Abstract
Despite decades of research presenting insulin-like growth factor-1 receptor (IGF1R) as an attractive target for cancer therapy, IGF1R inhibitors ultimately failed in clinical trials. This was surprising due to the known cancer-promoting functions of IGF1R, including stimulation of cell invasion, proliferation, and survival. Discourse in the literature has acknowledged that a lack of patient stratification may have impacted the success of IGF1R-inhibitor trials. This argument alludes to the possibility that IGF1R function may be contingent on tumor type and cellular composition. Looking into the known roles of IGF1R, it becomes clear that this receptor interacts with a multitude of different proteins and even has tumor-suppressing functions. IGF1R is implicated in both cell–cell and cell–surface adhesion dynamics, and the effects of either IGF1R downregulation or pharmacological inhibition on cellular adhesion remain poorly understood. In turn, adhesion receptors modulate IGF1R signaling. In addition, our understanding of IGF1R function in tumor-associated immune and stromal cells is lacking, which could contribute to the overwhelming failure of IGF1R inhibitors in the clinic. In this review, we re-investigate clinical trial data to make connections between the failure of these drugs in human cancer patients and the understudied facets of IGF1R function. We describe lesser-known and potentially tumor-suppressive functions of IGF1R that include promoting cell–cell adhesion through E-cadherin, augmenting a pro-inflammatory macrophage phenotype, and stimulating B cells to produce immunoglobulins. We also highlight the important role of adhesion receptors in regulating IGF1R function, and we use this information to infer stratification criteria for selecting patients that might benefit from IGF1R inhibitors.
Introduction
Growth factors, such as epidermal growth factor and platelet-derived growth factor, and their receptors play a major role in modulating cancer cell mitogenicity and metastasis and can make excellent prognostic markers (Aaronson 1991). However, one growth factor receptor, insulin-like growth factor-1 receptor (IGF1R), has a convoluted history as a target for cancer therapy. Previously, IGF1R was considered a promising candidate for drug targeting due to its frequent overexpression in various cancers, including pancreatic and prostate cancer (Bohula et al. 2003, Riedemann & Macaulay 2006). Functionally, IGF1R plays a well-established role in promoting the proliferation of various cell types and cancers (Baserga et al. 1993, Wu & Yu 2014). IGF1R also promotes vascularization (Kondo et al. 2003, Dallinga et al. 2018) and an invasive cancer phenotype (Lopez & Hanahan 2002, Sachdev et al. 2010). However, when IGF1R blocking antibodies and tyrosine kinase (TK) inhibitors were developed for clinical trials, results were poor due to toxicity from the TK inhibitors and futility in an overwhelming majority of cases (Chen & Sharon 2013, Beckwith & Yee 2015, Ekyalongo & Yee 2017). Interest in potential tumor-suppressor functions of IGF1R spurred the research into models of IGF1R knockdown and inhibition. Surprisingly, the loss of IGF1R in the prostate epithelium in a p53-compromised mouse prostate model resulted in accelerated tumor formation and in less differentiated, more aggressive prostate tumors (Plymate et al. 1997, Sutherland et al. 2008). Similarly, inhibition of IGF signaling via expression of a dominant-negative IGF1R in the mammary epithelium of a Wnt1-driven mouse mammary tumor model was sufficient to convert poorly metastatic tumors to a highly metastatic carcinoma (Rota et al. 2014, Obr et al. 2018, Obr et al. 2022). These findings support a dual role for IGF1R in both tumor promotion and suppression and are consistent with patient data that reveal a negative correlation between IGF1R expression and overall patient survival (Obr et al. 2018). Although the tumor-promoting functions of IGF1R have been well established, its suppressive functions are currently under investigation. Prior and recent findings delineate a role for IGF1R in promoting cell differentiation (for review, see Bulatowicz & Wood 2022). Here, we focus on the underappreciated functions of IGF1R in cell adhesion and the tumor microenvironment (TME), both as a mediator of cell–ECM and cell–cell interactions and as a critical modulator of immune and stromal cell function. We will also make connections between these functions and the hallmarks of cancer, namely sustained proliferative signaling and tumor-promoting inflammation (Hanahan & Weinberg 2011).
Physiologic role of the IGF axis
IGF signaling functions through IGF1R to promote mammalian growth and development and, like the insulin receptor (INSR), regulate metabolism (Petersen & Shulman 2018, Forbes et al. 2020). IGF signaling is particularly complex due to its crosstalk with INSR signaling. IGF1R and INSR are tetrameric receptor tyrosine kinases (RTKs) that are the main effectors of IGF ligand signaling (Singh et al. 2014). IGF1R and INSR have about 70% protein homology (Riedemann & Macaulay 2006), and both can bind the respective cognate ligands, including insulin, IGF1, and IGF2, although in some cases only at non-physiological concentrations (Withers & White 2000). To further complicate this axis, IGF1R and INSR stochastically hybridize to form heterodimers, called ‘Hybrid-R’s,’ which have proliferative but not anti-apoptotic effects, unlike IGF1R signaling (Pandini et al. 2007, Chen et al. 2018). The TK domain of both receptors activates the insulin-receptor substrate (IRS) proteins (Butler & LeRoith 2001), which transduce the RTK signal to activate downstream signaling pathways and modulate cellular metabolism (Haeusler et al. 2018). IGF1R-mediated activation of the MAPK/Erk and Akt pathways promotes cellular survival and response to hypoxia (Riedemann & Macaulay 2006). Despite their homology and overlapping effects, IGF1R preferentially mediates growth effects, whereas INSR preferentially regulates metabolism (Petersen & Shulman 2018). As cell growth and pro-metabolic effects are essential for cancer progression, both receptors play an integral role in carcinogenesis. INSR also has two isoforms, A and B, each with distinct functions. Research on the effects of each isoform in cancer is an emerging and exciting area of study; however, the breadth of information on this topic is vast, so for the purpose of this review, we will focus on IGF1R.
