GH and IGF1 in cancer therapy resistance

in Endocrine-Related Cancer
Authors:
Reetobrata Basu Edison Biotechnology Institute, Athens, Ohio, USA

Search for other papers by Reetobrata Basu in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0001-8415-1356
and
John J Kopchick Edison Biotechnology Institute, Athens, Ohio, USA
Molecular and Cellular Biology Program, Ohio University, Athens, Ohio, USA
Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA

Search for other papers by John J Kopchick in
Current site
Google Scholar
PubMed
Close

Correspondence should be addressed to R Basu: basu@ohio.edu

This paper is part of a themed collection on the role of Growth Hormone in Endocrine Cancers. The Guest Editor for this collection was John Kopchick, Ohio University, USA.

John Kopchick was not involved in the review or editorial process for this paper, on which he is listed as an author.

Free access

Sign up for journal news

Despite landmark advances in cancer treatments over the last 20 years, cancer remains the second highest cause of death worldwide, much ascribed to intrinsic and acquired resistance to the available therapeutic options. In this review, we address this impending issue, by focusing the spotlight on the rapidly emerging role of growth hormone action mediated by two intimately related tumoral growth factors – growth hormone (GH) and insulin-like growth factor 1 (IGF1). Here, we not only catalog the scientific evidences relating specifically to cancer therapy resistance inflicted by GH and IGF1 but also discuss the pitfalls, merits, outstanding questions and the future need of exploiting GH–IGF1 inhibition to tackle cancer treatment successfully.

Abstract

Despite landmark advances in cancer treatments over the last 20 years, cancer remains the second highest cause of death worldwide, much ascribed to intrinsic and acquired resistance to the available therapeutic options. In this review, we address this impending issue, by focusing the spotlight on the rapidly emerging role of growth hormone action mediated by two intimately related tumoral growth factors – growth hormone (GH) and insulin-like growth factor 1 (IGF1). Here, we not only catalog the scientific evidences relating specifically to cancer therapy resistance inflicted by GH and IGF1 but also discuss the pitfalls, merits, outstanding questions and the future need of exploiting GH–IGF1 inhibition to tackle cancer treatment successfully.

Introduction

Resistance to therapy is one of the major hurdles in tackling cancer – the second highest causal factor for all-cause, all-age human mortality in the United States between the period of 2001 and 2020, as per the Center for Disease Control, USA (https://wisqars.cdc.gov/data/lcd/home). Within these last 20 years, intensive research has significantly updated the identity of cancer as a disease, by clarifying the key molecular details of inter- and intra-tumor heterogeneity (Dagogo-Jack & Shaw 2018), the tumor microenvironment (TME) (Binnewies et al. 2018), the epithelial-to-mesenchymal transition (EMT) process (Yang et al. 2020), the full spectrum of multidrug efflux (Robey et al. 2018), metabolic reprogramming (Tan et al. 2022), epigenetic reprogramming (Cheng et al. 2019), senescence (Wang et al. 2022) and immune-evasion (Thelen et al. 2021). Between that period, critical milestones in detection (Fitzgerald et al. 2022) and precision therapeutic options have been reached in cancer, including unique targeted therapies (Aggarwal 2010, Labrie et al. 2022), immunotherapies (Waldman et al. 2020), antibody–drug conjugates (ADCs) (Drago et al. 2021, Fu et al. 2022) and machine learning-based personalized therapy (Lehmann et al. 2021), adding to the repertoire of broader spectrum anti-cancer therapies (radiation therapy and chemotherapy) from the last century. Consequently, between 2000 and 2020, deaths due to cancers have also decreased by 27% in the US (https://seer.cancer.gov/). However, in the current year (2022), as per the National Cancer Institute, an estimated 609,360 deaths will be ascribed to cancer, only in the US (https://seer.cancer.gov/) – underlining not only unmet needs in detection, treatment and accessibility but also a re-assessment of mechanistic intervention strategies based on current knowledge of cancer therapy resistance. In this regard, recent empirical evidence compels a re-evaluation of targeting the growth hormone (GH) and the insulin-like growth factor 1 (IGF1) axis.

Massive amount of research over the last 70 years have established that GH and IGF1 have both overlapping and mutually exclusive roles in driving multiple aspects of cancer initiation and progression. Excellent reviews have periodically summarized these updates regarding the role of GH and IGF1 in cancer (Cohen et al. 2000, Chhabra et al. 2011, Perry et al. 2017, Simpson et al. 2017, Basu & Kopchick 2019) and will not be discussed in this review. Here we aim at providing a consolidated discussion of the specific role of these two intimately related and potent growth factors in driving a multi-modal mechanism of cancer therapy resistance. We will briefly discuss the relevant roles of GH and IGF1 in modulating each of the present-day therapeutic approaches in cancer and conclude with a discussion of the outstanding questions and our opinion on the future trajectories of scientific investigation in this area.

The GH/IGF1 axis in cancer: current knowledge

Human GH is a 191-amino acid peptide hormone secreted by the pituitary somatotroph cells of the anterior pituitary and exerts its action on many tissues in an endocrine manner (Brooks & Waters 2010). In the pituitary, somatotropic GH secretion is mainly regulated positively by hypothalamic input of GHRH or negatively by somatostatin (Finidori 2000) – a pattern seldom maintained in the peripheral sites of GH production, including tumors, wherein the secreted GH works in an autocrine/paracrine manner. Additional regulatory arms include inducing actions of the gastric peptide ghrelin and negative feedback loops to the hypothalamus and pituitary via GH and its downstream mediator IGF1 (Finidori 2000). Evidence suggests that unlike the drastic ebb of pituitary GH production at somatopause, non-pituitary GH production often increases with age – correlating with tumor development (Chesnokova et al. 2021). Endocrine GH binds and activates pre-dimerized GH receptors (GHR), expressed on almost all cells of all tissues in the body including the liver, adipose tissue, skin, brain, kidneys, spleen, intestines, stomach, heart, lung, bone, muscle, cartilage, the vasculatures and immune cells (Brooks & Waters 2010). GH plays critical roles in post-natal longitudinal growth, organ development, reproductive maturity and metabolic homeostasis and is also a determinant of net human lifespan due to its well-studied roles in several pathophysiology including but not limited to insulin resistance, cancer, glomerulosclerosis, cardiomyopathies, acromegaly, neurocognitive decline, Laron syndrome, GH deficiency (GHD) and aging (Ayuk & Sheppard 2006, Basu et al. 2018). Classically, GH-induced activation of the GHR enables activation of the GHR-associated Janus kinase 2 (JAK2) initiating a downstream signaling cascade of transcriptional activation via STAT5 as well as STAT1 and STAT3 in a tissue-dependent manner. GHR activation also triggers multiple SRC family kinases leading to the downstream activation of MAPK as well as the PI3K-AKT-mTOR pathways (Carter-Su et al. 2016). A principal physiological effect of GH is the STAT5-induced hepatic production of IGF1, a 70 amino acid long peptide with a systemic mitogenic effect. Importantly, endocrine GH-induced hepatocyte GHR activation leads to the production of ~75% of the circulating IGF1 in humans. The bioavailability of IGF1 in circulation is regulated by seven different IGFBP 1–7 (Blum et al. 2018). IGF1 primarily binds and activates the IGF1 receptor (IGF1R), a receptor tyrosine kinase (RTK). IGF1-induced downstream signaling primarily involves the IRS1 and 2, PI3K-AKT-mTOR, the MAPK and SRC family of kinases (Blum et al. 2018). IGF1 action amplifies and mediates several of the physiologic effects of GH during growth and development. GHR and IGF1R are abundantly expressed on numerous cancer cell types and share multiple downstream oncogenic signaling nodes, and the confluence of these intracellular signaling pathways drive tumor proliferation, suppress cell death, induce migration/invasion and active drug efflux, initiate metabolic and epigenetic reprogramming and promote metastasis.

Moreover, the full spectrum of GH and IGF1 action in cancer cells, beyond the mediation of GHR and IGF1R, requires relevant mention at this point. Human GH is known to exert a lactogenic effect due to its unique capacity of binding and potently activating the prolactin receptor (PRLR) as well, due to the high degree of sequence similarity of human GH and PRL (Xu et al. 2013). In several cancers like that of the breast and prostate, PRLR expression is often found upregulated and inversely correlated with survival. In such cancers, GH is expected to induce an oncogenic hyper-signaling cascade via activation of both GHR and PRLR (Goffin 2017).

On the other hand, IGF1 can additionally bind to and activate the IGF1R-Insulin receptor A [IR(A)] hybrids (Belfiore et al. 2017). It is important to note that another member from the same family of growth factors – IGF2 – can potently activate IGF1R (Blum et al. 2018, Andersson et al. 2019). Several tumors of mesenchymal and epithelial origin secrete IGF2 which potently activates the IGF1R, IR(A) and IGF2-IR(A) hybrids and are designated as ‘IGF2-omas’ characterized by IGF2-induced hypoglycemia with suppressed GH and IGF1 levels (Dynkevich et al. 2013). Therefore, IGF2 possesses the potential to bypass IGF1R inhibition or IGF1 depletion in cancer (Baserga 2013). Extensive work on the role of IGF2 in specific types of cancer and in determining therapeutic success exists (Dynkevich et al. 2013, Livingstone 2013, Andersson et al. 2019, Belfiore et al. 2023) and is beyond the scope of this review. Herein, we specifically summarize the current evidence pertaining to cancer therapy resistance in the context of GH action and of IGF1 as an extension and principal target of systemic GH action.

Numerous studies with cultured cells and mouse models with either congenital deficits of GH and IGF1, as well as engineered mouse models of GH or IGF1 excess, deficit or antagonism (congenital or treatment induced) conclusively and consistently indicate that attenuation of GH/IGF1 axis suppresses tumor proliferation and invasive tumor growth, while GH excess promotes it (Cohen et al. 2000, Chhabra et al. 2011). For example, GH transgenic mice with supra-physiologic levels of GH and IGF1 develop tumors at a high frequency and rate, while the opposite is observed in mice with either GH resistance (GHR knock-out, GHRKO) or GH deficiency (Ames, Snell, lit/lit, GH knock-out or GHKO mice) (Basu et al. 2018). Reports from human epidemiological studies in the last 20 years, with patients of acromegaly (GH excess due to a hypersecreting pituitary adenoma leading to high serum IGF1), albeit some confounding factors (surveillance bias, normalization of serum IGF1, effects of treatments, difficulty in comparing cause-of-death against appropriate controls), corroborate the findings from corresponding mouse studies (Dal et al. 2018). The most compelling evidence of the involvement of GH and IGF1 in promoting cancer comes from patients with Laron syndrome (LS; GH resistance due to loss-of-function mutations of the GHR resulting in very low IGF1) from independent studies in Israel (Shevah & Laron 2007) and Ecuador (Guevara-Aguirre et al. 2011) spanning several decades. In both of these cohorts totaling more than 300 patients, zero cases of any malignant neoplasms were identified as the cause of death, while the rate of malignancy in their relatives were as much as 20%. Transcriptomic analyses of lymphoblasts from patients with LS have revealed upregulation of several intrinsic cancer suppressive pathways (Werner et al. 2019). More recently, post-natal genetic ablation of GHR in 6-month-old mice leads to a marked decrease in hepatic IGF1 output and was reported to confer an onco-protective effect and lifespan extension in the animals (Duran‐Ortiz et al. 2021), similar to that observed in congenital GHRKO animals (Ikeno et al. 2009) – indicating that a late-life intervention in the GH/IGF1 axis may have beneficial effects. Furthermore, prolonged metabolic manipulations, like fasting or fasting-mimicking-diets (FMD) which lead to a blunted GH action as well as markedly reduces serum IGF1, have been found to significantly protect against cancer development or (Inagaki et al. 2008, Wei et al. 2017, Brandhorst 2021) and also abetted therapeutic resistance in clinical trials (de Groot et al. 2020, Ligorio et al. 2022). Collectively, these findings firmly establish that GH and IGF1 play a potent onco-driver role. In the wake of these reports, pharmaceutical interest first piqued toward targeting the IGF1R in cancer, resulting in scores of IGF1R inhibitors (small molecules and monoclonal antibodies) entering clinical trials in the last 20 years, with a record of remarkable results in pre-clinical models of IGF1R inhibition (Xue et al. 2012). To date, neither the one approved nor several other candidate GHR antagonists in development have been tried in human cancer clinical trials.

