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Insulin-Like Growth Factor System
Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis.
The IGF system regulates a variety of physiological processes including aging, glucose metabolism, growth, and differentiation . Alterations in IGF equilibrium result in different pathologies including endocrine disorders, skin diseases and cancer . Accordingly, multiple anti-IGF targeted therapies were developed and tested in different tumor types  but, in spite of encouraging preclinical results, clinical studies have been largely disappointing . Excellent reviews have recently discussed patients’ response to IGF inhibitors . Notably, among solid tumors, a few but significant achievements were obtained in sarcomas, particularly in Ewing sarcoma . Major factors limiting the efficacy of anti-IGF1R therapy in the clinic include (i.) the lack of validated biomarkers of response for patient selection; (ii.) the development of primary and/or acquired resistance, with absence of significant activity of anti-IGF agents particularly as monotherapy; (iii.) underestimation of the molecular complexity surrounding the IGF axis . The variety of biological responses elicited by the IGFs is not solely depending on its canonical components but it also relies on functional cross-talks integrating signals from other factors . The IGF system is finely tuned by a variety of growth factors and hormones , post-transcriptional regulators like RNA-binding proteins and non-coding RNAs . The IGF system also interacts with other pathways, including EGFR, HER2, cMET, ALK, or functional partners, like DDR1, E-cadherin, decorin, leading to signaling redundancy or compensatory activity . To date, combinatorial therapy with anti-IGFs agents represents an attractive therapeutic option.
2. Therapeutic Approaches to Block the IGF System
2.1. Anti-IGF1R mAbs
2.2. Tyrosine Kinase Inhibitor Small Molecules
2.3. IGFs Neutralizing Antibodies and Ligands TRAP
Dysregulation of the IGF system drives cancer cell proliferation, migration, EMT, and drug resistance. Accordingly, multiple anti-IGF therapeutic strategies have been developed to block this pathway, including IGF1R monoclonal antibodies, tyrosine-kinase inhibitors, IGFs neutralizing antibodies or the new IGF-TRAP and IGF1R—targeted antibody—drug conjugates. After decades of research in the field, clinical relevance of therapeutic agents targeting the IGF system in cancer appears limited to subsets of sarcomas. This is in line with the exceptional dependence of these diseases on IGF-driven processes. Still, even in those tumors, molecular profiling to identify patients who would better respond to anti-IGF-based treatment is still an urgent clinical need. In addition, any therapeutic strategy solely targeting the IGF axis is likely insufficient to block tumor growth. The majority of the information obtained to date shows the complexity of the IGF axis regulation and the multiplicity of interactions with other cancer-relevant pathways, which either potentiate or compensate molecular signaling mediated by the IGF system. A better understanding of this network of signaling pathways might contribute to the identification of novel and more effective therapeutic combinations for sarcoma treatment.
The entry is from 10.3390/cells10082075
- Stanley, T.L.; Fourman, L.T.; Zheng, I.; McClure, C.M.; Feldpausch, M.N.; Torriani, M.; Corey, K.E.; Chung, R.T.; Lee, H.; Kleiner, D.E.; et al. Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease. J. Clin. Endocrinol. Metab. 2021, 106, e520–e533.
- Hakuno, F.; Takahashi, S.I. IGF1 receptor signaling pathways. J. Mol. Endocrinol. 2018, 61, T69–T86.
- Frystyk, J.; Teran, E.; Gude, M.F.; Bjerre, M.; Hjortebjerg, R. Pregnancy-associated plasma proteins and Stanniocalcin-2—Novel players controlling IGF-I physiology. Growth Horm. IGF Res. Off. J. Growth Horm. Res. Soc. Int. IGF Res. Soc. 2020, 53–54, 101330.
- Osher, E.; Macaulay, V.M. Therapeutic Targeting of the IGF Axis. Cells 2019, 8, 895.
- de Groot, S.; Rottgering, B.; Gelderblom, H.; Pijl, H.; Szuhai, K.; Kroep, J.R. Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma. Cancers 2020, 12, 3568.