IGF1R in cancer
A synopsis of IGF1R function in cancer progression and cellular differentiation and a summary of mouse models used to study altered IGF1R function were recently published in a review from our lab (Bulatowicz & Wood 2022), so for the purpose of the current review, we will focus on the mechanisms of IGF1R function in adhesion dynamics and the TME and make connections to the clinical data. The previous review by Bulatowicz and Wood highlights that the body of literature on IGF1R function in cancer has an apparent contradiction: IGF1R inhibitors largely failed clinical trials despite the known oncogenic effects of IGF1R activation. This appears paradoxical but indicates that our current understanding of IGF1R in cancer is insufficient. To address what is already known, a schematic of tumor-promoting and tumor-suppressing functions of IGF1R is illustrated in Fig. 1. To evaluate the gaps in our knowledge of IGF1R function in cancer, we will begin by exploring the important but underappreciated crosstalk between IGF1R and adhesion receptors since changes in cell–cell adhesion and cell–matrix adhesion positively and negatively regulate diverse processes in tumor progression including cell migration, invasion, intravasation, and metastatic colonization.
Summary of prominent tumor-promoting and -suppressing IGF1R functions in cancer cells.
Citation: Endocrine-Related Cancer 30, 10; 10.1530/ERC-23-0031
IGF1R and adhesion: a sticking point in understanding cancer physiology
Direct association between IGF1R and integrins
Integrins are implicated in angiogenesis, migration, invasion, and various other processes related to cancer progression (Desgrosellier & Cheresh 2010). They are assembled into heterodimers of alpha and beta subunits in the endoplasmic reticulum (Hamidi & Ivaska 2019) and primarily mediate cell–matrix and not cell–cell adhesion (Pignatelli et al. 1992, Weitzman et al. 1995). Integrin-mediated adhesion is also critical in facilitating cancer cell extravasation and metastasis (Bendas & Borsig 2012). The binding specificity of integrins is variable, as some integrins, such as αvβ3, bind multiple substrates including fibronectin and vitronectin, whereas other integrins are specific to a single substrate (Slack et al. 2022). Some integrins are more closely linked to malignancy; for example, integrin β3 expression is associated with malignant breast cancer phenotypes, whereas β6 is more closely linked to less aggressive tumors (Singh et al. 2018). Integrins α6β4 and αvβ3 are frequently overexpressed in cancer and are known, prominent binding partners of IGF1R (Stewart & O'Connor 2015, Takada et al. 2017, Singh et al. 2018). Interestingly, αvβ3 integrin binding to IGF1 is permissive for IGF1R signaling (Takada et al. 2017, Saegusa et al. 2009). Consistent with this finding, disruption of α5β1 integrin impedes IGF1-dependent MDA-231BO bone-seeking, triple-negative breast cancer cell motility (Zhang & Yee 2002). Indeed, integrins are so commonly involved in cancer progression that cilengitide, an αvβ3 and αvβ5 integrin inhibitor, entered a phase III clinical trial for the treatment of glioblastoma before ultimately being abandoned due to lack of efficacy (Stupp et al. 2014). Several integrin inhibitors have been approved by the FDA for indications other than cancer, and many more have undergone clinical trials (Slack et al. 2022). Like IGF1R inhibitors, integrin inhibitors appear to translate poorly from animal studies into human cancer trials.
Integrins are also accrued in focal adhesions, and more information is emerging about IGF1R’s function at focal adhesion sites. Focal adhesions are complexes of various proteins at the leading edge of a cell that is essential for migration (Mishra & Manavathi 2021). IGF1R colocalizes with β1 Integrin and FER TK at sites of focal adhesion in MCF7 and MDA-MB-231 human breast cancer cell lines (Stanicka et al. 2018). In this study, the IGF1R complex promoted the activation of FER, a pro-tumorigenic kinase, in an IGF1-dependent manner. This phenomenon affects downstream signaling; however, it is unclear how the IGF1R-integrin complex alters cellular adhesion, and this poses a major gap in our understanding of IGF1R crosstalk with its integrin binding partners. IGF1R translocation is also dependent on cell-cell contacts and on cell type. In MCF7 human breast cancer cells, high confluency promotes IGF1R localization to sites of cell–cell adhesion (Nagle et al. 2018), but this is not consistent in Hs578T human breast cancer cells, in which confluency promotes IGF1R localization to the Golgi apparatus (Rieger et al. 2020). Rieger and colleagues further found that phosphorylation of specific IGF1R tyrosine residues Tyr1250/1251 was necessary for IGF1R translocation to the Golgi and subsequent cell migration. Cells expressing nonphosphorylatable IGF1R Tyr1250/1251 were unable to internalize the receptor. Furthermore, the authors found that BMS-754807 (BMS), a TK inhibitor of IGF1R, abrogated IGF1-mediated enhancement of Tyr1250/1251 phosphorylation. It is unclear from these results if IGF1R inhibition promotes a sustained interaction between IGF1R and adhesion receptors at the cell membrane due to impaired receptor internalization.
In a separate study, investigators found that IGF1R-integrin complex formation was dependent on IGF1 binding but independent of IGF1R phosphorylation status in Chinese hamster ovary cells (Fujita et al. 2013, Takada et al. 2017). A clear physical interaction between IGF1R and integrins exists, but this field of study has focused on downstream signaling alterations and not the impact of the IGF1R–integrin physical interaction on cancer cell adhesion. The effect of this interaction on a malignant phenotype remains an open question.
Insulin receptor substrates in adhesion signaling
IGF axis involvement in adhesion signaling is not limited to IGF1R–integrin interactions. The IRS proteins are also involved in cell adhesion, and the literature indicates that integrin function is essential for insulin and IGF signaling through IRS proteins. For instance, IRS-1 and αvβ3 complex upon insulin stimulation of HIRcB Rat-1 fibroblasts stably expressing the human INSR (Vuori & Ruoslahti 1994), although the consequences of this association have not been delineated. IRS-2 activation was shown to promote motility in MDA-231BO cells (Jackson et al. 2001). IRS-2 knockdown increased adherence to fibronectin and abrogated the effect of IGF1 stimulation on cell adhesion in this study, suggesting that IRS-2 expression is permissive for IGF1-dependent effects on cell adhesion to fibronectin in these cells.
