Anti-Insulin-Like Growth Factor Therapy in Breast Cancer

Home , Figitumumab, Ganitumab, Metastatic breast cancer, Somatomedin receptor

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Journal of Molecular D Yee IGF1R inhibition in breast cancer 61:1 T61–T68 Endocrinology THEMATIC REVIEW

Douglas Yee

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA

Correspondence should be addressed to D Yee: [email protected]

This paper forms part of a special section on 40 Years of IGF1. The guest editors for this section were Derek LeRoith and Emily Gallagher.

Abstract

Early preclinical and population data suggested a role for the type I insulin-like growth Key Words factor receptor (IGF1R) in the regulation of breast cancer growth and survival. To target ff breast cancer this pathway, multiple monoclonal antibodies and tyrosine kinase inhibitors were ff type I insulin-like growth developed and tested in clinical trials. While some of the early clinical trials suggested a factor receptor benefit for these drugs, none of the attempts showed improved outcomes when compared ff insulin receptor to conventional therapy. This failure of the IGF1R inhibitors was pronounced in breast ff estrogen receptor cancer; multiple trials testing IGF1R inhibition in estrogen receptor-positive breast cancer were conducted, none showed benefit. This review will evaluate the rationale for IGF1R Journal of Molecular inhibition, discuss results of the clinical trials and suggest a path forward. Endocrinology (2018) 61, T61–T68

Introduction

Decreasing mortality rates in breast cancer have been even for women with metastatic disease, life expectancy observed since the late 1980s. This decline has been is increasing (Mariotto et al. 2017) presumably due to the attributed to populationwide screening mammography development of many new systemic therapies. programs and the greater use of systemic adjuvant therapy Because of this, there has been greater emphasis on (Berry et al. 2005). These clinical results underlie the fact development of new strategies to target malignant cells. that mortality in breast cancer is driven by metastatic In this regard, breast cancer has been at the forefront spread of the primary tumor to distant organs. Screening of showing that manipulation of endocrine pathways mammography detects disease early before metastatic results in clinical improvements. In 1890, Beatson spread can occur, but it is controversial as to whether this removed young woman’s ovaries resulting in regression early detection truly results in decreased breast cancer death of her locally advanced breast cancer (Beatson 1896). The (Mandelblatt et al. 2009, Biller-Andorno & Juni 2014). discovery of the molecular structure of estrogen receptor-α Systemic therapy in early-stage operable breast cancer (ER), the identification of molecules disrupting estrogen either eliminates or modulates the behavior of micro- binding to ER, the inhibition of peripheral conversion of metastatic distant metastases that occurred prior to the precursors into estradiol by aromatase and the disruption clinical detection of the primary breast cancer. In contrast of signaling pathways influencing ER have all resulted in to mammography, it is clear greater use of adjuvant therapy new drugs approved to treat breast cancer. accounts for reduced deaths in women with operable breast There was great hope disruption of the type I insulin- cancer (Palmieri & Jones 2012, Peto et al. 2012). Further, like growth factor receptor (IGF1R) could serve as an