Analyses of available human cancer patient transcriptomic data reveal that while IGF1Rs are overexpressed in several cancer types almost ubiquitously, GHRs are overexpressed in selected cancers (Chhabra et al. 2011). This view requires an update in the light of the developing identity of cancer as a disease – with a structure and function resembling more a heterogeneous organ than a homogeneous mass of cells (Hanahan 2022). The hallmark heterogeneity of cancer cells offer the possibility of less of a uniform overexpression of GHR (or IGF1R) across the tumor but rather several sub-sets of cells within the tumor with marked overexpression of either of GH, GHR, PRLR, IGF1, IGF1R or InsR or combinations of them – setting up a very efficient autocrine/paracrine milieu. Additionally, non-tumor cells in the TME express the aforementioned proteins of the GH/IGF1 axis and the current knowledge about their actions strongly indicate a tumor-supportive action, the extent of which remains completely uninvestigated. As we know today, intercellular communication methods like exosomes now allow for efficient crosstalk between sub-clusters of cells with differential gene expression patterns in the TME. Revolutionary technologies like the single-cell sequencing now enables access to these unknowns. However, a mounting body of recent research is already pointing to a new and covert action of GH and IGF1 in cancer – driving therapeutic resistance. In the mechanistic modalities of this phenomenon, there are exclusive actions as well as expected overlaps between GH and IGF1. We will briefly discuss these in the following review.

GH and IGF1 in cancer radiation therapy resistance

Ionizing radiations (IRs) are one of the most extensively used anti-cancer therapies alone or in concordance with surgery and chemotherapy and is a subject well-studied to be associated with GH and IGF1. Here, we will summarize some of the salient points of these documented effects on IR specifically relating to cancer treatment. IR therapy induces cell death by inflicting extensive DNA damage, increasing DNA–protein crosslinking and increasing reactive oxygen species (ROS) levels drastically. The protective effect of GH against irradiation in non-tumor tissues has been documented in (i) GH-mediated rescue from IR-induced enteritis in adult male Wistar rats (Prieto et al. 1998), (ii) hGH-mediated rescue from cell death and of cytokine profile in irradiated peripheral blood lymphocytes (Lempereur et al. 2003) and (iii) restoration of hematologic and immune recovery by post-irradiation GH treatment in BALB/c mice and non-human primates (Chen et al. 2010). Only in the last study, radioprotective effects of GH were suggested to be IGF1 mediated (Chen et al. 2010). In cancer studies, the effect of GH in reversing irradiation challenge was consistent with that observed in non-tumor cells, as is reported in (i) GH treatment-induced post-irradiation survival and DNA damage repair in breast and endometrial cancer cells (Bougen et al. 2012), (ii) suppression of GH treatment induced radioprotection in colon cancer cells using anti-GHR antibody (Wu et al. 2014) and (iii) pegvisomant (first and only FDA-approved efficacious GHR antagonist discovered in our laboratory in the 1990s) treatment-induced reduction in angiogenesis and endometrial cancer xenograft growth following gamma irradiation in immunodeficient mice (Evans et al. 2016). A retrospective study comparing pre-operative biopsy and post-irradiation specimens in 98 patients of rectal cancer concluded a poorer response to therapy associated with higher GHR expression (Wu et al. 2006). The major underlying mechanisms of GH-induced radio-resistance, as recently described by Melmed and colleagues, largely lie in radiation-induced DNA damage, leading to a p53-induced GH production in the TME, GH-induced increased DNA damage repair (DDR) gene expression in tumor cells and upregulation of anti-apoptotic (Bcl2) and downregulation of pro-apoptotic (Bax, BAD, caspases-3, -8, -9, and PPARg) mediators (Chesnokova & Melmed 2020). Paradoxically, in non-transformed cells, GH is a p53 target gene and GH increases DNA damage in an autocrine negative feedback loop by suppressing the DDR gene ATM kinase – facilitating oncogenesis (Chesnokova et al. 2016, 2019a,b).

Targeted studies manipulating IGF1 action reports of similar radio-protective effects (Chesnokova & Melmed 2020). IGF1 treatment improves post-irradiation DDR by RAD51 recruitment and homologous recombination in multiple human and mouse cell types. Conversely, IGF1R inhibition using either antisense or siRNA or small-molecule inhibitors sensitized human prostate (Rochester et al. 2005, Turney et al. 2012, Chitnis et al. 2014) cancer cell lines to IR via suppression of ATM kinase and reduced DDR. In fact, an immunohistochemical assessment of diagnostic biopsies of 136 patients with prostate cancer identified increased IGF1R expression to correlate with post-radiotherapy cancer recurrence (Aleksic et al. 2017). Colon cancer cells either expressing a non-functional IGF1R or transfected with IGF1R-directed siRNA display reduced transcription of DDR gene BRCA2 and sensitization of tumor cells to IR (Yavari et al. 2010, Venkatachalam et al. 2017, Zong et al. 2021). Moreover, analysis of human transcriptomic data in The Cancer Genome Atlas (TCGA) database (Chen et al. 2017a ), as well as a retrospective analysis of pre-treatment and postoperative specimens in 87 rectal cancer patients undergoing preoperative radiotherapy followed by surgical resection (Wu et al. 2014), validates tumoral IGF1R expression as a predictor of radiotherapy sensitivity in colorectal cancer. Similar reports of IGF1 induced radio-resistance and IGF1R inhibition mediated radio-sensitivity have also been reported in lung cancer (Iwasa et al. 2009, Liu et al. 2018), breast cancer (Li et al. 2013), esophageal cancer (Zhao & Gu 2014), oral squamous cell carcinoma (Zhang et al. 2017), upper respiratory tract cancers (Riesterer et al. 2011), nasopharyngeal carcinoma (Wang et al. 2019), osteosarcoma (Wang et al. 2009) and pediatric high-grade glioma (Simpson et al. 2020).

Therefore, GH and IGF1 are strongly implicated as a major determinant of irradiation success in cancer treatment (Table 1), whereas in some cases like colorectal cancer, both GHR and IGF1R have been attributed as major negative prognostic factors. Although almost none of the studies have dissected the exclusivity of GH vs IGF1 actions in this approach, it is apparent that overlapping signaling intermediates between GH and IGF1 co-operate in an irradiated tumor. Moreover, separate clusters of GH- and/or IGF1-responsive cells in the same tumor can putatively provide a heterogenic advantage in post-irradiation recovery – a postulate that awaits testing and can in turn direct appropriate combination therapeutic choices.

Table 1

GH and IGF1 in cancer radiation therapy resistance.

Cancer type Study type Summary of effect Reference
Growth hormone (GH)
Human breast and endometrial cancer Cell lines Autocrine GH → IR resistance

GHR antagonist → IR sensitization
(Bougen et al. 2012)
Human colorectal cancer Cell lines Autocrine GH → IR resistance

GHR antagonist → IR sensitization
(Wu et al. 2014)
Human endometrial cancer Mouse GHR antagonist → IR sensitization (Evans et al. 2016)
Human breast cancer Mouse Autocrine GH → IR resistance (Bougen et al. 2012)
Human rectal cancer Human High GHR → IR resistance (Wu et al. 2006)
Insulin-like growth factor 1 (IGF1)
Human prostate cancer Cell lines IGF1R depletion → IR sensitization (Turney et al. 2012)
Human prostate cancer Cell lines IGF1R inhibition → IR sensitization (Chitnis et al. 2014)
Human lung squamous carcinoma Cell lines IGF1R inhibition → IR sensitization (Liu et al. 2018)
Human esophageal cancer Cell lines IGF1R inhibition → IR sensitization (Zhao & Gu 2014)
Human oral squamous cell carcinoma Cell lines IGF1R inhibition → IR sensitization (Zhang et al. 2017)
Human upper respiratory tract cancer Cell lines IGF1R inhibition → IR sensitization (Riesterer et al. 2011)
Human nasopharyngeal carcinoma Cell lines IGF1R inhibition → IR sensitization (Wang et al. 2019)
Human osteosarcoma Cell lines IGF1R inhibition → IR sensitization (Wang et al. 2009)
Human pediatric high-grade glioma Cell lines IGF1R inhibition → IR sensitization (Simpson et al. 2020)
Human colon cancer Cell lines, mouse IGF1R inhibition → IR sensitization (Yavari et al. 2010, Venkatachalam et al. 2017, Zong et al. 2021)
Human non-small-cell lung cancer Cell lines, mouse IGF1R inhibition → IR sensitization (Iwasa et al. 2009)
Human breast cancer Cell lines, mouse IGF1R inhibition → IR sensitization (Li et al. 2013)
Human prostate cancer Human High IGF1R → Post-IR relapse (Aleksic et al. 2017)
Human colorectal cancer Human High IGF1R → IR resistance (Chen et al. 2017a )
Human colorectal cancer Human High IGF1R → IR resistance (Wu et al. 2014)

GH and IGF1 in cancer chemotherapy resistance

Chemotherapy compounds (alkylating agents, nitrosoureas, antimetabolites, anthracyclines, topoisomerase inhibitors, mitotic inhibitors, corticosteroids and others) exert a broad-spectrum antineoplastic effect by inducing extensive DNA damage (single- and double-strand breaks) in the highly proliferating cells of the tumor (29623040). Therefore, chemotherapy, on one hand, is indiscriminate toward all rapidly proliferating cells of the body and, on the other hand, minimally effective against dormant tumor cells. However, chemotherapy to date remains one of the most accessible and prescribed therapeutic options in cancer treatment, greatly thwarted by almost inevitable and rapid onset of intrinsic and acquired tumoral chemoresistance (Vasan et al. 2019). Mechanistically, as chemotherapy resembles radiation therapy in induction of DNA damage, one major pathway by which GH and IGF1 do resist the cytotoxic effects of chemotherapy involves that of radio-resistance discussed above. Additional mechanisms of GH- and IGF1-supported chemoresistance involve suppression of apoptosis, upregulation of ATP-binding cassette containing multidrug efflux pumps (ABC transporters) and activation of the EMT program (Yeldag et al. 2018).

Early studies that implicated GH action to chemoresistance ascribed the effects to an observed inhibition of chemo-induced apoptosis in the tumor cells. For example, in triple negative breast cancer (TNBC) cells, GH effected an IGF1-independent suppression of doxorubicin-induced apoptosis via c-fos activation, while pegvisomant reversed these effects (Zatelli et al. 2009, Minoia et al. 2012). Autocrine GH was also found to dampen the efficacy of the alkylating agent mitomycin-C in breast and endometrial cancers by upregulating DDR and reducing apoptosis (Bougen et al. 2011). Moreover, in endometrial cancer cells, GH lowered pro-apoptotic caspase 3/7 activation via a ERK1/2- and PKC-dependent pathway and rendered resistance against doxorubicin, paclitaxel and cisplatin treatments (Minoia et al. 2012, Gentilin et al. 2017). In the same study, pegvisomant treatment reversed the endometrial chemoresistance (Gentilin et al. 2017). Subsequent studies from our laboratory in human melanoma cells additionally identified a GH-mediated differential upregulation of specific ABC transporters (ABCB1, ABCB5, ABCB8, ABCC1, ABCC2, ABCG1 and ABCG2) and subsequent decreased intracellular drug retention underlying melanoma resistance against doxorubicin, paclitaxel and cisplatin (Basu et al. 2017a ). Knock-down of GHR expression using si-RNAs rendered acute sensitivity to the above chemotherapy treatments in melanoma cells (Basu et al. 2017a ). Transcriptomic analysis of treatment-naïve murine melanoma allografts in GH transgenic mice (bGH mice; high GH, high IGF1) reveal a state of intrinsic chemoresistance by virtue of a consistently upregulated expression of ABC transporter expression compared to that in wild-type (WT) counterparts (Qian et al. 2020). The distinct role of GH vs IGF1 in promoting ABC transporter expression was further clarified using murine melanoma allografts in GHRKO (high GH, low IGF1) vs WT mice. Comparing the results against bGH vs WT mouse study, we identified that GH preferentially upregulates the ABCB1 and ABCG2 transporters while IGF1 drives the ABCC group of transporters as well as that of ABCB1 (Qian et al. 2020). We further employed another syngeneic model using mice transgenic for a GHR antagonist (GHA mice) allografted with murine melanoma cells and treated with cisplatin to study the outcome of a combination of GHR antagonism and chemotherapy. While the GHR antagonist or cisplatin alone had comparable effects in suppressing melanoma growth, the combination of cisplatin in GHA mice markedly improved cisplatin efficacy, leading to rapid tumor shrinkage compared to that in WT mice (Basu et al. 2022). An orthogonal study with a fourth syngeneic model of GHKO vs WT mice did not exhibit the chemo-sensitizing effect of GHR antagonism – highlighting the role of autocrine GH action which was effectively attenuated by the GHR antagonist in the GHA mice but not in the GHKO mice (Basu et al. 2022). Subsequent independent rodent studies in breast cancer corroborated these findings. For example, in one study using ER-negative breast cancer xenografts in Nude mice, GHR abrogation abetted docetaxel resistance by downregulation of ABCG2 expression (Arumugam et al. 2019), while in another study in GH-deficient spontaneous dwarf rats supplemented with GH, only the stoppage of GH supplementation allowed tumor regression under doxorubicin treatment, unlike that in GH-sufficient control animals which remained doxorubicin resistant (Lantvit et al. 2021). Furthermore, we and others have shown that chemotherapy induces GH production which temporally coincides with increased transcription of ABC transporter genes, which harbor multiple STAT5-binding sites within 500 base pairs of their transcription start sites (Basu et al. 2019). An upregulated ABC transporter expression serves to not only efflux the chemotherapy out of the cell but also sequesters the same away from the cytoplasm into intracellular compartments like melanosomes in case of melanoma. We found that GH drives this melanosomal drug sequestration via upregulating ABC transporters and the MITF, the master regulator of melanosomal transcription via STAT5- and SRC-dependent pathways (Basu et al. 2019). GHR knockdown abrogated these effects and restored chemosensitivity in melanoma cells (Basu et al. 2019). Lastly, a drastic increase in tumoral ABC transporter expression facilitates the generation of a sub-population of extreme drug-resistant and dormant tumor cells which are known as cancer stem cells (CSC) (Begicevic & Falasca 2017). These dormant CSCs lack the hyper-replication potential and therefore evades the chemotherapeutic challenge, only to be reactivated by cessation of treatment causing a drug-resistant relapse. Forced GH expression in tumors were found to drive upregulated ABCG2 expression and induction of CSC properties in both liver (Chen et al. 2017b ) and colorectal cancer (Wang et al. 2017) cells.