Focal adhesion kinase (FAK), a prominent pro-adhesion protein implicated in integrin signaling, facilitates IGF axis interplay with cellular adhesion. In one study, cell adhesion via FAK was found to be necessary for IRS-1 expression (Lebrun et al. 2000). Lebrun et al. demonstrated that either FAK deletion or lack of an appropriate adhesion substrate, such as fibronectin, was sufficient to reduce IRS-1 mRNA expression in NIH3T3 embryonic mouse fibroblasts. This indicates that FAK signaling is permissive for INSR and IGF1R signaling through IRS-1. Interestingly, no effect on IRS-2 expression was observed. In another study concentrating on α6β4 integrin, Shaw reported that ligation of either the alpha or beta subunit of this integrin with a selective antibody induced IRS-dependent phosphoinositide 3-kinase (PI3K) activation (Shaw 2001), which is striking due to the prominent tumor-promoting function of this kinase (Yang et al. 2019). This mechanism was either IRS-1- or IRS-2-mediated, depending on the cell line used. In MDA-MB-435 human melanoma cells, which are IRS-1Low and IRS-2High, PI3K activity was associated with IRS-2; in T47D human breast carcinoma, which are IRS-1High and IRS-2Low, PI3K activity instead was associated with IRS-1. Although not tested in this study, the bidirectionality of this association would be an interesting topic to explore. How does IGF1R or INSR stimulation affect integrin signaling? Does pharmacological inhibition of IGF1R affect integrin signaling, and what is the net effect on metastasis? This area of study needs more development before conclusions can be made.
IGF1R, E-cadherin, and cell–cell adhesion
In contrast to cell–surface adhesion, cell–cell adhesion is regulated by a different category of surface proteins, namely the cadherins (Ilina et al. 2020). E-cadherin, a critical member of the cadherin family of proteins, is a transmembrane receptor that mediates intercellular adhesions between epithelial cells and is closely related to cancer progression (Yu et al. 2019). In their review, Yu and colleagues describe the multifaceted role of E-cadherin in modulating cellular polarity, epithelium integrity and β-catenin signaling. They also discuss its prominent tumor-suppressor function, as loss of this cadherin is common in advanced carcinoma and promotes an invasive phenotype. Other classical cadherins include N-cadherin and P-cadherin, both of which enhance the metastatic potential of carcinoma (Kaszak et al. 2020). Forced expression of E-cadherin is sufficient to revert a malignant phenotype to a benign one (Christofori & Semb 1999).
New studies are building on a body of literature that indicate a relationship between IGF1R and E-cadherin function that is context dependent. For instance, IGF1R complexes with E-cadherin and promotes cell–cell adhesion in MCF7 breast cancer cells which express high levels of E-cadherin (Mauro et al. 2001). In this study, overexpression of IGF1R in MDA-MB-231 cells, which express low levels of E-cadherin, did not promote cell aggregation. Surprisingly, co-expression of E-cadherin and IGF1R in MDA-MB-231 cells did promote cell aggregation, indicating that the IGF1R–E-cadherin complex promotes cell–cell adhesion and may suppress metastasis. Despite these findings, other studies suggest a different story. In ovarian carcinoma, IGF1 stimulation induced E-cadherin downregulation (Lau & Leung 2012). This effect was dependent on mTOR activation, as the PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin both abrogated the IGF1-dependent downregulation of E-cadherin in these cells. This effect is likely modulated at the level of transcription, as IGF1 stimulated the expression of Snail and Slug, both transcriptional suppressors of E-cadherin, in this study. Another study corroborated these results, as IGF1 stimulation of nasopharyngeal carcinoma cells induced E-cadherin downregulation and other hallmarks of the epithelial–mesenchymal transition or transition to an invasive phenotype (Wang et al. 2016). Thus, IGF1R-mediated regulation of E-cadherin is context-dependent and complex, as IGF1R association augments E-cadherin-mediated cell–cell adhesion, but IGF1R stimulation promotes E-cadherin downregulation.
E-cadherin is also implicated in cancer invasion and migration via its interaction with the IGF axis. In another study, MDA-MB-435 cells overexpressing E-cadherin were treated with either IGF1 or insulin, which increased invasion above baseline; however, invasion of the cells overexpressing E-cadherin was notably less invasive than the empty-vector control cells, even when stimulated with IGF1 or insulin (de-Freitas-Junior et al. 2013). It is unclear from this study if E-cadherin overexpression reduces the effect of IGF1 on invasion. A recent study found that the loss of E-cadherin enhances IGF1-mediated invasion and migration in invasive lobular breast carcinoma (Elangovan et al. 2022), indicating that E-cadherin suppresses IGF1R signaling. As described in this study, the loss of E-cadherin enhanced IGF1 binding to its cognate receptor, conferring a more aggressive phenotype. This is fascinating, as we have already covered a study indicating that IGF1R complexing with E-cadherin promotes cell–cell adhesion (Mauro et al. 2001). It appears that the physical interaction between IGF1R and E-cadherin favors E-cadherin function to the detriment of IGF1R function. A schematic of this interaction, among others we have reviewed, is illustrated in Fig. 2.
Summary of known interactions between adhesion molecules, IGF1R and IRS proteins. (A) E-cadherin, αv integrin and IGF1R form a ternary complex that promotes cell–cell adhesion (Canonici et al. 2008). (B) αvβ3 integrin binds directly to IGF1 and permits signaling through IGF1R (Saegusa et al. 2009). (C) IGF1R and E-cadherin complex and synergistically promote cell–cell adhesion (Mauro et al. 2001). (D) Insulin stimulation promotes IRS association with αvβ3 integrin in Rat-1 fibroblasts expressing human insulin receptor (IR) (Vuori & Ruoslahti 1994).