-17-0261 Journal of Molecular D Yee IGF1R inhibition in breast cancer 61:1 T62 Endocrinology effective therapy for breast cancer. Similar to ER, IGF1R the liver. Originally called somatomedin C because of is important in normal growth and development, IGF1R its role in somatic growth, IGF1 interacts with receptors initiates signaling events important for cancer cell growth in essentially all normal tissues (Binoux et al. 1986). In and survival, is frequently expressed in breast cancer cells mice, IGF2 is a fetal somatomedin. After birth, rodents and has a targetable biochemical function. Further, the experience a decline in serum IGF2 levels. In humans, first demonstration inhibition of IGF1R could be effective IGF2 levels persist during life. However, in adult humans, in breast cancer preclinical models (Arteaga et al. 1989), a clear physiologic role for IGF2 has still not yet been occurred at about the same time the human epidermal identified. In serum and extracellular fluids, IGFs are found growth factor receptor-2 (HER2) targeting monoclonal bound to high-affinity IGF-binding proteins (IGFBPs). Six antibodies were being evaluated in clinical trials (Pegram well-characterized binding proteins have been identified, et al. 1998). Thus, it made eminent sense to develop and each has the ability to affect release of ligand to the similar drugs in cancer designed to target another growth receptor (Perks & Holly 2008). factor receptor. There have been several excellent reviews outlining Ligand suppression the preclinical and population science rationale for targeting this receptor (Pollak 2008, 2012). Briefly, the IGF Before drugs were developed to suppress estradiol levels, signaling pathway regulates several key aspects of cancer there were surgical methods to suppress ER-expressing hallmarks (Hanahan & Weinberg 2011). IGF1R stimulation breast cancers. Oophorectomy in premenopausal women results in proliferation, survival and metastasis. Further, was a commonly used strategy. In postmenopausal women, studies from population-based studies suggested IGF1 both adrenalectomy and hypophysectomy were performed. levels correlated with cancer risk (Chan et al. 1998). Since the pituitary is the source of GH, this surgical ablation Humans with low levels of serum IGF1, because of growth certainly resulted in lowered levels of IGF1. While clinical hormone receptor mutation, appear to be refractory to benefits of hypophysectomy were seen after adrenalectomy, cancer development (Guevara-Aguirre et al. 2011). Thus, this clinical benefit cannot be solely attributed to suppression targeting IGF1R function could serve to prevent and treat of serum IGF1, although it is possible, this could be the breast cancer. reason for the therapeutic benefits of hypophysectomy after all sources of estradiol were surgically removed (Pearson & Ray 1960, Fracchia et al. 1971). Strategies to block IGF1R Just as drugs were created to suppress pituitary The IGF1R is similar in structure to the insulin receptor. regulation of estradiol, pegvisomant was created to disrupt IGF1R is a single gene and once transcribed, the protein is GH production (Yin et al. 2007). Despite preclinical processed into two separate chains. The alpha subunit is evidence demonstrating efficacy in mouse models extracellular and ligand binding. It is covalently bonded (Divisova et al. 2006), this drug was never developed in to the beta subunit which contains a short extracellular breast cancer. Somatostatin analogs can also be used to domain, the transmembrane domain and an intracellular suppress GH expression, but first-generation analogs were tyrosine kinase domain. An alpha-beta subunit is bound not successful in combination with tamoxifen (Ingle et al. to a partner; thus, the functional receptor complex is a 1999, Pritchard et al. 2011). heterodimeric structure (Krywicki & Yee 1992). Because of Ligand neutralization is also a possible strategy this structure, the extracellular alpha subunits must bind to block receptor/ligand interactions. Two drugs have ligand for receptor activation. been described and tested in early-stage clinical trials The two high-affinity ligands for IGF1R are IGF1 and (Friedbichler et al. 2014, Haluska et al. 2014). Both IGF2. Both IGFs are similar in structure and sequence to are monoclonal antibodies with high affinity to both insulin. They all share a common structure composed of IGF1 and IGF2. Currently, xentuzumab is in trial in intra-chain disulfide cross-links. Insulin, but not IGF1 or combination with the CDK4/6 inhibitor abemaciclib in IGF2, has its internal domain (C-peptide) proteolytically endocrine-resistant breast cancer (NCT03099174). cleaved to form a two chain ligand (Leroith et al. 1993). IGF1 and -II are expressed by many tissues and can Tyrosine kinase inhibition activate IGF1R by endocrine, paracrine and autocrine pathways. In adults, post-pubertal expression of growth It is well established that the first step in IGF1R signaling hormone (GH) results in increased IGF1 production by is autophosphorylation. As in the development of

