61 1 Journal of Molecular D Yee IGF1R inhibition in breast cancer 61:1 T61–T68 Endocrinology THEMATIC REVIEW 40 YEARS OF IGF1 Anti-insulin-like growth factor therapy in breast cancer 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 f breast cancer this pathway, multiple monoclonal antibodies and tyrosine kinase inhibitors were f 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 f insulin receptor to conventional therapy. This failure of the IGF1R inhibitors was pronounced in breast f 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 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 -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 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 T63 Endocrinology 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