Citation: Endocrine-Related Cancer 30, 10; 10.1530/ERC-23-0031
P-cadherin has a completely different role from E-cadherin in the context of IGF1R signaling. One study found that in malignant oral keratinocytes, P-cadherin enhanced IGF1R signaling (Lysne et al. 2014). In this study, overexpression of P-cadherin in oral squamous carcinoma increased IGF1R protein levels and, strikingly, amplified both the magnitude and duration of IGF1-induced MAPK phosphorylation. Indeed, this crosstalk appears to be tumor-promoting in other cancers as well, as another study found that P-cadherin–IGF1R crosstalk mediates the pro-metastatic effects of GnRH in ovarian cancer (Cheung et al. 2011). Also in ovarian carcinoma, disruption of P-cadherin-mediated cell adhesion decreased cell survival and invasiveness (Usui et al. 2014); however, it is unclear if IGF1R is involved in this process.
In our recent studies, we investigated cadherin expression in a mouse mammary tumor model of IGF1R-deficient, Wnt1-dependent basal breast cancer and found the percentage of basal epithelial cells co-expressing E-cadherin and P-cadherin was enhanced compared to control Wnt1 tumors (Obr et al. 2022). The IGF1R-deficient tumors were also characterized by reduced E-cadherin protein, again highlighting an important crosstalk between IGF1R and cadherins that has yet to be completely delineated. In breast cancer patients, E-cadherin mRNA expression similarly correlates positively with IGF1R expression, whereas P-cadherin expression is negatively correlated with IGF1R expression (Fig. 3) (Obr et al. 2022). We previously showed that low IGF1R expression is associated with worse breast cancer patient outcomes (Obr et al. 2018), and taken together, these data indicate that the most aggressive breast cancers have an IGF1Rlow, E-cadherinlow, and P-cadherinhigh phenotype. This finding also suggests that despite having low IGF1R expression levels, these cancers may still exhibit heightened IGF1R signaling via loss of E-cadherin and amplification by P-cadherin expression. Integrins may be involved in promoting IGF1R signaling in these cancers, but more work is needed to confirm this. It is also unclear if low IGF1R protein confers a selective advantage to these cancers through altered adhesion or increased motility.
In human breast tumors, E-cadherin mRNA expression is positively correlated with IGF1R expression, whereas P-cadherin expression is negatively correlated with IGF1R expression. Data were mined and analyzed from the METABRIC dataset. Adapted from Figure 7e, Obr…Wood Front Oncol. 12, 2022 (Obr et al. 2022). Link to the license: https://creativecommons.org/licenses/by/4.0/
Citation: Endocrine-Related Cancer 30, 10; 10.1530/ERC-23-0031
Elucidating the mechanisms by which IGF1R modulates cancer cell interactions with other cancer cells and the ECM is not enough to understand IGF1R function in tumor physiology. We will now focus on IGF1R as a growth factor receptor in other tumor-associated cell types to infer how IGF1R inhibitors may affect tumor-promoting inflammation.
IGF1R in the tumor microenvironment
Cancer-associated fibroblasts (CAFs)
CAFs play a complex role in modulating cancer progression, and their effects depend on CAF subtype and cancer stage. It is hypothesized that CAFs are tumor-suppressive in the early stages of a tumor and tumor-promoting in the later stages (Ping et al. 2021). As outlined in the review from Ping et al., CAFs contain a broad variety of potential progenitor cells that give rise to either inflammatory or myofibroblast subtypes. IGF1R function in CAFs affects both metastasis and therapy resistance. In one study, CAFs exposed to radiation therapy upregulated paracrine IGF1 secretion (Tommelein et al. 2018), likely as a pro-survival mechanism. In this study, the addition of the IGF1R inhibitor teprotumumab in combination with radiation therapy completely abrogated liver metastasis in a cohort of 11 xenograft mice of colorectal adenocarcinoma, whereas 5 out of 11 mice in the radiation-only cohort had metastases. These findings reiterate the potent pro-survival effects of IGF signaling and highlight the notion that these effects are not limited to tumor cells. These data make a compelling case for the use of IGF1R inhibitors in late-stage cancer, because as mentioned previously, CAFs at this stage may primarily be tumor promoting. Are late-stage cancers better candidates for IGF1R inhibitors, and are these drugs equally potent against the CAF subtypes? There is a critical need to investigate these questions if IGF1R inhibitors are to be pursued further.
CAFs may also promote cancer through the secretion of IGF2, a ligand that, like IGF1, activates IGF1R (LeRoith & Helman 2004). A recent study found that compared to normal fibroblasts, CAFs secrete more IGF2 in colorectal carcinoma patients (Zhang et al. 2022). In this study, stimulation of colorectal carcinoma cells with a CAF-conditioned medium enhanced cell proliferation, migration, and invasion. SiRNA-induced IGF2 knockdown in CAFs was sufficient to block the effects of the conditioned medium, indicating that CAF-derived IGF2 promotes a malignant cancer phenotype. Moreover, in breast cancer, CAF-derived IGF2 is an indicator of malignant phenotypes, whereas CAF expression of IGF1 is common in benign tumors (Cullen et al. 1991). These results convey an entirely cancer-promoting function of CAF-derived IGF2 and a potential protective effect of CAF IGF1 expression. However, the TME is a diverse environment, and there are many other cell types that are affected by the IGFs.
Macrophages
Tumor-associated macrophages (TAMs) are an interesting component of the TME due to having both tumor-promoting and tumor-suppressing effects (Noy & Pollard 2014) similar to IGF1R. One study found that IGF2 stimulation of maturing macrophages promotes an anti-inflammatory phenotype (Du et al. 2019). In this study, IGF2 administration inhibited IL-1β expression and promoted PD-L1 expression in maturing, but not adult, bone marrow-derived macrophages. This is consistent with an anti-inflammatory and pro-tumorigenic M2 phenotype (Pan et al. 2020). Although it is unclear if this phenomenon extends to TAMs, these findings could have important ramifications in tumor biology. As we have discussed, CAFs are a prominent source of IGF2, suggesting that CAFs promote macrophage differentiation into a tumor-promoting phenotype. In another study, IGF1 stimulation of macrophages primed them for enhanced TNFα secretion upon LPS exposure, indicating that IGF1 promotes an inflammatory, tumor-killing macrophage phenotype in contrast to IGF2 (Bekkering et al. 2018). Since both ligands signal through IGF1R yet have conflicting effects in this context, IGF1R inhibitors likely promote both tumor-promoting and tumor-suppressing macrophage functions with an unclear net effect. More research is needed to delineate the variable effects of IGF1 and IGF2 stimulation on macrophage phenotype, but the data we have covered unveil a complex system with tumor-suppressive characteristics.