HER2-targeted therapies, tyrosine kinase inhibitors were This trial demonstrated no evidence of benefit for the also developed. However, the high homology between combination; if anything, the combination of ganitumab IGF1R and insulin receptor (INSR) have made it impossible with endocrine targeting suggested inferior outcomes. to make an IGF1R-specific inhibitor. While these kinase Overall survival was worse in the patients who received inhibitors had activity in early phase clinical trials, they ganitumab. The major toxicity of this combination was were not pursued because of toxicity (Yee 2015) and in the hyperglycemia, and this toxicity might explain the results. case of linsitnib, a lack of efficacy in a randomized phase A reason for these worse outcomes was suggested by 3 trial of adrenal cortical cancer was also a major reason Gradishar and coworkers (2016) when receptor levels were (Fassnacht et al. 2015). measured in the patient’s tumors. In this trial, the antibody cixutumumab was given with or without an aromatase inhibitor in patients who had already progressed through Monoclonal antibodies first-line endocrine therapy. A trial arm of cixutumumab In a pathway parallel to the development of anti-HER2 alone was also studied. Similar to the trial of ganitumab, therapies, multiple monoclonal antibodies were created cixutumumab offered no significant benefit when added to bind IGF1R. These drugs shared similar properties; to endocrine therapy or by itself. they were either fully human or humanized, they had A novel aspect of this trial included the evaluation little binding to the INSR, they resulted in receptor of tumor expression of IGF1R and INSR expression by downregulation and they disrupted the negative feedback RT-qPCR. These authors showed the level of INSR far pathway between GH, IGF1 and insulin. The development exceeded the level of IGF1R, the intended therapeutic of these drugs has been reviewed (Iams & Lovly 2015, target. Further, the two isoforms of INSR were measured. Ekyalongo & Yee 2017). The fetal isoform, INSR-A was expressed at higher levels than the adult isoform, INSR-B. This is a significant finding as INSR-A has been shown to have high affinity Early phase clinical trials for the ligand IGF2 (Sciacca et al. 1999). Tyrosine kinase inhibitors in breast cancer The downregulation of IGF1R was demonstrated in both preclinical and clinical data of endocrine-resistant The tyrosine kinase inhibitor linsitinib was evaluated in breast cancers. We showed cells selected for resistance phase I clinical trials in two different dosing schedules: to tamoxifen had little IGF1R (Fagan et al. 2012). Drury continuous and intermittent (Jones et al. 2015, Puzanov and coworkers demonstrated a loss of tumor IGF1R et al. 2015). Despite evidence of single agent activity in expression after patients progressed through tamoxifen these studies and preclinical evidence the IGF1R and INSR (Drury et al. 2011). pathways played a role in endocrine-resistant breast cancer Thus, it is not surprising any drug targeting the IGF1R (Fox et al. 2011); this drug was not further developed. receptor, expressed at very low levels in these endocrine- BMS-754807 has a similar mechanism of action, but the resistant breast cancers, had any possibility of working. drug sponsor discontinued a randomized phase II clinical Further, the elevation of serum insulin has been described trial comparing BMS-754807 alone or in combination as a ‘class effect’ of IGF1R monoclonal antibodies with the aromatase inhibitor letrozole (NCT01225172). (Haluska et al. 2007). This induction of hyperinsulinemia is thought to be secondary to the disruption of a negative feedback to the pituitary, which controls IGF1 levels Randomized clinical trials of IGF1R inhibitors in ER+ via GH. By blocking IGF1 sensing in the brain, GH breast cancer levels become elevated resulting in increased free fatty Given the preclinical evidence suggesting IGF1R signaling- acid output from the liver resulting in hyperglycemia enhanced ER function (Becker et al. 2011), many trials were and compensatory hyperinsulinemia (Yee 2015). This conducted in patients with ER+ breast cancer. Almost all hyperinsulinemia likely diminished any beneficial effect trials included women who had previously been treated of IGF1R inhibition. Indeed, Gradishar and coworkers with endocrine therapy; by definition, these tumors were suggested this as a possibility in their trial. As shown endocrine resistant. by Gradishar and coworkers, the tumors with the top Ganitumab in combination with the aromatase quartile of IR expression had the poorest progression- inhibitor exemestane or the selective estrogen receptor free survival (Gradishar et al. 2016). While this does not modulator fulvestrant (Robertson et al. 2013) was reported. negate the possibility that anti-IGF1R strategies have