Multiple studies have implicated IGF1 action with chemoresistance. An upregulation of IGF1R expression was observed with diminishing response to multiple cycles of platinum-taxol treatment in primary tumors of ovarian cancer patients (Singh et al. 2014). Early intervention with picropodophyllin, an IGF1R inhibitor, was found to alleviate this observed resistance to cisplatin and paclitaxel (Singh et al. 2014). An IGF1R anti-idiotypic antibody antagonist also sensitized ovarian cancer cells to cisplatin treatment (Weiwei et al. 2021). In another study, R1507 (mAb against IGF1R) and IR markedly sensitized small-cell lung cancer xenografts to a triple combination therapy including IR and cisplatin (Ferté et al. 2013). A tetravalent bi-specific antibody (istiratumab or MM-141) targeting both IGF1R and ErbB3 also markedly sensitized ovarian cancer cells to cisplatin and paclitaxel (Camblin et al. 2019) and pancreatic cancer xenograft models to gemcitabine and nab-paclitaxel treatments (Camblin et al. 2018) leading to subsequent human clinical trials in pancreatic cancer (Kundranda et al. 2020). Ganitumab (AMG479), a fully humanized anti-IGF1R mAb from Amgen, is one of the latest and highly efficacious inhibitors of IGF1, IGF2 or insulin-mediated activation of IGF1R (Calzone et al. 2013). Ganitumab markedly potentiates the cytotoxic effects of carboplatin or paclitaxel in ovarian cancer (Beltran et al. 2014) of paclitaxel along with metformin in stage 2/3 breast cancer (Yee et al. 2021) and multiple others leading to a slew of human clinical trials of ganitumab in combination with different types of chemotherapy in breast cancer (Robertson et al. 2013), ovarian cancer (Konecny et al. 2021), advanced solid tumors (Murakami et al. 2012, Rosen et al. 2012), metastatic pancreatic cancer (Kindler et al. 2012, Okusaka et al. 2014, Fuchs et al. 2015), extensive-stage small-cell lung cancer (Glisson et al. 2017) and metastatic colorectal cancer (Cohn et al. 2013). In fact, ganitumab has been approved by the US Food and Drug Administration as an orphan drug for Ewing sarcoma in 2017. The molecular mechanisms underlying IGF1-induced chemoresistance overlap largely with that of GHR – (i) inhibition of apoptosis by inducing anti-apoptotic and suppressing pro-apoptotic factors (Chesnokova & Melmed 2020), (ii) upregulation of multidrug efflux ABC transporters (Shen et al. 2012, Benabbou et al. 2013, 2014) and (iii) promoting DDR via promoting Chk1 and Chk2 phosphorylation and increased homologous recombination (Chesnokova & Melmed 2020).

In the study of GH- and IGF1-regulated cancer chemoresistance, a review of the above information (Table 2) hints at definite IGF1-independent actions of GH, which had not been addressed by any studies, except two, of which only one identified a GH-specific upregulation of ABCB1 and ABCG2 and an IGF1-specifc upregulation of ABCB1 and ABCC group of transporters (Qian et al. 2020). Given the substantial overlap in substrate specificity among the ABC transporters, it appears that a targeted attenuation of IGF1R may not be adequate to restrict drug efflux from the tumor. A GHR blockade, on the other hand, attenuates both the GH action and the IGF1 supply from the liver – effectively rendering a ‘double whammy’ in suppressing ABC transporter increase at the tumor cell surface. Notably, although a plethora of combination therapy clinical trials involving IGF1R inhibition and chemotherapy ensued in the last 20 years, there has been none involving GHR antagonism yet.

Table 2

GH and IGF1 in cancer chemotherapy resistance.

Cancer type Study type Summary of effect Reference
Growth hormone (GH)
Human breast cancer Cell lines GH → doxorubicin resistance (Minoia et al. 2012)
Human breast cancer Cell lines GH → doxorubicin resistance

GHR antagonist → doxorubicin sensitization
(Zatelli et al. 2009)
Human breast and endometrial cancer Cell lines Autocrine GH → mitomycin-C resistance (Bougen et al. 2011)
Human endometrial cancer Cell lines Autocrine GH → doxorubicin, cisplatin, resistance

GHR antagonist → chemotherapy sensitization
(Gentilin et al. 2017)
Human melanoma Cell lines GH → doxorubicin, cisplatin, paclitaxel resistance

GHR silencing → chemotherapy sensitization
(Basu et al. 2017a )
Human liver cancer Cell lines Autocrine GH → cancer stem cell (Chen et al. 2017b )
Human colorectal cancer Cell lines, mouse Autocrine GH → cancer stem cell (Wang et al. 2017)
Mouse melanoma Mouse High GH → intrinsic chemoresistance (Qian et al. 2020)
Mouse melanoma Mouse GHR antagonist → cisplatin sensitization (Basu et al. 2022)
Human breast cancer Mouse GHR silencing → docetaxel sensitization (Arumugam et al. 2019)
Rat breast cancer Rat GH treatment → doxorubicin resistance (Lantvit et al. 2021)
Insulin-like growth factor 1 (IGF1)
Human prostate cancer Cell lines IGF1R inhibition → mitoxantrone, etoposide sensitization (Rochester et al. 2005)
Human ovarian cancer Cell lines IGF1R inhibition → chemotherapy sensitization (Camblin et al. 2019)
Human ovarian cancer Cell lines, mouse IGF1R inhibition → cisplatin sensitization (Weiwei et al. 2021)
Human small cell lung cancer Cell lines, mouse IGF1R inhibition → IR + cisplatin sensitization (Ferté et al. 2013)
Human pancreatic cancer Cell lines, mouse IGF1R inhibition → gemcitabine, paclitaxel sensitization (Camblin et al. 2018)
Human ovarian cancer Cell lines, mouse IGF1R inhibition → cisplatin, carboplatin, paclitaxel sensitization (Beltran et al. 2014)
Human ovarian cancer Human High IGF1R → chemotherapy resistance

IGF1R inhibition → cisplatin, paclitaxel sensitization
(Singh et al. 2014)

GH and IGF1 in cancer-targeted therapy response

The expression of cancer-specific neo-antigens as well as overexpression of specific growth factor receptors on specific types of cancer have allowed the first inroads toward a precision therapeutic approach in the form of targeted therapies, prime examples of which are imatinib (BCR-ABL inhibitor), Herceptin/trastuzumab (anti-HER2 mAb) and Avastin/bevacizumab (anti-VEGFR2 mAb). Cytokine receptors like GHR and RTKs like IGF1R often harbor cross-talks with other receptors and regulate mutual intracellular signaling and trafficking (Huang et al. 2003). For example, GH action is well studied to increase EGFR levels in mouse liver (Johansson et al. 1989, González et al. 2010, 2021). Moreover, not only GH acts as an almost equipotent ligand for both GHR and PRLR but also hybrid hetero-multimeric receptors of GHR–PRLR have been postulated (Liu et al. 2016). Similar correlates exist between IGF1R and InsR as well as between IGF1R and EGFRs (Roudabush et al. 2000). In an entity necessitating a sustained proliferative signaling, like a tumor, such receptor cross-talks are upregulated and exert insurmountable resistance to targeted therapies, including endocrine/hormone therapies in cancer (Osborne et al. 2005).

Despite the known association between GHR and EGFR, as well as that of GHR and PRLR, no studies have as yet focused on their extent and implications in any cancer types. In our studies with human melanoma cells, we had reported a GHR-associated change in the ErbB3 and HGF (Basu et al. 2017b ), although the therapeutic ramifications of this observation await a systematic investigation. However, multiple reports provocatively implicate GH action in anti-cancer therapy resistance. For example, GHR expression inversely correlates with ruxolitinib (JAK2 inhibitor) efficacy in endocrine-resistant breast cancer cells (Holtz et al. 2018), whereas GH inhibits apoptotic effects of PPARg ligands in human colon cancer cells (Bogazzi et al. 2004). In human melanoma cells, we observed a GH-dependent increase in EC50 of the BRAF-V600E inhibitor vemurafenib as well as increased vemurafenib sensitivity following a GHR knockdown-mediated suppression of ABCC2 and ABCG2 (Basu et al. 2017a). In a recent in vivo study, we reported the role of GH in augmenting sorafenib resistance in human liver cancer cells (Basu et al. 2022). Using the GHA and WT mice implanted with murine hepatoma cells, we observed notable improvement in sorafenib efficacy in the GHA mice, wherein the combination of GHR antagonist with sorafenib achieved a markedly superior tumor clearance compared to the same in the WT counterparts (Basu et al. 2022). Most recent studies from MD Anderson Cancer Center in hepatocellular carcinoma (HCC) strongly validate these findings. Following the establishment of a definite role of GH in promoting hepatocarcinogen-induced liver tumors in GHRKO vs WT mice (Haque et al. 2022), the group observed a more aggressive disease and poorer clinical outcomes correlated with higher serum GH levels in a cohort of 767 HCC patients compared against 200 healthy controls (Kaseb et al. 2022). In vitro and in vivo studies using nude mice confirmed a sorafenib-sensitizing effect of pegvisomant, which they then extended to two human patients presenting advanced stage HCC with sorafenib resistance. Pegvisomant treatment at 10 mg/day for 6 weeks resulted in ‘stable disease’ and halted tumor progression (Kaseb et al. 2022).

The association of IGF1R with other RTKs, especially the EGFR, has been more frequently exploited in anti-cancer drug development. For example, in ovarian and breast cancer cells, IGF1R inhibitors sensitize the cells to PARP-inhibitor treatment by suppressing RAD51 levels (Amin et al. 2015). It was found that a concomitant activation of IGF1R with ErbB3 induce ovarian cancer resistance to trastuzumab (Herceptin, anti-HER2 mAb) (Jia et al. 2013), which was reversed by LMAb1, an IGF1R-targeted mAb (Wang et al. 2014). Similarly, based on their highly consistent co-expression profile, the approach of dual inhibition of IGF1R and EGFR/HER2 was adopted and have shown significant success in multiple pre-clinical models of different cancer – viz. (i) a bi-specific (anti-IGF1R and -EGFR) antibody XGFR in pancreatic cancer (Schanzer et al. 2016), (ii) IGF1R inhibitor linsitinib with EGFR inhibitors lapatinib or gefitinib in esophageal squamous cell carcinoma (Kang et al. 2022), (iii) a ligand-based enediyne-energized bi-specific fusion protein (anti-IGF1R and -EGFR) in esophageal (Cao et al. 2017) and non-small-cell lung cancer (Guo et al. 2017), (iv) AVE1642 (anti-IGF1R mAb) and gefitinib in HCC (Desbois-Mouthon et al. 2009), (v) ganitumab and panitumumab (anti-EGFR mAb) in advanced cancers (non-small-cell lung cancer and sarcoma) (Vlahovic et al. 2018) and (vi) ganitumab and panitumumab in metastatic colorectal cancer (Van Cutsem et al. 2014), to name a few. Interestingly, the anti-diabetic ‘wonder drug’ metformin is reported to affect a downregulation of IGF1R and thereby enhance the efficacy of figitumumab (mAb against IGF1R) in small-cell lung cancer (Cao et al. 2015) and non-small-cell lung cancer (Cao et al. 2016). IGF1R inhibition has additional therapy-sensitizing effects in the case of endocrine therapy-resistant breast and prostate cancers (Fahrenholtz et al. 2013), which have been comprehensively summarized in other excellent reviews (Hua et al. 2020).