Lymphocytes
Lymphocytes include a variety of cell subtypes, such as effector T cells, regulatory T cells, and B cells, each with a unique role in cancer progression (Lei et al. 2020). In the review from Lei and colleagues, effector T cells (CD4+ and cytotoxic CD8+ cells) are described as firmly antitumor, whereas regulatory T cells are tumor-promoting and B-cell functions remain controversial. In one study, a subset of B cells dubbed ‘regulatory’ B cells enhanced breast cancer metastasis through enhancement of the regulatory T-cell population (Olkhanud et al. 2011). In this study, the depletion of CD25+B220+ B cells diminished lung metastasis in a mouse model of mammary adenocarcinoma, highlighting a cancer-promoting function of B cells. Indeed, B cells often comprise a large portion of infiltrating lymphocytes in a variety of cancers, including breast, ovarian, and prostate; however, across multiple cancer types and studies, a high B-cell signature often correlates with positive outcomes (Flynn et al. 2017). A recent systematic review supports this finding in breast cancer as well (Lam & Verrill 2023). However, due to the controversial nature of these findings, we will not make conclusive statements about the effects of B-cell IGF1R function on cancer progression.
Both IGF1R and INSR are expressed in B and T lymphocytes, and in a mouse model of IGF1R deletion (IGF1R−/−) in B and T cells: neither B- nor T-cell differentiation was hindered (Baudler et al. 2005). This mouse model was generated by transplanting fetal liver cells from nonviable IGF1R−/− mouse embryos into RAG2-deficient mice. Interestingly, in the B- and T-cell IGF1R−/− models, B-cell response was reduced. Immunization of IGF1R−/− mice with T-cell-independent antigen resulted in a reduced concentration of various antigen-specific immunoglobulins compared to control, indicating that B-cell response is dependent on functional B-cell IGF1R. The authors went on to demonstrate that IGF1 enhances immunoglobulin production without promoting cell proliferation in vitro. These are important results to consider in the context of introducing systemic IGF1R inhibitors. Would inhibition of IGF1R on B cells diminish the B-cell-dependent immune response in the tumor?
Turning our attention to T cells, one interesting research focus is the interplay between the IGF axis and tumor immune evasion. Antisense suppression of IGF1 expression in rat glioma cells permitted CD8+ T-cell killing and completely abrogated tumor formation in a syngeneic model of rat glioblastoma (Trojan et al. 1993), indicating a potential immunosuppressive effect of IGF1 secretion. In a more recent study, IGF1 stimulation of syngeneic mouse lung tumors mediated resistance to PD-1 inhibitors (Ajona et al. 2020). From this same study, samples from patients with non-small-cell lung carcinoma resistant to PD-1/PD-L1 inhibition had significantly higher IGF1 (in plasma) and IGF1R (in tissue) protein levels than samples from patients with a durable clinical benefit from PD-1 immunotherapy. Taken together, these findings indicate that IGF1 likely promotes tumor immune evasion, although whether this mechanism is present in other cancers remains unclear. Additionally, this reveals little about the role of T-cell IGF1R function in cancer progression. Research on IGF1R function in solid tumor-infiltrating T cells is lacking; however, data exist on IGF1R in T-cell malignancies. For instance, in nucleophosmin-anaplastic lymphoma kinase-positive T-cell lymphoma, IGF1R expression is elevated compared to nonmalignant T cells (Vishwamitra et al. 2015), likely conferring enhanced cell survival. Even in non-transformed T lymphocytes, IGF1R plays a crucial role in cell survival (Walsh et al. 2002). Thus, T-cell IGF1R activation could have a major impact on tumor progression that might depend on relative effector vs regulatory T-cell levels. In addition, pharmacologic inhibition of IGF1R could kill tumor-suppressing T cells which may confer a malignant TME.
Endothelial cells
As mentioned previously, IGF1R promotes vascularization and thus plays a critical function in endothelial cells. For example, IGF2 stimulation was necessary for the initiation of angiogenesis by tip cells in a culture of human primary endothelial cells (Dallinga et al. 2018). In this study, IGF1R and IGF2 knockdown each decreased the ratio of CD34+ tip cells in HUVEC human endothelial cell cultures. Both IGF1R and IGF2 knockdown reduced angiogenic sprouting, and IGF2 stimulation of endothelial cell cultures stimulated sprouting, indicating a potent angiogenic effect. This effect is not limited to IGF2; however, Tie2-expressing monocyte-derived IGF1 was also found to promote angiogenesis and metastasis in a mouse xenograft model of human ovarian carcinoma (Wang et al. 2017). Wang and colleagues demonstrated that overexpression of Tie2 in monocytes led to enhanced angiogenesis and metastasis in their ovarian carcinoma model, but administration of an IGF1-blocking antibody reduced tumor bulk and the rate of metastasis. While the IGF axis plays a largely pro-metastatic role in endothelial cell function, we conclude this section on the TME by reiterating that IGF1R function in stromal and immune cells does not neatly fall into the tumor-promoting or tumor-suppressing category.
IGF1R inhibitors in the clinic
In our previous 2022 review, we briefly mention that IGF1R inhibitors in clinical trials failed either due to systemic toxicity (often in the case of the TK inhibitors of IGF1R and INSR) or futility. Here, we will delve deeper into the available data on IGF1R inhibitor performance in the clinic with an additional focus on breast cancer trials. We will then attempt to link these findings to the breadth of information we have summarized thus far on IGF1R function in the different components of solid tumors. In Table 1, we summarize the results of each trial reviewed.
