growth hormone receptor antagonist. Int. J. Biochem. Cell.
104. Anisimov, V. N. & Bartke, A. The key role of growth hormone–insulin–IGF-1 sig- Biol. 68, 101–108 (2015).
naling in aging and cancer. Crit. Rev. Oncol. Hematol. 87, 201–223 (2013). 135. Siebel, S. et al. Humanization and characterization of a human growth hormone
105. Bartke, A. & Darcy, J. GH and ageing: Pitfalls and new insights. Best Pract. Res. receptor (GHR) antagonist antibody RN172. Endocr. Rev. 35 (2014). [Link]
Clin. Endocrinol. Metab. 31, 113–125 (2017). [Link]/meetings/endo-annual-meetings.
106. Junnila, R. K., List, E. O., Berryman, D. E., Murrey, J. W. & Kopchick, J. J. The GH/ 136. Sun, F., Liu, Y., Sun, H. & Tian, B. Development and characterization of a novel
IGF-1 axis in ageing and longevity. Nat. Rev. Endocrinol. 9, 366–376 (2013). GHR antibody antagonist, GF185. Int. J. Biol. Macromol. 79, 864–870 (2015).
107. Spadaro, O. et al. Growth hormone receptor deficiency protects against age- 137. Yang, N. et al. Activation of growth hormone receptors by growth hormone and
related NLRP3 inflammasome activation and immune senescence. Cell Rep. 14, growth hormone antagonist dimers: insights into receptor triggering. Mol.
1571–1580 (2016). Endocrinol. 22, 978–988 (2008).
108. Bartke, A. Healthspan and longevity can be extended by suppression of growth 138. Rosengren, L., Parrow, V., Chmielewska, J., Mode, A. & Fhölenhag, K. In vivo
hormone signaling. Mamm. Genome 27, 289–299 (2016). evaluation of a novel, orally bioavailable, small molecule growth hormone
109. Milman, S. et al. Low insulin-like growth factor-1 level predicts survival in receptor antagonist. Growth Horm. IGF Res. 17, 47–53 (2007).
humans with exceptional longevity. Aging Cell 13, 769–771 (2014). 139. Rosengren, L. et al. Antisense and sense RNA probe hybridization to immobi-
110. van der Spoel, E. et al. Growth hormone secretion is diminished and tightly lized crude cellular lysates: a tool to screen growth hormone antagonists. J.
controlled in humans enriched for familial longevity. Aging Cell 15, 1126–1131 Biomol. Screen. 10, 260–269 (2005).
(2016). 140. Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635
111. Schally, A. V., Varga, J. L. & Engel, J. B. Antagonists of growth-hormone-releasing (2017).
hormone: an emerging new therapy for cancer. Nat. Clin. Pract. Endocrinol. 141. Schwartz, D. M. et al. JAK inhibition as a therapeutic strategy for immune and
Metab. 4, 33–43 (2008). inflammatory diseases. Nat. Rev. Drug. Discov. 16, 843–862 (2017).
112. Rai, U., Thrimawithana, T. R., Valery, C. & Young, S. A. Therapeutic uses of 142. Schwartz, D. M., Bonelli, M., Gadina, M. & O’Shea, J. J. Type I/II cytokines, JAKs,
somatostatin and its analogues: current view and potential applications. Phar- and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol. 12,
macol. Ther. 152, 98–110 (2015). 25–36 (2016).
113. Zarandi, M. et al. Synthesis and structure-activity studies on novel analogs of 143. Dankner, M., Rose, A. A. N., Rajkumar, S., Siegel, P. M. & Watson, I. R. Classifying
human growth hormone releasing hormone (GHRH) with enhanced inhibitory BRAF alterations in cancer: new rational therapeutic strategies for actionable
activities on tumor growth. Peptides 89, 60–70 (2017). mutations. Oncogene 37, 3183–3199 (2018).
114. Van Der Lely, A. J. & Kopchick, J. J. Growth hormone receptor antagonists. 144. Caunt, C. J., Sale, M. J., Smith, P. D. & Cook, S. J. MEK1 and MEK2 inhibitors
Neuroendocrinology 83, 264–268 (2006). and cancer therapy: the long and winding road. Nat. Rev. Cancer 15, 577–592 (2015).
115. Pradhananga, S., Wilkinson, I. & Ross, R. J. M. Pegvisomant: Structure and 145. Perry, J. K., Mohankumar, K. M., Emerald, B. S., Mertani, H. C. & Lobie, P. E. The
function J. Mol. Endocrinol. 29, 11–14 (2002). contribution of growth hormone to mammary neoplasia. J. Mammary Gland Biol.
116. Chen, W. Y., Wight, D. C., Wagner, T. E. & Kopchick, J. J. Expression of a mutated Neoplasia 13, 131–145 (2008).
bovine growth hormone gene suppresses growth of transgenic mice. Proc. Natl 146. Mertani, H. C. et al. Autocrine human growth hormone (hGH) regulation of
Acad. Sci. 87, 5061–5065 (1990). human mammary carcinoma cell gene expression. Identification of CHOP as a
117. Kopchick, J. J. History and future of growth hormone research. Horm. Res. 60 mediator of hGH-stimulated human mammary carcinoma cell survival. J. Biol.
(Suppl 3), S103–S112 (2003). Chem. 276, 21464–21475 (2001).
118. Chen, W. Y., Chen, N. Y., Yun, J., Wagner, T. E. & Kopchick, J. J. In vitro and in vivo 147. Fukuda, I., Hizuka, N., Muraoka, T. & Ichihara, A. Adult growth hormone defi-
studies of antagonistic effects of human growth hormone analogs. J. Biol. Chem. ciency: current concepts. Neurol. Med. Chir. 54(Suppl 3), 599–605 (2014).
269, 15892–15897 (1994). 148. Kargi, A. Y. & Merriam, G. R. Diagnosis and treatment of growth hormone
119. Clark, R. et al. Long-acting growth hormones produced by conjugation with deficiency in adults Nat. Rev. Endocrinol. 9, 335–345 (2013).
polyethylene glycol. J. Biol. Chem. 271, 21969–21977 (1996). 149. Reed, M. L., Merriam, G. R. & Kargi, A. Y. Adult growth hormone deficiency -
120. Sheppard, M. C. Primary medical therapy for acromegaly. Clin. Endocrinol. 58, benefits, side effects, and risks of growth hormone replacement. Front. Endo-
387–399 (2003). crinol. 4, 64 (2013).
121. Sherlock, M., Woods, C. & Sheppard, M. C. Medical therapy in acromegaly. Nat. 150. Monson, J. P., Brooke, A. M. & Akker, S. in Endotext (eds. De Groot, L. J. et al.)
Rev. Endocrinol. 7, 291–300 (2011). ([Link], Inc., South Dartmouth (MA), 2000). [Link]
122. van der Lely, A. J. et al. Long-term treatment of acromegaly with pegvisomant, a books/NBK278982/.
growth hormone receptor antagonist. Lancet 358, 1754–1759 (2001). 151. Thomas, J. D. et al. Characterisation of myocardial structure and function in
123. Ramos-Levi, A. M. et al. Long-term treatment with pegvisomant for acromegaly: adult-onset growth hormone deficiency using cardiac magnetic resonance.
a 10-year experience. Clin. Endocrinol. 84, 540–550 (2016). Endocrine 54, 778–787 (2016).
124. Feenstra, J. et al. Combined therapy with somatostatin analogues and weekly 152. Campos, V. C. et al. Infectious diseases and immunological responses in adult
pegvisomant in active acromegaly. Lancet 365, 1644–1646 (2005). subjects with lifetime untreated, congenital GH deficiency. Endocrine 54,
125. Bianchi, A. et al. Long-term treatment of somatostatin analog-refractory growth 182–190 (2016).
hormone-secreting pituitary tumors with pegvisomant alone or combined with 153. Pereira-Gurgel, V. M. et al. Abnormal vascular and neural retinal morphology in
long-acting somatostatin analogs: a retrospective analysis of clinical practice congenital lifetime isolated growth hormone deficiency. Growth Horm. IGF Res.
and outcomes. J. Exp. Clin. Cancer Res. 32, 40 (2013). 30–31, 11–15 (2016).