The above discussion collectively emphasizes that the combination of GHR antagonism or IGF1R inhibition with targeted therapies presents untapped potential in sensitizing tumors to treatment effects (Table 3). An assessment of compensatory changes in receptor expression pre- and posttreatment with targeted therapies in different types of cancer might help to identify effective drug combination partners from the existing repertoire of antineoplastic agents.

Table 3

GH and IGF1 in cancer-targeted therapy resistance.

Cancer type Study type Summary of effect Reference
Growth hormone (GH)
Human breast cancer Cell lines High GHR → JAK2-inhibitor resistance (Holtz et al. 2018)
Human colorectal cancer Cell lines Autocrine GH → PPARg ligand resistance (Bogazzi et al. 2004)
Human melanoma Cell lines GH → V600E-BRAF inhibitor resistance

GHR silencing → V660E-BRAF inhibitor sensitization
(Basu et al. 2017a )
Mouse liver cancer Mouse GHR antagonist → kinase inhibitor sensitization (Basu et al. 2022)
Human liver cancer Human High GH → kinase inhibitor resistance (Kaseb et al. 2022)
Human liver cancer Human GHR inhibition → kinase inhibitor sensitization (Kaseb et al. 2022)
Insulin-like growth factor 1 (IGF1)
Human breast and ovarian cancer Cell lines IGF1R inhibition → PARP inhibitor sensitization (Amin et al. 2015)
Human ovarian cancer Cell lines IGF1R → HER2 inhibitor resistance (Jia et al. 2013)
Human ovarian cancer Cell lines IGF1R inhibition → HER2 inhibitor sensitization (Wang et al. 2014)
Human pancreatic cancer Cell lines IGF1R inhibition → EGFR inhibition sensitization (Schanzer et al. 2016)
Human esophageal cancer Cell lines, mouse IGF1R inhibition → EGFR, Lidamycin inhibition sensitization (Cao et al. 2017, Kang et al. 2022)
Human non-small cell lung cancer Cell lines, mouse IGF1R inhibition → EGFR, Lidamycin inhibition sensitization (Guo et al. 2017)
Human liver cancer Cell lines IGF1R inhibition → EGFR inhibition sensitization (Desbois-Mouthon et al. 2009)
Human non-small cell lung cancer and sarcoma Human IGF1R inhibition → EGFR inhibition sensitization (Vlahovic et al. 2018)
Human small cell lung cancer Cell lines IGF1R inhibition → MEK/ERK inhibitor sensitization (Cao et al. 2015)

GH and IGF1 in cancer immunotherapy resistance

Immunotherapy, which involves augmenting the body’s intrinsic immune system to detect and eliminate tumor growth, has revolutionized anti-cancer therapy in the 21st century. However, the response of cancer patients to immunotherapy, at different stages of the disease, vary considerably based on several factors including but not limited to age and immune fitness of the patient, the type of cancer, the composition of the TME, loss of antigen processing in the tumor, tumor mutational burden and tumor heterogeneity (Wang et al. 2021a ). Moreover, the target of immune checkpoint inhibitors (ICIs) is often expressed by a small fraction of the total cells of the tumor offering a strictly limited response (Wang et al. 2021a ). Over the last 2 years, a growing line of scientific evidence have started to indicate that not only is circulating GH/IGF1 status a prognostic marker of immunotherapy response but also that attenuation of GH action or IGF1 action or both might significantly enhance immunotherapy success across multiple cancers.

Plasma GH levels in human patients have been found to be associated with poorer response to immunotherapy combinations in at least two different human cancers – (i) in the first study, in 31 male and 6 female HCC patients undergoing the combination therapy of atezolizumab (anti-PDL1 mAb) and bevacizumab (anti-VEGFR2 mAb) at the MD Anderson Cancer Center, the 1-year survival rate was significantly lower at 33% in the patients with higher GH levels (>0.9 µg/L in men and >3.7 µg/L in women) compared to 70% in the ones with lower GH (Mohamed et al. 2022). Median overall survival also showed a similar significant difference (18.9 vs 9.3 months;P =0.014), while progression-free survival was marginal (6.6 vs 2.9 months; P = 0.053) between GH-high and GH-low patients (Mohamed et al. 2022). (ii) In the second study, 75 patients of advanced gastric cancer in the Hebei Medical University, China, were treated with anti-PD1 mAb and post-treatment serum GH levels were measured and correlated with treatment outcome (Zhao et al. 2022). Between the high-GH and the low-GH groups of patients, significant differences in disease control rate (30% vs 53.3%, P = 0.046), overall survival (P = 0.052) and progression free survival (P=0.016) were observed (Zhao et al. 2022). In both of these studies, despite the confounding factor that due to the short half-life of GH in circulation (~15 min) a once daily GH sampling often does not elicit the GH status accurately, the implications of the observation are profound. Knowledge of the serum IGF1 status can further clarify if this is an IGF1 independent effect of GH.

There are no direct studies implicating IGF1 with immunotherapeutic success, but the current circumstantial evidences are highly suggestive. A pharmacologic caloric restriction using the FMD, which markedly lowers serum IGF1 among other effects, has been shown to improve anti-PDL1 and anti-OX40 therapy in poorly immunogenic TNBC (Cortellino et al. 2022). Similarly, short-term starvation was found to dampen IGF1R signaling and IGF1 levels and was associated with sensitization of lung tumor allografts in syngeneic mouse models to anti-PD1 ICIs via a CD8 T-cell-dependent process (Ajona et al. 2020). The same study observed resistance to anti-PD1-PDL1 immunotherapy in patients with non-small-cell lung cancer to be associated with higher plasma IGF1 or higher tumoral IGF1R levels (Ajona et al. 2020). Reduced caloric intake associated with a marked reduction in IGF1 has also been reported to augment immunotherapy, especially in glucose-resistant, overweight individuals (Eriau et al. 2021). Overall, the results indicate that IGF1 action can be a therapeutic target of interest in boosting immunotherapeutic outcomes in selected cancers.

Immunotherapy is one of the latest approaches in cancer treatment and studies relating it to the pathophysiology of GH and IGF1 have only just begun (Table 4). We are yet to understand the underlying mechanisms, for example, how the different immune checkpoint protein expression varies under GH or IGF1 action or inhibition, in tumor cell subsets. The first results, as listed above, are highly provocative and promising enough for large-scale investigations, as the field of anti-cancer therapy has begun to turn toward immunotherapy as a standard for cure.

Table 4

GH and IGF1 in cancer immunotherapy resistance.

Cancer type Study type Summary of effect Reference
Growth hormone (GH)
Human liver cancer Human High GH → anti-PDL1 + anti-VEGFR2 resistance (Mohamed et al. 2022)
Human gastric cancer Human High GH → anti-PD1 resistance (Zhao et al. 2022)
Insulin-like growth factor 1 (IGF1)
Human breast cancer Mouse IGF1 suppression → anti-PDL1, anti-OX40 sensitization (Cortellino et al. 2022)
Human lung cancer Mouse IGF1R inhibition → anti-PD1 sensitization (Ajona et al. 2020)
Human lung cancer Human High IGF1, high IGF1R → anti-PD1-PDL1 sensitization (Ajona et al. 2020)

GH and IGF1 in anti-cancer therapy: present and future

Scores of human cancer clinical trials have been conducted with a multitude of IGF1R inhibitors (small molecule or biologics). Highly promising IGF1R inhibitors like linsitinib, ganitumab, figitimumab and xentuzumab were tried in several different types of cancers, alone or in combination with chemo- or targeted-therapies. Almost all of them have failed in sustaining the promising efficacies shown in pre-clinical models as well as in early phase clinical trials. Later phase trials encountered either high toxicity or sub-optimal improvements in prognostic parameters with the best outcome being disease stabilization in selected cancers, which in most cases were not reproducible in subsequent larger clinical trials – leading majority of the pharmaceutical organizations to abandon their pursuit of targeting IGF1R in cancer. Importantly, several of the candidate IGF1R inhibitors were clinically potent, and subsequent re-purposing in other disease areas like thyroid eye disease has earned them FDA approval (Dolgin 2020). Post-mortem of the astounding disappointment of IGF1R inhibitors in cancer has been done in several excellent reviews (Baserga 2013, Chen & Sharon 2013, Beckwith & Yee 2015, Crudden et al. 2015). Indeed, this stunning failure of IGF1R targeting imparted some salvageable lessons and novel opportunities. Some of the notable reasons for the lack of success of IGF1R inhibition in the human trials against cancer include (i) elevated secretion of GH due to inhibition of the IGF1-regulated negative feedback loop in the hypothalamic–pituitary axis, (ii) the aforementioned ligand-receptor promiscuity in the IGF system which allow mainly local IGF2-mediated sustained autocrine/paracrine signaling via IR(A), and the IGF1R-IR(A) and IGF2-IR(A) hybrids and the shared nodes in downstream signaling cascade, (iii) compensatory over-expression and activation of IGF1R-associated RTKs like EGFR as well as G-protein-coupled receptors, (iv) increased integrin signaling by accumulating IGF1 in the event of non-availability of IGF1R binding, (v) constitutive activation of AKT due to loss of PTEN and (vi) lack of appropriate patient selection, stratification and follow-up biomarker for therapeutic efficacy. Moreover, Chesnokova et al. have recently reported a marked increase in colon GHR levels following IGF1R inhibition (Chesnokova et al. 2019b ), which increases the GH action in the pre-tumoral niche as well as the TME and remains to be verified in other tissues of the body. These assessments, however, point us toward a unique target – the GHR.

The anti-cancer effects of abrogating IGF1 action can be partly exploited by targeting the GHR instead. As stated earlier, no GHR antagonist have ever been into any cancer clinical trial, except one initiated by Pfizer in 2013, for figitumumab–pegvisomant combination for six different solid tumors but was discontinued midway as Pfizer shelved the figitumumab project. It is apparent from our discussion that the actions of GH and IGF1 are intimately related, and targeted IGF1R blockage in turn upregulates the GH effects tremendously causing a cascade of cancer supportive consequences – (i) increased GH production due to a de-repression of negative feedback, (ii) increased GH action leading to systemic insulin resistance (an effect of GH known since the 1930s) and hyperinsulinemia, (iii) increase of multiple direct tumor-supportive effects of the excess GH and insulin and lastly (iv) the overlooked effects of GH on the TME. The effects of GH (as well as IGF1) in the TME are remarkably understudied to date despite long-standing knowledge of GH being produced in the tumor and surrounding tissues (Harvey 2010, Perry et al. 2017) and the effects of GH on several components of the TME. For example, GH is known to (i) drive angiogenesis (Brunet-Dunand et al. 2009), lymphangiogenesis (Banziger-Tobler et al. 2008) and fibrosis (Kopchick et al. 2022), which are hallmarks of the TME; (ii) promote fibroblast proliferation (Lee et al. 2010) and fibrosis (Kopchick et al. 2022), which allow tumoral expansion and immune evasion (Sahai et al. 2020); (iii) lipolysis in adipocytes leading to production of free fatty acids (Kopchick et al. 2020), which allow tumor metabolic reprogramming and cancer associated fibroblast generation (Cao 2019, Wu et al. 2021); and (iv) polarization of macrophage to an anti-inflammatory M2-type (Lu et al. 2013), which are one of the most negative prognostic factors in cancer due to profound and multi-factorial immune-suppressive effects (Pittet et al. 2022). In addition to this, Melmed and colleagues have proposed a ‘field cancerization’ model of GH action in promoting cancer in the TME by dint of its role in promoting DNA damage in aging non-transformed cells (Chesnokova et al. 2019a, 2021), repairing DNA damage in tumor cells (Chesnokova & Melmed 2020) and as a significant member of the senescence-associated secretory phenotype (SASP) (Chesnokova et al. 2013, Chesnokova & Melmed 2022). Also relevant are the totally understudied effects of GH–PRLR interactions at the TME. In addition to this, one of the most important systemic effects of GH remains hepatic IGF1 production – which is responsible for up to 75% of the circulating IGF1 in humans (Blum et al. 2018). Importantly, GH parallelly increases hepatic IGFBP3 production which is argued to limit IGF1 availability and thus its effect (Cohen et al. 2000). However, it is now understood that elevated presence of matrix metalloproteinases in the TME cleave IGFBPs to generate bio-available IGF1 feeding the tumoral IGF1Rs (Mañes et al. 1997, 1999, Egeblad & Werb 2002). Moreover, IGF1 action at the TME has also not been investigated adequately and includes critical prognostic factors like immune-suppression (Somri-Gannam et al. 2020). Therefore, distilation of the information we present here above clearly directs us to a simple yet transformative and feasible solution – human trials of GHR attenuation in cancer to achieve a dual inhibition of GH and IGF1 actions in tumor growth and therapy resistance without the detriments of IGF1R blockade. Notably, as we mentioned before, GHR-blockade-induced IGF1 depletion (as part of our proposed strategy) can be bypassed by IGF2 (Dynkevich et al. 2013). However, incidentally, Pfizer pegvisomant trial in healthy human subjects have shown that even a 14-day pegvisomant treatment leads to a consistent and significant sustained suppression of free IGF1 (up to 33%), IGFBP3 (up to 46%) and IGF2 (up to 35%), implicating GHR antagonist use in IGF1 and IGF2 responsive cancers (Yin et al. 2007).