Summary of reviewed IGF1R inhibitor cancer clinical trials.
| Drug | Disease | Phase | Status | Summary |
|---|---|---|---|---|
| Ganitumab (combination) | Metastatic Ewing sarcoma (and related cancers) | 3 | Complete | No improvement in event-free survival |
| Ganitumab (with gemcitabine) | Metastatic adenocarcinoma of the pancreas | 3 | Terminated | Futility, no safety concern |
| Ganitumab (alone) | Advanced carcinoid and pancreatic neuroendocrine tumors | 2 | Complete | 0% response rate, 15% of patients with hyperglycemia |
| Ganitumab (with metformin and standard neoadjuvant breast cancer therapy) | Stage 2–3 breast cancer | 2 | Active, arm is closed | Nonsignificant improvement in pathologic complete response; unacceptable hyperglycemia in 8.5% of patients |
| Ganitumab (with dasatinib) | Rhabdomyosarcoma | 1 | Terminated | Toxicity due to dasatinib, no hyperglycemia |
| Figitumumab (with erlotinib) | Refractory non-small cell lung cancer | 3 | Terminated | Futility, with noted clinical benefit in some patients |
| Figitumumab (with exemestane) | Advanced hormone receptor-positive breast cancer | 2 | Terminated | Slight but statistically insignificant improvement in median progression-free survival of patients with low hemoglobin A1c |
| Linsitinib (alone) | Locally advanced or metastatic adrenocortical carcinoma | 3 | Complete | No improvement in overall patient survival |
| Linsitinib (combination) | Hormone-sensitive metastatic breast cancer | 2 | Terminated | Toxicity; inefficacy |
| BMS-754807 (alone or with letrozole) | Hormone receptor-positive breast cancer resistant to non-steroidal aromatase inhibitors | 2 | Terminated | No data on primary outcome of progression-free survival rate; high frequency of low-grade GI distress and glucose intolerance |
| Cixutumumab/A12 (with cisplatin and etoposide) | Extensive stage and recurrent small-cell-lung carcinoma | 2 | Complete | No improvement in progression-free survival; increased serious and nonserious hyperglycemia |
| Cixutumumab/A12 (with mitotane) | Stages iii and iv and recurrent adrenocortical carcinoma | 2 | Terminated | Futility |
| Cixutumumab/A12 (with capecitabine and lapatinib) | Advanced her2+ breast cancer | 2 | Complete | No clinical benefit |
| Cixutumumab/A12 (with temsirolimus) | Locally recurrent or metastatic breast cancer | 2 | Complete | 0% response rate; frequent toxicity |
| Cixutumumab/A12 (with or without antiestrogen therapy) | Progressive breast cancer on antiestrogen therapy | 2 | Complete | Inefficacy, acceptable safety |
| Dalotuzumab (with ridaforolimus and exemestane) | Advanced breast cancer | 2 | Complete | No improvement in progression-free survival |
Ganitumab
Ganitumab is an IGF1R-blocking antibody that is one of the few IGF1R inhibitors to reach phase III clinical trials in cancer. Currently, a study on ganitumab as an adjunct therapy in the treatment of Ewing sarcoma (and other similar, aggressive cancers) has recently concluded with a negative result (DuBois et al. 2023). Unfortunately, patients in the ganitumab arm of this study have a greater rate of serious adverse events, including disorders of the gastrointestinal, respiratory, nervous, and other systems, than the standard therapy arm. This is especially disappointing since ganitumab was sufficient to induce a complete response in one Ewing sarcoma patient from a previous trial (Tolcher et al. 2009). Another phase III trial assessed ganitumab combination therapy with gemcitabine in the treatment of adenocarcinoma of the pancreas, although this study was ultimately terminated due to futility (https://clinicaltrials.gov/study/NCT01231347).
Ganitumab was also tested in combination with dasatinib, a Src family kinase inhibitor, for the treatment of rhabdomyosarcoma but was discontinued shortly after a phase II study began patient recruitment (https://clinicaltrials.gov/study/NCT03041701). In the phase I trial, at dose level 1 during dose escalation, only one patient of seven experienced unacceptable toxicity related to ganitumab; however, four of these patients experienced unacceptable toxicity related to dasatinib. At dose level two, in which dasatinib administration frequency was increased but ganitumab dosing was unchanged, patient toxicity remained unacceptable. No instances of hyperglycemia, a common adverse effect of TK inhibitors of IGF1R due to off-target inhibition of the INSR (de Groot et al. 2020), were reported.
In another phase II study assessing ganitumab, under the name AMG 479 as a treatment against neuroendocrine, carcinoid, and pancreatic neuroendocrine tumors, ganitumab elicited an underwhelming 0% objective response rate while causing toxicity in nearly a third of the patients analyzed (https://clinicaltrials.gov/study/NCT01024387). Of the serious adverse events recorded, hyperglycemia was the most common adverse effect occurring in 15% of patients. Indeed, hyperglycemia is a common adverse effect of both IGF1R and mTOR inhibitors (Goldman et al. 2016). Thus, ganitumab makes a poor argument for pursuing IGF1R inhibitors in endocrine-related cancers due to the lack of efficacy and prominent toxicity.
Figitumumab
Figitumumab, another IGF1R-blocking monoclonal antibody, was combined with erlotinib, a TK inhibitor of EGFR, to treat refractory non-SCLC in a separate phase III trial, which was ultimately terminated due to lack of efficacy compared to erlotinib alone (https://clinicaltrials.gov/study/NCT00673049). Interestingly, despite the termination of the study, some patients continued to receive treatment due to observed clinical benefits and ethical imperative.
Linsitinib
Despite the completion of a phase III trial for the treatment of adrenocortical carcinoma, linsitinib, a TK inhibitor of IGF1R and INSR, did not improve the primary endpoint of overall patient survival over placebo (Fassnacht et al. 2015). However, it should be noted that adrenocortical carcinoma is a particularly aggressive and difficult cancer to treat, and treatment options for metastatic cases are palliative (Fareau et al. 2008, Hallanger-Johnson 2020). The most common adverse events due to linsitinib in this trial were fatigue (most common), nausea and hyperglycemia. Taken together with the results of the other phase III tested IGF1R inhibitors, these drugs consistently underperformed in human studies and rarely produced clinical benefit.