http://jme.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/JME-17-0261 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 12:32:49AM via free access Journal of Molecular D Yee IGF1R inhibition in breast cancer 61:1 T64 Endocrinology some therapeutic value, it clearly suggests tumors with by 4 cycles (given every 2 or 3 weeks) of doxorubicin high IR levels do poorly, perhaps because of the increased and cyclophosphamide. There was no benefit for adding levels of serum insulin seen after administration of IGF1R ganitumab to conventional cytotoxic chemotherapy moAbs (Haluska et al. 2007). Certainly, in most clinical in this trial as pathologic complete response rates were trials, the reporting of grade 2 hyperglycemia by Common similar in the ganitumab-treated group compared to the Terminology Criteria for Adverse Events (fasting glucose control group (Yee et al. 2017). However, a preliminary greater than 160) is an underestimation of the stability of analysis of the data suggests metformin did not maintain glucose homeostasis. glucose homeostasis. Hemoglobin A1C increased after One trial has been reported to overcome the ganitumab therapy. Thus, as seen with therapies in ER+ issues noted earlier. The IGF1R monoclonal antibody patients, elevation of insulin levels might be an alternative figitumumab was tested in a randomized phase II trial in pathway to activate similar signaling pathways to those previously untreated patients with metastatic ER+ breast activated by the IGFs. cancer. These patients received exemestane alone or exemestane with figitumumab. This patient population Is there a future for IGF1R inhibitors as might have had higher levels of IGF1R as they had not yet cancer therapies? been exposed to endocrine therapy. While these data were only presented in abstract form, there were potentially The disappointing results of the first generation of IGF1R important observations made in this trial (Ryan et al. inhibitors in breast cancer, as well as in other cancers, have 2011). First, in the overall population, there was no decreased interest in the further commercial development benefit to adding figitumumab to the aromatase inhibitor of this class of receptor targeting drugs. However, there exemestane. Second, a subpopulation of women with were also important lessons learned from these first a hemoglobin A1C less than 5.7% suggested potential clinical trials that might be used for further development benefit for adding figitumumab. While this subgroup of of inhibitors of this pathway. There are several ways in patients was too small to draw firm statistical conclusions which the next generation of clinical trials targeting IGF (hazard ratio = 0.60, CI: 0.32–1.1), the data suggested signaling could be improved. women with normal glucose homeostasis prior to drug therapy had benefit from the combination. Unfortunately, Predictive biomarkers for IGF1R-driven tumors this drug is no longer being pursued. should be used for future clinical trials

The biology of IGF signaling is complex; it is clear some of Early phase clinical trials of IGF1R inhibitors with the functions of IGF1R activation are not easily observable chemotherapy in breast cancer in clinical trials. It is well-recognized IGF1R activation Compared to trials in endocrine therapy of breast cancer, may enhance cell motility and metastasis, independent there has been little evaluation of IGF1R inhibitors with of enhancement of proliferation (Sachdev et al. 2004). cytotoxic chemotherapy. To date, only the I-SPY 2 trial has The two adaptor proteins, INSR substrate (IRS) -1 and reported such a combination. The I-SPY 2 trial evaluates -2 function differently in breast cancer cells (Nagle et al. the combination of paclitaxel with investigational agents 2004, Dearth et al. 2006, Ma et al. 2006, Mardilovich in the neoadjuvant therapy of breast cancer (Yee et al. & Shaw 2009). It is also evident that mRNA expression 2012). Patients enrolled on this trial have high-risk tumors profiling could be used to identify IGF-driven tumors as measured by tumor size (>2.5 cm). If ER+, then they also (Creighton et al. 2008, Becker et al. 2016). must have high genomic risk scores as determined by the Serum levels of IGF ligands were also associated with 70-gene assay (Cardoso et al. 2016). The primary endpoint response as demonstrated in a trial using ganitumab in of the trial is pathological complete response, no invasive pancreas cancer (McCaffery et al. 2013). In this trial, tumor in breast or lymph nodes, after completion of patients with higher levels of IGF1 and IGF2 benefited chemotherapy. from the addition of IGF1R inhibition to cytotoxic In this trial, ganitumab was tested in combination chemotherapy. with paclitaxel. Because of the known hyperglycemia Thus, using an unselected group of patients to study induced by ganitumab, patients were also given metformin IGF1R inhibitors will not be successful if only a subgroup (850 mg po BID) to manage glucose. Therapy was 12 weeks of patients has ‘IGF1R-driven’ tumors. Further, identifying in combination with paclitaxel and ganitumab, followed key downstream molecules associated with enhanced