Targeting the GH action is unique due to its multi-pronged (GHR activation, PRLR activation, IGF1 production) anti-cancer effects not only on the tumor but also tumor supportive cells in the TME which altogether orchestrate therapy resistance as discussed above. Increased tumoral GHR expression correlates significantly with patient mortality in TNBC, prostate cancer, endometrial cancer, ovarian cancer, bladder cancer and gastric cancer (The Cancer Genome Atlas database), while the effects of GHR expression and action in the TME and its correlation with patient survival is anticipated with the expansion of single-cell-sequencing techniques. It is essential to remember that tumors are markedly heterogeneous in composition and sub-populations of cells with differential expression of ligands and receptors of the GH/IGF1 axis can be a key determinant in predicting the outcome of GHR targeting in any specific cancer type and individual patient. Lastly, we would like to emphasize that the evidence compiled in this review appears to justify the need for well-designed clinical studies to validate if GHR inhibition can be an effective adjuvant for multiple antineoplastic approaches to significantly enhance their respective efficacies.

The current landscape of development of GHR antagonists and inhibitors is encouraging and has been reviewed recently (Lu et al. 2019). Our laboratory had pioneered the first ever GHR antagonist in the early 1990s, termed pegvisomant, which won FDA approval for the treatment of acromegaly and was marketed by Pfizer under the brand name Somavert (pegvisomant for injection) (Kopchick et al. 2014). Pegvisomant is known to normalize plasma IGF1 safely and effectively in almost 90% of patients (Paisley et al. 2004). Moreover, pegvisomant has a reported beneficial side effect of lowering insulin resistance (Higham et al. 2009), which can be a beneficial indirect effect in anti-cancer therapy. Development of multiple additional small-molecule and peptide-based GHR antagonists are currently underway in our laboratory (Basu et al. 2021) as well as in others (Chen et al. 2020, Tamshen et al. 2020, Wang et al. 2020, 2021b , van der Velden et al. 2022) – which should be powerful tools in subsequent cancer clinical trials to effect therapeutic sensitization as discussed in this review.

Conclusion

Targeting GH and IGF1 action via GHR inhibition is a scientifically sound and beneficial strategy for anti-cancer therapy (Fig. 1), with the potential of transforming cancer prognosis in patients, not only due to their well-documented proliferative effects on tumors but more due to their role in driving therapy refractory disease, an intrinsic hallmark of cancer. The reasons behind the falter of IGF1R inhibition in cancer trials also strongly justify the need of GHR antagonism in cancer trials – which exerts a dual effect of blocking both GH and IGF1 actions, as well as imparting insulin sensitivity – a rarely encountered ‘win–win’ situation in pharmacology. There is indeed rarely a cancer target which encompasses the multifactorial nature of cancer as a disease. Cancer drug discovery is thwarted largely by cancer drug resistance, costing human lives around the globe, every minute. Attenuating GH and IGF1 actions by targeting GHR is steadily becoming ‘the elephant in the room’ in tackling this hurdle in cancer treatment and deserves appropriate human clinical trials in the immediate future.

Figure 1
Figure 1

Growth hormone (GH) and insulin-like growth factor 1 (IGF1) regulation of cancer therapy resistance. GH binding and activation of the GH receptor (GHR) exert multiple direct tumor-supportive actions as well as production of hepatic (and extra-hepatic?) IGF1 production. Circulating IGF1-mediated activation of the IGF1 receptor (IGF1R) in turn exerts multiple direct tumor-promoting effects. Particular therapy refractory effects, exclusive to either GH or IGF1, as well as those overlapped by both GH and IGF1, from the tumor and TME as the source, drive ABC multidrug transporter levels, epithelial-to-mesenchymal transition (EMT) activation, apoptosis inhibition, increased DNA damage repair, increased stemness and metabolic re-programming of the tumor cells. Additionally, GH and IGF1 inflict cross-activation of related growth factor receptors including PRLR, PRLR-GHR hybrids, insulin receptors (InsR) and InsR-IGF1R hybrids exerting pro-tumorigenic, anti-therapeutic effects on the tumor and the tumor microenvironment (TME). Moreover, in the TME, autocrine/paracrine GH potentially drives lipolysis in the cancer-associated adipocytes, proliferation in cancer-associated fibroblasts, macrophage polarization in tumor-associated macrophages, immune-suppression and production of IGF1, while autocrine/paracrine IGF1 is known to promote clonal proliferation of TME cells and induce immune-suppression via dendritic cell (DC) inactivation. Importantly, IGF1 exerts a systemic effect of reducing pituitary GH production via a negative feedback loop – which is inhibited by IGF1R inhibitors leading to increased GH production. Therefore, GHR inhibition is a putatively superior and breakthrough approach in not only attenuating direct effects of GH on the tumor and TME but also in suppressing systemic and peripheral IGF1 production, thus largely inhibiting IGF1-regulated therapy refractory effects in cancer as well. A full color version of this figure is available at https://doi.org/10.1530/ERC-22-0414.

Citation: Endocrine-Related Cancer 30, 9; 10.1530/ERC-22-0414

Declaration of interest

The authors declare no conflict of interest.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

JJK is supported by the state of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, AMVETS, NIH 1RO1AG059779-01 and The Edison Biotechnology Institute and Diabetes Institute at Ohio University.

References

  • Aggarwal S 2010 Targeted cancer therapies. Nature Reviews. Drug Discovery 9 427428. (https://doi.org/10.1038/nrd3186)

  • Ajona D, Ortiz-Espinosa S, Lozano T, Exposito F, Calvo A, Valencia K, Redrado M, Remírez A, Lecanda F, Alignani D, et al.2020 Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade. Nature Cancer 1 7585. (https://doi.org/10.1038/s43018-019-0007-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Aleksic T, Verrill C, Bryant RJ, Han C, Worrall AR, Brureau L, Larré S, Higgins GS, Fazal F, Sabbagh A, et al.2017 IGF-1R associates with adverse outcomes after radical radiotherapy for prostate cancer. British Journal of Cancer 117 16001606. (https://doi.org/10.1038/bjc.2017.337)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Amin O, Beauchamp MC, Nader PA, Laskov I, Iqbal S, Philip CA, Yasmeen A & & Gotlieb WH 2015 Suppression of Homologous Recombination by insulin-like growth factor-1 inhibition sensitizes cancer cells to PARP inhibitors. BMC Cancer 15 817. (https://doi.org/10.1186/s12885-015-1803-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Andersson MK, Åman P & & Stenman G 2019 IGF2/IGF1R signaling as a therapeutic target in MYB-positive adenoid cystic carcinomas and other fusion gene-driven tumors. Cells 8. (https://doi.org/10.3390/cells8080913)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Arumugam A, Subramani R, Nandy SB, Terreros D, Dwivedi AK, Saltzstein E & & Lakshmanaswamy R 2019 Silencing growth hormone receptor inhibits estrogen receptor negative breast cancer through ATP-binding cassette sub-family G member 2. Experimental and Molecular Medicine 51 113. (https://doi.org/10.1038/s12276-018-0197-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ayuk J & & Sheppard MC 2006 Growth hormone and its disorders. Postgraduate Medical Journal 82 2430. (https://doi.org/10.1136/pgmj.2005.036087)

  • Banziger-Tobler NE, Halin C, Kajiya K & & Detmar M 2008 Growth hormone promotes lymphangiogenesis. American Journal of Pathology 173 586597. (https://doi.org/10.2353/ajpath.2008.080060)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Baserga R 2013 The decline and fall of the IGF-I receptor. Journal of Cellular Physiology 228 675679. (https://doi.org/10.1002/jcp.24217)

  • Basu R, Baumgaertel N, Wu S & & Kopchick JJ 2017a Growth hormone receptor knockdown sensitizes human melanoma cells to chemotherapy by attenuating expression of ABC drug efflux pumps. Hormones and Cancer 8 143156. (https://doi.org/10.1007/s12672-017-0292-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Basu R, Wu S & & Kopchick JJ 2017b Targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways. Oncotarget 8 2157921598. (https://doi.org/10.18632/oncotarget.15375)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Basu R, Qian Y & & Kopchick JJ 2018 Mechanisms in endocrinology: lessons from growth hormone receptor gene disrupted mice: are there benefits of endocrine defects? European Journal of Endocrinology 178 R155R181. (https://doi.org/10.1530/EJE-18-0018)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Basu R & & Kopchick JJ 2019 The effects of growth hormone on therapy resistance in cancer. Cancer Drug Resistance 2 827846. (https://doi.org/10.20517/cdr.2019.27)

  • Basu R, Kulkarni P, Qian Y, Walsh C, Arora P, Davis E, Duran-Ortiz S, Funk K, Ibarra D, Kruse C, et al.2019 Growth hormone upregulates melanocyte-inducing transcription factor expression and activity via JAK2-STAT5 and SRC signaling in GH receptor-positive human melanoma. Cancers 11 1352. (https://doi.org/10.3390/cancers11091352)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Basu R, Nahar K, Kulkarni P, Kerekes O, Sattler M, Hall Z, Neggers S, Holub JM & & Kopchick JJ 2021 A novel peptide antagonist of the human growth hormone receptor. Journal of Biological Chemistry 296 100588. (https://doi.org/10.1016/j.jbc.2021.100588)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Basu R, Qian Y, Mathes S, Terry J, Arnett N, Riddell T, Stevens A, Funk K, Bell S, Bokal Z, et al.2022 Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo. Frontiers in Oncology 12 936145. (https://doi.org/10.3389/fonc.2022.936145)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Beckwith H & & Yee D 2015 Minireview: were the IGF signaling inhibitors all bad? Molecular Endocrinology (Baltimore, Md.) 29 15491557. (https://doi.org/10.1210/me.2015-1157)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Begicevic RR & & Falasca M 2017 ABC transporters in cancer stem cells: beyond chemoresistance. International Journal of Molecular Sciences 18. (https://doi.org/10.3390/ijms18112362)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Belfiore A, Malaguarnera R, Vella V, Lawrence MC, Sciacca L, Frasca F, Morrione A & & Vigneri R 2017 Insulin receptor isoforms in physiology and disease: an updated view. Endocrine Reviews 38 379431. (https://doi.org/10.1210/er.2017-00073)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Belfiore A, Rapicavoli RV, Le Moli R, Lappano R, Morrione A, De Francesco EM & & Vella V 2023 IGF2: a role in metastasis and tumor evasion from immune surveillance? Biomedicines 11. (https://doi.org/10.3390/biomedicines11010229)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Beltran PJ, Calzone FJ, Mitchell P, Chung YA, Cajulis E, Moody G, Belmontes B, Li CM, Vonderfecht S, Velculescu VE, et al.2014 Ganitumab (AMG 479) inhibits IGF-II-dependent ovarian cancer growth and potentiates platinum-based chemotherapy. Clinical Cancer Research 20 29472958. (https://doi.org/10.1158/1078-0432.CCR-13-3448)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Benabbou N, Mirshahi P, Cadillon M, Soria J, Therwath A & & Mirshahi M 2013 Hospicells promote upregulation of the ATP-binding cassette genes by insulin-like growth factor-I via the JAK2/STAT3 signaling pathway in an ovarian cancer cell line. International Journal of Oncology 43 685694. (https://doi.org/10.3892/ijo.2013.2017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Benabbou N, Mirshahi P, Bordu C, Faussat AM, Tang R, Therwath A, Soria J, Marie JP & & Mirshahi M 2014 A subset of bone marrow stromal cells regulate ATP-binding cassette gene expression via insulin-like growth factor-I in a leukemia cell line. International Journal of Oncology 45 13721380. (https://doi.org/10.3892/ijo.2014.2569)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC, et al.2018 Understanding the tumor immune microenvironment (TIME) for effective therapy. Nature Medicine 24 541550. (https://doi.org/10.1038/s41591-018-0014-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Blum WF, Alherbish A, Alsagheir A, El Awwa A, Kaplan W, Koledova E & & Savage MO 2018 The growth hormone-insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders. Endocrine Connections 7 R212R222. (https://doi.org/10.1530/EC-18-0099)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bogazzi F, Ultimieri F, Raggi F, Russo D, Vanacore R, Guida C, Brogioni S, Cosci C, Gasperi M, Bartalena L, et al.2004 Growth hormone inhibits apoptosis in human colonic cancer cell lines: antagonistic effects of peroxisome proliferator activated receptor-γ ligands. Endocrinology 145 33533362. (https://doi.org/10.1210/en.2004-0225)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bougen NM, Yang T, Chen H, Lobie PE & & Perry JK 2011 Autocrine human growth hormone reduces mammary and endometrial carcinoma cell sensitivity to Mitomycin C. Oncology Reports 26 487493. (https://doi.org/10.3892/or.2011.1305)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bougen NM, Steiner M, Pertziger M, Banerjee A, Brunet-Dunand SE, Zhu T, Lobie PE & & Perry JK 2012 Autocrine human GH promotes radioresistance in mammary and endometrial carcinoma cells. Endocrine-Related Cancer 19 625644. (https://doi.org/10.1530/ERC-12-0042)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brandhorst S 2021 Fasting and fasting-mimicking diets for chemotherapy augmentation. GeroScience 43 12011216. (https://doi.org/10.1007/s11357-020-00317-7)