Cixutumumab/A12
Like ganitumab, cixutumumab is a monoclonal blocking antibody against IGF1R. In a phase II study of cixutumumab combination therapy with cisplatin and etoposide, cixutumumab did not improve the primary outcome measure, progression-free survival, above cisplatin and etoposide therapy alone in the treatment of recurrent and extensive stage small-cell lung cancer (SCLC) (https://clinicaltrials.gov/study/NCT00887159). Despite these lackluster results, a prior study found that IGF1R inhibition sensitized SCLC cells to etoposide and carboplatin (Warshamana-Greene et al. 2005), both current mainstay treatments for SCLC (Kashima & Okuma 2022). These contradictory results highlight an important theme: despite promising results in pre-clinical studies, IGF1R inhibitors time and again falter when introduced in human patients. Looking deeper into this phase II study, cixutumumab conferred no increase in response rate over the standard therapy. Interestingly, there was a nonsignificant increase in overall survival in the cixutumumab arm of the study; however, this was a secondary outcome measure that did not justify continuation into phase III trials. Notably, the rate of nonserious hyperglycemia was more than quintupled in the cixutumumab arm over standard therapy, reiterating that hyperglycemia is a major concern when treating patients with IGF1R inhibitors. The rate of serious hyperglycemia more than tripled in the cixutumumab arm over standard therapy; however, the amount of increase was rather low (1.89–7.69% of patients).
In another phase II trial, cixutumumab was administered in conjunction with the adrenal cortex inhibitor mitotane for the treatment of late-stage and recurrent adrenocortical carcinoma (https://clinicaltrials.gov/study/NCT00778817). This trial was ultimately terminated due to futility, as only 16.7% of the patients saw progression-free survival with the cixutumumab and mitotane combination therapy, again showcasing a disappointing performance by an IGF1R inhibitor in the clinic.
IGF1R inhibitor trials in breast cancer
Unfortunately, no IGF1R inhibitor used to date has been promising enough to reach phase III trials for the treatment of breast cancer, so we will focus on phase II studies. Like the inhibitors we have reviewed thus far, IGF1R inhibitors in breast cancer trials produced unacceptable toxicities and lacked clinical benefit. In a study assessing linsitinib combination therapy for the treatment of hormone-sensitive metastatic breast cancer, both toxicity and inefficacy resulted in study termination (https://clinicaltrials.gov/study/NCT01205685). All patients experienced nonserious adverse events, and 5/11 patients experienced nonserious hyperglycemia, although the contributions of erlotinib (epidermal growth factor receptor inhibitor), letrozole (aromatase inhibitor), and goserelin (gonadotropin-releasing hormone agonist) vs linsitinib to patient toxicity cannot be determined from the available data.
BMS-754807 (BMS), a nonselective IGF1R and INSR small molecule TK inhibitor, was tested in a phase II study assessing BMS efficacy in hormone receptor-positive breast cancer. The primary outcome measure of progression-free survival was not collected due to early termination of the study (https://clinicaltrials.gov/study/NCT01225172). Despite a relatively low rate (one in seven) of serious adverse events in patients treated with BMS alone, patients did experience a high rate of low-grade gastrointestinal distress and glucose intolerance. Interestingly, the combination therapy of BMS with letrozole, an aromatase inhibitor, appeared to elicit an increased rate of hyperglycemia in patients compared to BMS alone; however, more patients were treated with the combination therapy, so we take caution in drawing conclusions from these findings.
Cixutumumab was assessed in several phase II breast cancer trials that were completed. In combination with capecitabine, a cytotoxic chemotherapeutic agent, and lapatinib, a TK inhibitor of Her1 and Her2, for the treatment of advanced Her2+ breast cancer, cixutumumab did not improve progression-free or overall survival and severe adverse reactions and quality of life were unchanged (Haddad et al. 2021). When combined with the mTOR inhibitor, temsirolimus, for the treatment of locally recurrent or metastatic breast cancer, cixutumumab produced a 0% response rate and caused grade 3 or higher toxicity in 8/22 patients (https://clinicaltrials.gov/study/NCT00699491). In this phase II study, all patients experienced nonserious adverse events, most commonly fatigue (86.36% of patients), hyperglycemia (72.73%), and decreased hemoglobin (72.73%). Cixutumumab was also tested in patients with progressive breast cancer despite antiestrogen therapy (Gradishar et al. 2016). Despite an acceptable toxicity profile, the primary endpoint of progression-free survival was not improved. Notably, this study found that patients with lower mRNA expression of INSR had a better prognosis regardless of the treatment arm.
For the treatment of advanced hormone receptor-positive breast cancer, figitumumab was assessed in combination with the aromatase inhibitor exemestane in a phase II study, but the combination did not produce a statistically significant improvement in median progression-free survival vs exemestane alone (https://clinicaltrials.gov/study/NCT00372996). Interestingly, in patients with low hemoglobin A1c (less than 5.7% at baseline), figitumumab produced a modest yet statistically insignificant improvement in median progression-free survival. This is an intriguing observation, suggesting that figitumumab is more efficacious in patients that do not suffer from metabolic syndrome. It is important to note that this study was prematurely terminated for reasons unrelated to drug efficacy, so any potential observed benefit of figitumumab might have dissipated if the study was allowed to continue to completion.
Ganitumab was tested in combination with metformin and standard chemotherapy for the treatment of stage 2 and 3 breast cancer, and despite an increase in pathologic complete response in patients receiving the ganitumab arm, this combination did not reach the set threshold for significance (Yee et al. 2021). It should be noted that despite the addition of metformin, hyperglycemia remained a significant concern in patients treated with the ganitumab arm.