http://jme.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/JME-17-0261 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 12:32:49AM via free access Journal of Molecular D Yee IGF1R inhibition in breast cancer 61:1 T65 Endocrinology survival or unlimited proliferation by measuring serum While the IGF1R and INSR tyrosine kinase inhibitor ligands, expression of key adaptor proteins or expression BMS-53692 inhibited tumor progression in this mouse profiles may identify the subgroup of patients who could model of breast cancer (Novosyadlyy et al. 2010), the more benefit from IGF1R inhibition. specific inhibitor of INSR S961 was also effective Rostoker( et al. 2015). These data argue strongly for a specific role for INSR in breast cancer progression. Specific subtypes of breast cancer should be As mentioned, INSR exists in two isoforms A and B included in clinical trials with the fetal A isoform as the predominant INSR species As discussed earlier, the largest numbers of clinical trials in breast cancer. Our data show endocrine-resistant included women with ER+ tumors that were resistant tumors become more sensitive to insulin due to a relative to endocrine therapy. Other preclinical data suggesting lack of IGF1R (Fagan et al. 2012). In human tumors, IGF1R the activity of IGF1R inhibitors were most effective in resistant to tamoxifen also has lowered levels of this ER-negative breast cancers, and HER2-negative breast receptor (Drury et al. 2011). While these authors did not cancers were largely ignored (Litzenburger et al. 2011). In study levels of INSR in these tamoxifen resistant breast this work, the tyrosine kinase inhibitor BMS-754807 was cancers, there is little evidence to suggest INSR is regulated most effective in the ‘triple-negative’ breast cancer cell lines. by ER in breast cancer. In contrast, the regulation of IGF1R Moreover, the IGF1R-activated gene expression signature by estradiol is well characterized in ER+ breast cancer was completely reversed by the TKI in these cell lines. cells (Oesterreich et al. 2001). Presumably, in tamoxifen- Further data in breast cancer show IGF1R signals resistant cells, the drug continues to suppress IGF1R to ATM/ATR and sensitize breast cancer cells to DNA expression while INSR is unaffected. Inhibition of INSR damage caused by cisplatin (O’Flanagan et al. 2016). In results in diminished growth of tamoxifen-resistant breast triple-negative breast cancer cells, inhibition of IGF1R cancer cells in vitro (Chan et al. 2016, 2017). in combination with phosphatidyl-inositol 3-kinase Taken together, these data suggest an important role inhibitors has also been demonstrated (de Lint et al. 2016). for both IGF1R and INSR. While suppression of elevated Thus, the numerous clinical trials conducted in ER+ insulin levels after IGF1R suppression by monoclonal tumors might have been the wrong strategy. As noted antibodies or TKIs might be sufficient, it must be noted below, there are additional reasons why endocrine- a significant number of women with breast cancer, have resistant ER+ tumors were likely the wrong subtype of metabolic syndrome (Esposito et al. 2013, Bhandari et al. breast cancer to target with IGF1R inhibitors. 2014) and it is possible their tumors are driven by high levels of insulin. Thus, a dual approach to IGF1R and INSR may be needed to completely suppress this pathway. INSR is also a target in breast cancer

As noted earlier, Gradishar and coworkers showed Summary endocrine-resistant ER+ breast cancers had very little expression of IGF1R, yet, had much higher levels of There was great appeal to target IGF1R signaling in breast INSR (Gradishar et al. 2016). This observation by itself cancer; yet, the clinical trials testing drugs designed to might not have been a problem; however, the reflex target this pathway were unsuccessful. Perhaps this could hyperinsulinemia seen with IGF1R inhibition should have been expected due to the design of the trials; no have been addressed (Haluska et al. 2007). In this clinical biomarkers were used to stratify patients, patients were scenario, the ‘therapeutic’ drug was harmful for two enrolled with limited expression of the target, preclinical reasons. First, the actual target, IGF1R was not expressed data outlining a potential role in multiple subtypes of in these tumors. Second, the disruption of glucose breast cancer were not incorporated into clinical trial homeostasis could have resulted in hyperinsulinemia, designs, and the reflex increase of serum insulin levels stimulation of tumor INSR and enhanced proliferation, was not accounted for in trial design. Thus, there remains exactly the opposite of the intended therapeutic effect. hope targeting of IGF1R could be a successful breast An important role for INSR in breast cancer is clear. cancer therapy and ongoing clinical trials testing other In a mouse model of hyperinsulinemia, insulin alone is strategies to block this pathway, primarily by neutralizing enough to drive tumor progression (Fierz et al. 2010). monoclonal antibodies, are ongoing. Certainly, attention Further, this acceleration of breast cancer progression to the factors outlined in this review will be needed to occurs independently of IGF1R (Gallagher et al. 2013). best optimize this strategy for women with breast cancer.

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Received in final form 22 November 2017 Accepted 29 January 2018