  • Brooks AJ & & Waters MJ 2010 The growth hormone receptor: mechanism of activation and clinical implications. Nature Reviews. Endocrinology 6 515525. (https://doi.org/10.1038/nrendo.2010.123)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brunet-Dunand SE, Vouyovitch C, Araneda S, Pandey V, Vidal LJ-P, Print C, Mertani HC, Lobie PE & & Perry JK 2009 Autocrine human growth hormone promotes tumor angiogenesis in mammary carcinoma. Endocrinology 150 13411352. (https://doi.org/10.1210/en.2008-0608)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Calzone FJ, Cajulis E, Chung YA, Tsai MM, Mitchell P, Lu J, Chen C, Sun J, Radinsky R, Kendall R, et al.2013 Epitope-specific mechanisms of IGF1R inhibition by ganitumab. PLoS One 8 e55135. (https://doi.org/10.1371/journal.pone.0055135)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Camblin AJ, Pace EA, Adams S, Curley MD, Rimkunas V, Nie L, Tan G, Bloom T, Iadevaia S, Baum J, et al.2018 Dual inhibition of IGF-1R and ErbB3 enhances the activity of gemcitabine and nab-paclitaxel in preclinical models of pancreatic cancer. Clinical Cancer Research 24 28732885. (https://doi.org/10.1158/1078-0432.CCR-17-2262)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Camblin AJ, Tan G, Curley MD, Yannatos I, Iadevaia S, Rimkunas V, Mino-Kenudson M, Bloom T, Schoeberl B, Drummond DC, et al.2019 Dual targeting of IGF-1R and ErbB3 as a potential therapeutic regimen for ovarian cancer. Scientific Reports 9 16832. (https://doi.org/10.1038/s41598-019-53322-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cao H, Dong W, Shen H, Xu J, Zhu L, Liu Q & & Du J 2015 Combinational therapy enhances the effects of anti-IGF-1R mAb figitumumab to target small cell lung cancer. PLoS One 10 e0135844. (https://doi.org/10.1371/journal.pone.0135844)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cao H, Dong W, Qu X, Shen H, Xu J, Zhu L, Liu Q & & Du J 2016 Metformin enhances the therapy effects of anti-IGF-1R mAb figitumumab to NSCLC. Scientific Reports 6 31072. (https://doi.org/10.1038/srep31072)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cao H, Guo XF, Zhu XF, Li SS & & Zhen YS 2017 A ligand-based and enediyne-energized bispecific fusion protein targeting epidermal growth factor receptor and insulin-like growth factor-1 receptor shows potent antitumor efficacy against esophageal cancer. Oncology Reports 37 33293340. (https://doi.org/10.3892/or.2017.5606)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cao Y 2019 Adipocyte and lipid metabolism in cancer drug resistance. Journal of Clinical Investigation 129 30063017. (https://doi.org/10.1172/JCI127201)

  • Carter-Su C, Schwartz J & & Argetsinger LS 2016 Growth hormone signaling pathways. Growth Hormone and IGF Research 28 1115. (https://doi.org/10.1016/j.ghir.2015.09.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen BJ, Deoliveira D, Spasojevic I, Sempowski GD, Jiang C, Owzar K, Wang X, Gesty-Palmer D, Cline JM, Bourland JD, et al.2010 Growth hormone mitigates against lethal irradiation and enhances hematologic and immune recovery in mice and nonhuman primates. PLoS One 5 e11056. (https://doi.org/10.1371/journal.pone.0011056)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen HX & & Sharon E 2013 IGF-1R as an anti-cancer target--trials and tribulations. Chinese Journal of Cancer 32 242252. (https://doi.org/10.5732/cjc.012.10263)

  • Chen L, Zhu Z, Gao W, Jiang Q, Yu J & & Fu C 2017a Systemic analysis of different colorectal cancer cell lines and TCGA datasets identified IGF-1R/EGFR-PPAR-CASPASE axis as important indicator for radiotherapy sensitivity. Gene 627 484490. (https://doi.org/10.1016/j.gene.2017.07.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen X, Wu D, Zheng Y, Liu X & & Wang J 2020 Preparation of a growth hormone receptor/prolactin receptor bispecific antibody antagonist which exhibited anti-cancer activity. Frontiers in Pharmacology 11 598423. (https://doi.org/10.3389/fphar.2020.598423)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen YJ, You ML, Chong QY, Pandey V, Zhuang QS, Liu DX, Ma L, Zhu T & & Lobie PE 2017b Autocrine human growth hormone promotes invasive and cancer stem cell-like behavior of hepatocellular carcinoma cells by STAT3 dependent inhibition of CLAUDIN-1 expression. International Journal of Molecular Sciences 18 1274. (https://doi.org/10.3390/ijms18061274)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cheng Y, He C, Wang M, Ma X, Mo F, Yang S, Han J & & Wei X 2019 Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduction and Targeted Therapy 4 62. (https://doi.org/10.1038/s41392-019-0095-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chesnokova V & & Melmed S 2020 Peptide hormone regulation of DNA damage responses. Endocrine Reviews 41. (https://doi.org/10.1210/endrev/bnaa009)

  • Chesnokova V & & Melmed S 2022 GH and senescence: a new understanding of adult GH action. Journal of the Endocrine Society 6 bvab177. (https://doi.org/10.1210/jendso/bvab177)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chesnokova V, Zhou C, Ben-Shlomo A, Zonis S, Tani Y, Ren SG & & Melmed S 2013 Growth hormone is a cellular senescence target in pituitary and nonpituitary cells. Proceedings of the National Academy of Sciences of the United States of America 110 E3331E3339. (https://doi.org/10.1073/pnas.1310589110)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chesnokova V, Zonis S, Zhou C, Recouvreux MV, Ben-Shlomo A, Araki T, Barrett R, Workman M, Wawrowsky K, Ljubimov VA, et al.2016 Growth hormone is permissive for neoplastic colon growth. Proceedings of the National Academy of Sciences of the United States of America 113 E3250E3259. (https://doi.org/10.1073/pnas.1600561113)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chesnokova V, Zonis S, Barrett R, Kameda H, Wawrowsky K, Ben-Shlomo A, Yamamoto M, Gleeson J, Bresee C, Gorbunova V, et al.2019a Excess growth hormone suppresses DNA damage repair in epithelial cells. JCI Insight 4. (https://doi.org/10.1172/jci.insight.125762)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chesnokova V, Zonis S, Barrett RJ, Gleeson JP & & Melmed S 2019b Growth hormone induces colon DNA damage independent of IGF-1. Endocrinology 160 14391447. (https://doi.org/10.1210/en.2019-00132)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chesnokova V, Zonis S, Apostolou A, Estrada HQ, Knott S, Wawrowsky K, Michelsen K, Ben-Shlomo A, Barrett R, Gorbunova V, et al.2021 Local non-pituitary growth hormone is induced with aging and facilitates epithelial damage. Cell Reports 37 110068. (https://doi.org/10.1016/j.celrep.2021.110068)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chhabra Y, Waters MJ & & Brooks AJ 2011 Role of the growth hormone–IGF-1 axis in cancer. Expert Review of Endocrinology and Metabolism 6 7184. (https://doi.org/10.1586/eem.10.73)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chitnis MM, Lodhia KA, Aleksic T, Gao S, Protheroe AS & & Macaulay VM 2014 IGF-1R inhibition enhances radiosensitivity and delays double-strand break repair by both non-homologous end-joining and homologous recombination. Oncogene 33 52625273. (https://doi.org/10.1038/onc.2013.460)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cohen P, Clemmons DR & & Rosenfeld RG 2000 Does the GH-IGF axis play a role in cancer pathogenesis? Growth Hormone and IGF Research 10 297305. (https://doi.org/10.1054/ghir.2000.0171)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cohn AL, Tabernero J, Maurel J, Nowara E, Sastre J, Chuah BYS, Kopp MV, Sakaeva DD, Mitchell EP, Dubey S, et al.2013 A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer. Annals of Oncology 24 17771785. (https://doi.org/10.1093/annonc/mdt057)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cortellino S, Raveane A, Chiodoni C, Delfanti G, Pisati F, Spagnolo V, Visco E, Fragale G, Ferrante F, Magni S, et al.2022 Fasting renders immunotherapy effective against low-immunogenic breast cancer while reducing side effects. Cell Reports 40 111256. (https://doi.org/10.1016/j.celrep.2022.111256)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Crudden C, Girnita A & & Girnita L 2015 Targeting the IGF-1R: the tale of the tortoise and the hare. Frontiers in Endocrinology 6 64. (https://doi.org/10.3389/fendo.2015.00064)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dagogo-Jack I & & Shaw AT 2018 Tumour heterogeneity and resistance to cancer therapies. Nature Reviews. Clinical Oncology 15 8194. (https://doi.org/10.1038/nrclinonc.2017.166)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dal J, Leisner MZ, Hermansen K, Farkas DK, Bengtsen M, Kistorp C, Nielsen EH, Andersen M, Feldt-Rasmussen U, Dekkers OM, et al.2018 Cancer incidence in patients with acromegaly: a cohort study and meta-analysis of the literature. Journal of Clinical Endocrinology and Metabolism 103 21822188. (https://doi.org/10.1210/jc.2017-02457)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • de Groot S, Lugtenberg RT, Cohen D, Welters MJP, Ehsan I, Vreeswijk MPG, Smit VTHBM, de Graaf H, Heijns JB, Portielje JEA, et al.2020 Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nature Communications 11 3083. (https://doi.org/10.1038/s41467-020-16138-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoël MJ, Fartoux L, Venot C, Bladt F, Housset C & & Rosmorduc O 2009 Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clinical Cancer Research 15 54455456. (https://doi.org/10.1158/1078-0432.CCR-08-2980)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dolgin E 2020 IGF-1R drugs travel from cancer cradle to Graves. Nature Biotechnology 38 385388. (https://doi.org/10.1038/s41587-020-0481-8)

  • Drago JZ, Modi S & & Chandarlapaty S 2021 Unlocking the potential of antibody-drug conjugates for cancer therapy. Nature Reviews. Clinical Oncology 18 327344. (https://doi.org/10.1038/s41571-021-00470-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Duran‐Ortiz S, List EO, Ikeno Y, Young J, Basu R, Bell S, McHugh T, Funk K, Mathes S, Qian Y, et al.2021 Growth hormone receptor gene disruption in mature‐adult mice improves male insulin sensitivity and extends female lifespan. Aging Cell 20 e13506. (https://doi.org/10.1111/acel.13506)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dynkevich Y, Rother KI, Whitford I, Qureshi S, Galiveeti S, Szulc AL, Danoff A, Breen TL, Kaviani N, Shanik MH, et al.2013 Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive. Endocrine Reviews 34 798826. (https://doi.org/10.1210/er.2012-1033)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Egeblad M & & Werb Z 2002 New functions for the matrix metalloproteinases in cancer progression. Nature Reviews. Cancer 2 161174. (https://doi.org/10.1038/nrc745)