Dalotuzumab, another monoclonal antibody targeting IGF1R, when added to a regimen of the mTOR inhibitor ridaforolimus and exemestane, did not improve progression-free survival in patients with advanced breast cancer (Rugo et al. 2017). Both treatment arms caused a similar rate of hyperglycemia, but the control arm induced a higher incidence of stomatitis and pneumonitis – likely due to the higher dose of ridaforolimus in the control arm.
Summary
While the list of IGF1R inhibitors and their clinical trials we present here is not all-inclusive, it exposes a clear trend of failures in the treatment of various solid tumors. Frequently, these trials were terminated due to toxicity, and hyperglycemia was a common concern. The drugs that did make it to phase III trials ultimately did not confer clinical benefit. Thus, IGF1R inhibitors have failed on two fronts: improving the efficacy of current treatment regimens or maintaining efficacy while reducing toxicity. However, it is important to note that in some trials, a subset of patients did see a clinical benefit from IGF1R inhibitors.
Conclusion
From the work we have covered in this review, it is apparent that IGF1R plays a complex role across all tumor-associated cell types and is much more than a pro-survival, pro-invasive, pro-proliferative receptor. To make connections between the functions of IGF1R and relevant hallmarks of cancer, we will focus on the two most relevant hallmarks: sustained proliferative signaling and tumor-promoting inflammation (Hanahan & Weinberg 2011).
The clinical data make it evident that inhibition of IGF1R is a good therapeutic strategy in certain, currently unclear, situations. As previously mentioned, patients with non-SCLC continued to receive figitumumab in combination with erlotinib due to clinical benefit (https://clinicaltrials.gov/study/NCT00673049). In breast cancer patients, ganitumab increased pathologic complete response, albeit non-significantly (Yee et al. 2021). Activation of the insulin/IGF axis does appear to play a significant role in cancer prognosis, as evidenced by the finding that high INSR expression correlates with worse breast cancer prognosis (Gradishar et al. 2016). A lack of patient stratification has been identified as a main cause of IGF1R inhibitor failures, thus we predict that stratifying patients by IGF axis activation and inhibiting IGF1R in patients with high proliferative signaling through IGF1R will improve patient outcomes.
It is clear from the literature that IGF1R association with adhesion receptors affects IGF downstream signaling. Integrin binding in an IGF1–IGF1R–integrin ternary complex, as well as elevated P-cadherin expression, promote downstream signaling (Saegusa et al. 2009, Lysne et al. 2014), whereas E-cadherin expression dampens IGF1R signaling (Elangovan et al. 2022) (Fig. 1). Thus, we anticipate that tumor expression levels of E-cadherin, P-cadherin, and certain integrins could be used as a marker to indicate good patient candidates for treatment with IGF1R inhibitors. Specifically, low E-cadherin expression and high integrin and P-cadherin expression in tumor epithelial cells likely translates to enhanced IGF signaling and susceptibility to IGF1R inhibitors.
IGF1R likely affects tumor-promoting inflammation through multiple mechanisms as summarized in Fig. 4. The IGF axis is active in each tumor-associated cell type, and pharmacologic inhibition of IGF1R likely has unintended consequences by affecting the immune and stromal cell function. The IGF axis appears to strongly influence macrophage function, although this phenomenon appears to be dependent on IGF1 vs IGF2 stimulation (Bekkering et al. 2018, Du et al. 2019), and it is unclear if these mechanisms are active in TAMs in vivo. Inhibiting IGF2 stimulation of macrophages would likely yield clinical benefit; however, IGF1 stimulation of macrophages promotes a pro-inflammatory, tumor-killing phenotype. IGF1R inhibitors likely affect both processes, and the dominant effect of this inhibition may depend on the IGF1 vs IGF2 profile of the tumor. Additionally, CAF IGF2 expression is pro-tumorigenic (Cullen et al. 1991). Taken together, these findings suggest that IGF2 and not IGF1 promotes a pro-tumorigenic TME. As such, selective inhibition of IGF2 may confer clinical benefits.
Schematic of IGF-dependent effects in non-epithelial tumor-associated cell types.
Citation: Endocrine-Related Cancer 30, 10; 10.1530/ERC-23-0031
Finally, screening patients for metabolic syndrome and omitting them from IGF1R inhibitor treatment may be another effective strategy for stratification. As discussed, figitumumab may be more efficacious in patients without metabolic syndrome, as evidenced by a modest, albeit statistically insignificant, improvement in progression-free survival of patients with advanced hormone receptor-positive breast cancer and low hemoglobin A1c (https://clinicaltrials.gov/study/NCT00372996). It is not surprising that patients without metabolic syndrome see greater benefit from IGF1R inhibitors since a major and recurring symptom of the IGF1R inhibitors is hyperglycemia. Likely, these drugs exacerbate metabolic adverse events in patients with metabolic syndrome, leading to worse toxicity.
TME modulation, adhesion receptor profile, and the toxicity induced by IGF1R inhibitors all likely contribute to inefficacy in the clinic. Thus, we conclude by emphasizing the importance of considering cancer cell interaction with and regulation of the TME in prospective studies involving IGF1R inhibitors and cancer therapeutic agents in general. Finally, we point to a developing and exciting field of study involving IGF1R in cellular adhesion dynamics. Much has been discovered, but considerably more work is needed to delineate the mechanisms by which IGF1R affects cancer aggression.
Declaration of interest
The authors declare no conflicts of interest.
Funding
We acknowledge our funding sources: National Cancer Institute R01 CA204312 and New Jersey Commission on Cancer Research (NJCCR) Bridge Grant COCR23RBG003 to TLW, and NJCCR Pre-doctoral Fellowship COCR23PRF013 to CAG.
Author contribution statement
CAG wrote the main text, compiled summaries of the clinical trial data into Table 1, and illustrated the Figs. 1, 3, and 4 using BioRender. TLW gave guidance on topics for review and discussion and reviewed and edited the main text.
Acknowledgements
We especially thank current and former members of the Wood Lab, including J J Bulatowicz, K R Maingrette, M L Mather, D K Kantak, and A E Obr, for their invaluable insight and discussions.
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