Signal Transduction and Targeted Therapy (2019)4:3

 Targeting growth hormone function: strategies and therapeutic applications
Lu et al.
11
154. Chikani, V., Cuneo, R. C., Hickman, I. & Ho, K. K. Impairment of anaerobic capacity Open Access This article is licensed under a Creative Commons
in adults with growth hormone deficiency. J. Clin. Endocrinol. Metab. 100, Attribution 4.0 International License, which permits use, sharing,
1811–1818 (2015). adaptation, distribution and reproduction in any medium or format, as long as you give
155. Tanriverdi, F., Karaca, Z., Unluhizarci, K. & Kelestimur, F. Unusual effects of GH appropriate credit to the original author(s) and the source, provide a link to the Creative
deficiency in adults: a review about the effects of GH on skin, sleep, and coa- Commons license, and indicate if changes were made. The images or other third party
gulation. Endocrine 47, 679–689 (2014). material in this article are included in the article’s Creative Commons license, unless
156. Ivanov, A. A., Khuri, F. R. & Fu, H. Targeting protein–protein interactions as an indicated otherwise in a credit line to the material. If material is not included in the
anticancer strategy. Trends Pharmacol. Sci. 34, 393–400 (2013). article’s Creative Commons license and your intended use is not permitted by statutory
157. Arkin, M. R., Tang, Y. & Wells, J. A. Small-molecule inhibitors of protein–protein regulation or exceeds the permitted use, you will need to obtain permission directly
interactions: progressing toward the reality. Chem. Biol. 21, 1102–1114 from the copyright holder. To view a copy of this license, visit [Link]
(2014). org/licenses/by/4.0/.
158. Thanos, C. D., Randal, M. & Wells, J. A. Potent small-molecule
binding to a dynamic hot spot on IL-2. J. Am. Chem. Soc. 125, 15280–15281
(2003). © The Author(s) 2019

Signal Transduction and Targeted Therapy (2019)4:3