  • Eriau E, Paillet J, Kroemer G & & Pol JG 2021 Metabolic reprogramming by reduced calorie intake or pharmacological caloric restriction mimetics for improved cancer immunotherapy. Cancers 13. (https://doi.org/10.3390/cancers13061260)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Evans A, Jamieson SMF, Liu DX, Wilson WR & & Perry JK 2016 Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model. Cancer Letters 379 117123. (https://doi.org/10.1016/j.canlet.2016.05.031)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fahrenholtz CD, Beltran PJ & & Burnstein KL 2013 Targeting IGF-IR with ganitumab inhibits tumorigenesis and increases durability of response to androgen-deprivation therapy in VCaP prostate cancer xenografts. Molecular Cancer Therapeutics 12 394404. (https://doi.org/10.1158/1535-7163.MCT-12-0648)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ferté C, Loriot Y, Clémenson C, Commo F, Gombos A, Bibault JE, Fumagalli I, Hamama S, Auger N, Lahon B, et al.2013 IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: an opportunity to increase the efficacy of standard therapy. Molecular Cancer Therapeutics 12 12131222. (https://doi.org/10.1158/1535-7163.MCT-12-1067)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Finidori J 2000 Regulators of growth hormone signaling. Vitamins and Hormones 59 7197. (https://doi.org/10.1016/s0083-6729(0059004-9)

  • Fitzgerald RC, Antoniou AC, Fruk L & & Rosenfeld N 2022 The future of early cancer detection. Nature Medicine 28 666677. (https://doi.org/10.1038/s41591-022-01746-x)

  • Fu Z, Li S, Han S, Shi C & & Zhang Y 2022 Antibody drug conjugate: the ‘biological missile’ for targeted cancer therapy. Signal Transduction and Targeted Therapy 7 93. (https://doi.org/10.1038/s41392-022-00947-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, et al.2015 A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the gamma trial. Annals of Oncology 26 921927. (https://doi.org/10.1093/annonc/mdv027)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gentilin E, Minoia M, Bondanelli M, Tagliati F, Degli Uberti EC & & Zatelli MC 2017 Growth hormone differentially modulates chemoresistance in human endometrial adenocarcinoma cell lines. Endocrine 56 621632. (https://doi.org/10.1007/s12020-016-1085-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Glisson B, Besse B, Dols MC, Dubey S, Schupp M, Jain R, Jiang Y, Menon H, Nackaerts K, Orlov S, et al.2017 A randomized, placebo-controlled, phase 1b/2 study of rilotumumab or ganitumab in combination with platinum-based chemotherapy as first-line treatment for extensive-stage small-cell lung cancer. Clinical Lung Cancer 18 615625.e8. (https://doi.org/10.1016/j.cllc.2017.05.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goffin V 2017 Prolactin receptor targeting in breast and prostate cancers: new insights into an old challenge. Pharmacology and Therapeutics 179 111126. (https://doi.org/10.1016/j.pharmthera.2017.05.009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • González L, Díaz ME, Miquet JG, Sotelo AI, Fernández D, Dominici FP, Bartke A & & Turyn D 2010 GH modulates hepatic epidermal growth factor signaling in the mouse. Journal of Endocrinology 204 299309. (https://doi.org/10.1677/JOE-09-0372)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • González L, Díaz ME, Miquet JG, Sotelo AI & & Dominici FP 2021 Growth hormone modulation of hepatic epidermal growth factor receptor signaling. Trends in Endocrinology and Metabolism: TEM 32 403414. (https://doi.org/10.1016/j.tem.2021.03.004)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, et al.2011 Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Science Translational Medicine 3 70ra13. (https://doi.org/10.1126/scitranslmed.3001845)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guo XF, Zhu XF, Cao HY, Zhong GS, Li L, Deng BG, Chen P, Wang PZ, Miao QF & & Zhen YS 2017 A bispecific enediyne-energized fusion protein targeting both epidermal growth factor receptor and insulin-like growth factor 1 receptor showing enhanced antitumor efficacy against non-small cell lung cancer. Oncotarget 8 2728627299. (https://doi.org/10.18632/oncotarget.15933)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hanahan D 2022 Hallmarks of cancer: new dimensions. Cancer Discovery 12 3146. (https://doi.org/10.1158/2159-8290.CD-21-1059)

  • Haque A, Sahu V, Lombardo JL, Xiao L, George B, Wolff RA, Morris JS, Rashid A, Kopchick JJ, Kaseb AO, et al.2022 Disruption of growth hormone receptor signaling abrogates hepatocellular carcinoma development. Journal of Hepatocellular Carcinoma 9 823837. (https://doi.org/10.2147/JHC.S368208)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Harvey S 2010 Extrapituitary growth hormone. Endocrine 38 335359. (https://doi.org/10.1007/s12020-010-9403-8)

  • Higham CE, Rowles S, Russell-Jones D, Umpleby AM & & Trainer PJ 2009 Pegvisomant improves insulin sensitivity and reduces overnight free fatty acid concentrations in patients with acromegaly. Journal of Clinical Endocrinology and Metabolism 94 24592463. (https://doi.org/10.1210/jc.2008-2086)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Holtz AN, Yee D & & Beckwith H 2018 Abstract 5839: Growth hormone receptor (GHR) expression confers resistance to Ruxolitinib in endocrine-resistant breast cancer cells. Cancer Research 78 58395839. (https://doi.org/10.1158/1538-7445.AM2018-5839)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hua H, Kong Q, Yin J, Zhang J & & Jiang Y 2020 Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy. Journal of Hematology and Oncology 13 64. (https://doi.org/10.1186/s13045-020-00904-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Huang Y, Kim SO, Jiang J & & Frank SJ 2003 Growth hormone-induced phosphorylation of epidermal growth factor (EGF) receptor in 3T3-F442A cells. Modulation of EGF-induced trafficking and signaling. Journal of Biological Chemistry 278 1890218913. (https://doi.org/10.1074/jbc.M300939200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ikeno Y, Hubbard GB, Lee S, Cortez LA, Lew CM, Webb CR, Berryman DE, List EO, Kopchick JJ & & Bartke A 2009 Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 64 522529. (https://doi.org/10.1093/gerona/glp017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ & & Kliewer SA 2008 Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metabolism 8 7783. (https://doi.org/10.1016/j.cmet.2008.05.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Iwasa T, Okamoto I, Suzuki M, Hatashita E, Yamada Y, Fukuoka M, Ono K & & Nakagawa K 2009 Inhibition of insulin-like growth factor 1 receptor by CP-751,871 radiosensitizes non-small cell lung cancer cells. Clinical Cancer Research 15 51175125. (https://doi.org/10.1158/1078-0432.CCR-09-0478)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jia Y, , Zhang Y, , Qiao C, , Liu G, , Zhao Q, , Zhou T, , Chen G, , Li Y, , Feng J, , Li Y, et al.2013 IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model. Biochemical and Biophysical Research Communications 436 740745. (https://doi.org/10.1016/j.bbrc.2013.06.030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Johansson S, Husman B, Norstedt G & & Andersson G 1989 Growth hormone regulates the rodent hepatic epidermal growth factor receptor at a pretranslational level. Journal of Molecular Endocrinology 3 113120. (https://doi.org/10.1677/jme.0.0030113)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kang J, Guo Z, Zhang H, Guo R, Zhu X & & Guo X 2022 Dual inhibition of EGFR and IGF-1R signaling leads to enhanced antitumor efficacy against esophageal squamous cancer. International Journal of Molecular Sciences 23. (https://doi.org/10.3390/ijms231810382)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kaseb AO, Haque A, Vishwamitra D, Hassan MM, Xiao L, George B, Sahu V, Mohamed YI, Carmagnani Pestana R, Lombardo JL, et al.2022 Blockade of growth hormone receptor signaling by using pegvisomant: a functional therapeutic strategy in hepatocellular carcinoma. Frontiers in Oncology 12 986305. (https://doi.org/10.3389/fonc.2022.986305)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson JJ, Rocha-Lima CM, Safran H, Chan D, Kocs DM, Galimi F, et al.2012 A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Annals of Oncology 23 28342842. (https://doi.org/10.1093/annonc/mds142)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Konecny GE, Hendrickson AEW, Davidson TM, Winterhoff BJ, Ma S, Mahner S, Sehouli J, Fasching PA, Feisel-Schwickardi G, Poelcher M, et al.2021 Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer. Gynecologic Oncology 163 465472. (https://doi.org/10.1016/j.ygyno.2021.09.025)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kopchick JJ, List EO, Kelder B, Gosney ES & & Berryman DE 2014 Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications. Molecular and Cellular Endocrinology 386 3445. (https://doi.org/10.1016/j.mce.2013.09.004)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kopchick JJ, Berryman DE, Puri V, Lee KY & & Jorgensen JOL 2020 The effects of growth hormone on adipose tissue: old observations, new mechanisms. Nature Reviews. Endocrinology 16 135146. (https://doi.org/10.1038/s41574-019-0280-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kopchick JJ, Basu R, Berryman DE, Jorgensen JOL, Johannsson G & & Puri V 2022 Covert actions of growth hormone: fibrosis, cardiovascular diseases and cancer. Nature Reviews. Endocrinology 18 558573. (https://doi.org/10.1038/s41574-022-00702-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kundranda M, Gracian AC, Zafar SF, Meiri E, Bendell J, Algül H, Rivera F, Ahn ER, Watkins D, Pelzer U, et al.2020 Randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE). Annals of Oncology 31 7987. (https://doi.org/10.1016/j.annonc.2019.09.004)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Labrie M, Brugge JS, Mills GB & & Zervantonakis IK 2022 Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer. Nature Reviews. Cancer 22 323339. (https://doi.org/10.1038/s41568-022-00454-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lantvit DD, Unterberger CJ, Lazar M, Arneson PD, Longhurst CA, Swanson SM & & Marker PC 2021 Mammary tumors growing in the absence of growth hormone are more sensitive to doxorubicin than wild-type tumors. Endocrinology 162. (https://doi.org/10.1210/endocr/bqab013)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lee SW, Kim SH, Kim JY & & Lee Y 2010 The effect of growth hormone on fibroblast proliferation and keratinocyte migration. Journal of Plastic, Reconstructive and Aesthetic Surgery 63 e364e369. (https://doi.org/10.1016/j.bjps.2009.10.027)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lehmann BD, Colaprico A, Silva TC, Chen J, An H, Ban Y, Huang H, Wang L, James JL, Balko JM, et al.2021 Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes. Nature Communications 12 6276. (https://doi.org/10.1038/s41467-021-26502-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lempereur L, Brambilla D, Maria Scoto GM, D’Alcamo M, Goffin V, Crosta L, Palmucci T, Rampello L, Bernardini R & & Cantarella G 2003 Growth hormone protects human lymphocytes from irradiation-induced cell death. British Journal of Pharmacology 138 14111416. (https://doi.org/10.1038/sj.bjp.0705173)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li P, Veldwijk MR, Zhang Q, Li ZB, Xu WC & & Fu S 2013 Co-inhibition of epidermal growth factor receptor and insulin-like growth factor receptor 1 enhances radiosensitivity in human breast cancer cells. BMC Cancer 13 297. (https://doi.org/10.1186/1471-2407-13-297)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ligorio F, Fucà G, Provenzano L, Lobefaro R, Zanenga L, Vingiani A, Belfiore A, Lorenzoni A, Alessi A, Pruneri G, et al.2022 Exceptional tumour responses to fasting-mimicking diet combined with standard anticancer therapies: a sub-analysis of the NCT03340935 trial. European Journal of Cancer 172 300310. (https://doi.org/10.1016/j.ejca.2022.05.046)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu Y, Zhang Y, Jiang J, Lobie PE, Paulmurugan R, Langenheim JF, Chen WY, Zinn KR & & Frank SJ 2016 GHR/PRLR heteromultimer is composed of GHR homodimers and PRLR homodimers. Molecular Endocrinology 30 504517. (https://doi.org/10.1210/me.2015-1319)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu X, Chen H, Xu X, Ye M, Cao H, Xu L, Hou Y, Tang J, Zhou D, Bai Y, et al.2018 Insulin-like growth factor-1 receptor knockdown enhances radiosensitivity via the HIF-1α pathway and attenuates ATM/H2AX/53BP1 DNA repair activation in human lung squamous carcinoma cells. Oncology Letters 16 13321340. (https://doi.org/10.3892/ol.2018.8705)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Livingstone C 2013 IGF2 and cancer. Endocrine-Related Cancer 20 R321R339. (https://doi.org/10.1530/ERC-13-0231)

  • Lu C, Kumar PA, Sun J, Aggarwal A, Fan Y, Sperling MA, Lumeng CN & & Menon RK 2013 Targeted deletion of growth hormone (GH) receptor in macrophage reveals novel osteopontin-mediated effects of GH on glucose homeostasis and insulin sensitivity in diet-induced obesity. Journal of Biological Chemistry 288 1572515735. (https://doi.org/10.1074/jbc.M113.460212)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lu M, Flanagan JU, Langley RJ, Hay MP & & Perry JK 2019 Targeting growth hormone function: strategies and therapeutic applications. Signal Transduction and Targeted Therapy 4 3. (https://doi.org/10.1038/s41392-019-0036-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mañes S, Mira E, Barbacid MM, Ciprés A, Fernández-Resa P, Buesa JM, Mérida I, Aracil M, Márquez G & & Martínez-A C 1997 Identification of insulin-like growth factor-binding protein-1 as a potential physiological substrate for human stromelysin-3. Journal of Biological Chemistry 272 2570625712. (https://doi.org/10.1074/jbc.272.41.25706)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mañes S, Llorente M, Lacalle RA, Gómez-Moutón C, Kremer L, Mira E & & Martínez-A C 1999 The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. Journal of Biological Chemistry 274 69356945. (https://doi.org/10.1074/jbc.274.11.6935)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Minoia M, Gentilin E, Molè D, Rossi M, Filieri C, Tagliati F, Baroni A, Ambrosio MR, degli Uberti E & & Zatelli MC 2012 Growth hormone receptor blockade inhibits growth hormone-induced chemoresistance by restoring cytotoxic-induced apoptosis in breast cancer cells independently of estrogen receptor expression. Journal of Clinical Endocrinology and Metabolism 97 E907E916. (https://doi.org/10.1210/jc.2011-3340)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mohamed YI, Duda DG, Awiwi MO, Lee SS, Altameemi L, Xiao L, Morris JS, Wolff RA, Elsayes KM, Hatia RI, et al.2022 Plasma growth hormone is a potential biomarker of response to atezolizumab and bevacizumab in advanced hepatocellular carcinoma patients. Oncotarget 13 13141321. (https://doi.org/10.18632/oncotarget.28322)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Murakami H, Doi T, Yamamoto N, Watanabe J, Boku N, Fuse N, Yoshino T, Ohtsu A, Otani S, Shibayama K, et al.2012 Phase 1 study of ganitumab (AMG 479), a fully human monoclonal antibody against the insulin-like growth factor receptor type I (IGF1R), in Japanese patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology 70 407414. (https://doi.org/10.1007/s00280-012-1924-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Okusaka T, Ikeda M, Fukutomi A, Kobayashi Y, Shibayama K, Takubo T & & Gansert J 2014 Safety, tolerability, pharmacokinetics and antitumor activity of ganitumab, an investigational fully human monoclonal antibody to insulin-like growth factor type 1 receptor, combined with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer: a phase 1b study. Japanese Journal of Clinical Oncology 44 442447. (https://doi.org/10.1093/jjco/hyu034)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Osborne CK, Shou J, Massarweh S & & Schiff R 2005 Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clinical Cancer Research 11 865s70s. (https://doi.org/10.1158/1078-0432.865s.11.2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Paisley AN, Trainer P & & Drake W 2004 Pegvisomant: a novel pharmacotherapy for the treatment of acromegaly. Expert Opinion on Biological Therapy 4 421425. (https://doi.org/10.1517/14712598.4.3.421)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Perry JK, Wu ZS, Mertani HC, Zhu T & & Lobie PE 2017 Tumour-derived human growth hormone as a therapeutic target in oncology. Trends in Endocrinology and Metabolism 28 587596. (https://doi.org/10.1016/j.tem.2017.05.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pittet MJ, Michielin O & & Migliorini D 2022 Clinical relevance of tumour-associated macrophages. Nature Reviews. Clinical Oncology 19 402421. (https://doi.org/10.1038/s41571-022-00620-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Prieto I, Gómez de Segura IA, García Grande A, García P, Carralero I & & de Miguel E 1998 Morphometric and proliferative effects of growth hormone on radiation enteritis in the rat. Revista Espanola de Enfermedades Digestivas 90 163173.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Qian Y, Basu R, Mathes SC, Arnett NA, Duran-Ortiz S, Funk KR, Brittain AL, Kulkarni P, Terry JC, Davis E, et al.2020 Growth hormone upregulates mediators of melanoma drug efflux and epithelial-to-mesenchymal transition in vitro and in vivo. Cancers 12 3640. (https://doi.org/10.3390/cancers12123640)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Riesterer O, Yang Q, Raju U, Torres M, Molkentine D, Patel N, Valdecanas D, Milas L & & Ang KK 2011 Combination of anti-IGF-1R antibody A12 and ionizing radiation in upper respiratory tract cancers. International Journal of Radiation Oncology, Biology, Physics 79 11791187. (https://doi.org/10.1016/j.ijrobp.2010.10.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Robertson JF, Ferrero JM, Bourgeois H, Kennecke H, de Boer RH, Jacot W, McGreivy J, Suzuki S, Zhu M, McCaffery I, et al.2013 Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet. Oncology 14 228235. (https://doi.org/10.1016/S1470-2045(1370026-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE & & Gottesman MM 2018 Revisiting the role of ABC transporters in multidrug-resistant cancer. Nature Reviews. Cancer 18 452464. (https://doi.org/10.1038/s41568-018-0005-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rochester MA, Riedemann J, Hellawell GO, Brewster SF & & Macaulay VM 2005 Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer. Cancer Gene Therapy 12 90100. (https://doi.org/10.1038/sj.cgt.7700775)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rosen LS, Puzanov I, Friberg G, Chan E, Hwang YC, Deng H, Gilbert J, Mahalingam D, McCaffery I, Michael SA, et al.2012 Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors. Clinical Cancer Research 18 34143427. (https://doi.org/10.1158/1078-0432.CCR-11-3369)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Roudabush FL, Pierce KL, Maudsley S, Khan KD & & Luttrell LM 2000 Transactivation of the EGF receptor mediates IGF-1-stimulated shc phosphorylation and ERK1/2 activation in COS-7 cells. Journal of Biological Chemistry 275 2258322589. (https://doi.org/10.1074/jbc.M002915200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, Fearon D, Greten FR, Hingorani SR, Hunter T, et al.2020 A framework for advancing our understanding of cancer-associated fibroblasts. Nature Reviews. Cancer 20 174186. (https://doi.org/10.1038/s41568-019-0238-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schanzer JM, Wartha K, Moessner E, Hosse RJ, Moser S, Croasdale R, Trochanowska H, Shao C, Wang P, Shi L, et al.2016 XGFR*, a novel affinity-matured bispecific antibody targeting IGF-1R and EGFR with combined signaling inhibition and enhanced immune activation for the treatment of pancreatic cancer. mAbs 8 811827. (https://doi.org/10.1080/19420862.2016.1160989)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shen K, Cui D, Sun L, Lu Y, Han M & & Liu J 2012 Inhibition of IGF-IR increases chemosensitivity in human colorectal cancer cells through MRP-2 promoter suppression. Journal of Cellular Biochemistry 113 20862097. (https://doi.org/10.1002/jcb.24080)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shevah O & & Laron Z 2007 Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. Growth Hormone and IGF Research 17 5457. (https://doi.org/10.1016/j.ghir.2006.10.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Simpson A, Petnga W, Macaulay VM, Weyer-Czernilofsky U & & Bogenrieder T 2017 Insulin-like growth factor (IGF) pathway targeting in cancer: role of the IGF axis and opportunities for future combination studies. Targeted Oncology 12 571597. (https://doi.org/10.1007/s11523-017-0514-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Simpson AD, Soo YWJ, Rieunier G, Aleksic T, Ansorge O, Jones C & & Macaulay VM 2020 Type 1 IGF receptor associates with adverse outcome and cellular radioresistance in paediatric high-grade glioma. British Journal of Cancer 122 624629. (https://doi.org/10.1038/s41416-019-0677-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Singh RK, Gaikwad SM, Jinager A, Chaudhury S, Maheshwari A & & Ray P 2014 IGF-1R inhibition potentiates cytotoxic effects of chemotherapeutic agents in early stages of chemoresistant ovarian cancer cells. Cancer Letters 354 254262. (https://doi.org/10.1016/j.canlet.2014.08.023)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Somri-Gannam L, Meisel-Sharon S, Hantisteanu S, Groisman G, Limonad O, Hallak M & & Bruchim I 2020 IGF1R axis inhibition restores dendritic cell antitumor response in ovarian cancer. Translational Oncology 13 100790. (https://doi.org/10.1016/j.tranon.2020.100790)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tamshen K, Wang Y, Jamieson SMF, Perry JK & & Maynard HD 2020 Genetic code expansion enables site-specific pegylation of a human growth hormone receptor antagonist through click chemistry. Bioconjugate Chemistry 31 21792190. (https://doi.org/10.1021/acs.bioconjchem.0c00365)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tan Y, Li J, Zhao G, Huang KC, Cardenas H, Wang Y, Matei D & & Cheng JX 2022 Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells. Nature Communications 13 4554. (https://doi.org/10.1038/s41467-022-32101-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thelen M, Wennhold K, Lehmann J, Garcia-Marquez M, Klein S, Kochen E, Lohneis P, Lechner A, Wagener-Ryczek S, Plum PS, et al.2021 Cancer-specific immune evasion and substantial heterogeneity within cancer types provide evidence for personalized immunotherapy. NPJ Precision Oncology 5 52. (https://doi.org/10.1038/s41698-021-00196-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Turney BW, Kerr M, Chitnis MM, Lodhia K, Wang Y, Riedemann J, Rochester M, Protheroe AS, Brewster SF & & Macaulay VM 2012 Depletion of the type 1 IGF receptor delays repair of radiation-induced DNA double strand breaks. Radiotherapy and Oncology 103 402409. (https://doi.org/10.1016/j.radonc.2012.03.009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Van Cutsem E, Eng C, Nowara E, Swieboda-Sadlej A, Tebbutt NC, Mitchell E, Davidenko I, Stephenson J, Elez E, Prenen H, et al.2014 Randomized phase Ib/II trial of Rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer. Clinical Cancer Research 20 42404250. (https://doi.org/10.1158/1078-0432.CCR-13-2752)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • van der Velden LM, Maas P, van Amersfoort M, Timmermans-Sprang EPM, Mensinga A, van der Vaart E, Malergue F, Viëtor H, Derksen PWB, Klumperman J, et al.2022 Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis. Frontiers in Endocrinology 13 926210. (https://doi.org/10.3389/fendo.2022.926210)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vasan N, Baselga J & & Hyman DM 2019 A view on drug resistance in cancer. Nature 575 299309. (https://doi.org/10.1038/s41586-019-1730-1)

  • Venkatachalam S, Mettler E, Fottner C, Miederer M, Kaina B & & Weber MM 2017 The impact of the IGF-1 system of cancer cells on radiation response - an in vitro study. Clinical and Translational Radiation Oncology 7 18. (https://doi.org/10.1016/j.ctro.2017.09.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vlahovic G, Meadows KL, Hatch AJ, Jia J, Nixon AB, Uronis HE, Morse MA, Selim MA, Crawford J, Riedel RF, et al.2018 A Phase I trial of the IGF-1R antibody ganitumab (AMG 479) in combination with everolimus (RAD001) and panitumumab in patients with advanced cancer. Oncologist 23 782790. (https://doi.org/10.1634/theoncologist.2016-0377)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Waldman AD, Fritz JM & & Lenardo MJ 2020 A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nature Reviews. Immunology 20 651668. (https://doi.org/10.1038/s41577-020-0306-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang YH, Wang ZX, Qiu Y, Xiong J, Chen YX, Miao DS & & De W 2009 Lentivirus-mediated RNAi knockdown of insulin-like growth factor-1 receptor inhibits growth, reduces invasion, and enhances radiosensitivity in human osteosarcoma cells. Molecular and Cellular Biochemistry 327 257266. (https://doi.org/10.1007/s11010-009-0064-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang W, Zhang Y, Lv M, Feng J, Peng H, Geng J, Lin Z, Zhou T, Li X, Shen B, et al.2014 Anti-IGF-1R monoclonal antibody inhibits the carcinogenicity activity of acquired trastuzumab-resistant SKOV3. Journal of Ovarian Research 7 103. (https://doi.org/10.1186/s13048-014-0103-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang JJ, Chong QY, Sun XB, You ML, Pandey V, Chen YJ, Zhuang QS, Liu DX, Ma L, Wu ZS, et al.2017 Autocrine hGH stimulates oncogenicity, epithelial-mesenchymal transition and cancer stem cell-like behavior in human colorectal carcinoma. Oncotarget 8 103900103918. (https://doi.org/10.18632/oncotarget.21812)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang Z, Liu G, Mao J, Xie M, Zhao M, Guo X, Liang S, Li H, Li X & & Wang R 2019 IGF-1R inhibition suppresses cell proliferation and increases radiosensitivity in nasopharyngeal carcinoma cells. Mediators of Inflammation 2019 5497467. (https://doi.org/10.1155/2019/5497467)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang Y, Langley RJ, Tamshen