- Simpson, A.; Petnga, W.; Macaulay, V.M.; Weyer-Czernilofsky, U.; Bogenrieder, T. Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies. Target. Oncol. 2017, 12, 571–597.
- Cao, J.; Yee, D. Disrupting Insulin and IGF Receptor Function in Cancer. Int. J. Mol. Sci. 2021, 22, 555.
- Hua, H.; Kong, Q.; Yin, J.; Zhang, J.; Jiang, Y. Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: A challenge for cancer therapy. J. Hematol. Oncol. 2020, 13, 64.
- Mancarella, C.; Scotlandi, K. IGF system in sarcomas: A crucial pathway with many unknowns to exploit for therapy. J. Mol. Endocrinol. 2018, 61, T45–T60.
- Mancarella, C.; Scotlandi, K. IGF2BP3 From Physiology to Cancer: Novel Discoveries, Unsolved Issues, and Future Perspectives. Front. Cell Dev. Biol. 2019, 7, 363.
- Chen, B.; Li, J.; Chi, D.; Sahnoune, I.; Calin, S.; Girnita, L.; Calin, G.A. Non-Coding RNAs in IGF-1R Signaling Regulation: The Underlying Pathophysiological Link between Diabetes and Cancer. Cells 2019, 8, 1638.
- Mancarella, C.; Morrione, A.; Scotlandi, K. Novel Regulators of the IGF System in Cancer. Biomolecules 2021, 11, 273.
- Garofalo, C.; Mancarella, C.; Grilli, A.; Manara, M.C.; Astolfi, A.; Marino, M.T.; Conte, A.; Sigismund, S.; Care, A.; Belfiore, A.; et al. Identification of common and distinctive mechanisms of resistance to different anti-IGF-IR agents in Ewing’s sarcoma. Mol. Endocrinol. 2012, 26, 1603–1616.
- Sachdev, D.; Li, S.L.; Hartell, J.S.; Fujita-Yamaguchi, Y.; Miller, J.S.; Yee, D. A chimeric humanized single-chain antibody against the type I insulin-like growth factor (IGF) receptor renders breast cancer cells refractory to the mitogenic effects of IGF-I. Cancer Res. 2003, 63, 627–635.
- Sachdev, D.; Singh, R.; Fujita-Yamaguchi, Y.; Yee, D. Down-regulation of insulin receptor by antibodies against the type I insulin-like growth factor receptor: Implications for anti-insulin-like growth factor therapy in breast cancer. Cancer Res. 2006, 66, 2391–2402.
- Arteaga, C.L.; Kitten, L.J.; Coronado, E.B.; Jacobs, S.; Kull, F.C., Jr.; Allred, D.C.; Osborne, C.K. Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J. Clin. Investig. 1989, 84, 1418–1423.
- Zhang, T.; Shen, H.; Dong, W.; Qu, X.; Liu, Q.; Du, J. Antitumor effects and molecular mechanisms of figitumumab, a humanized monoclonal antibody to IGF-1 receptor, in esophageal carcinoma. Sci. Rep. 2014, 4, 6855.
- Huang, H.J.; Angelo, L.S.; Rodon, J.; Sun, M.; Kuenkele, K.P.; Parsons, H.A.; Trent, J.C.; Kurzrock, R. R1507, an anti-insulin-like growth factor-1 receptor (IGF-1R) antibody, and EWS/FLI-1 siRNA in Ewing’s sarcoma: Convergence at the IGF/IGFR/Akt axis. PLoS ONE 2011, 6, e26060.
- Shin, D.H.; Min, H.Y.; El-Naggar, A.K.; Lippman, S.M.; Glisson, B.; Lee, H.Y. Akt/mTOR counteract the antitumor activities of cixutumumab, an anti-insulin-like growth factor I receptor monoclonal antibody. Mol. Cancer Ther. 2011, 10, 2437–2448.
- Leiphrakpam, P.D.; Agarwal, E.; Mathiesen, M.; Haferbier, K.L.; Brattain, M.G.; Chowdhury, S. In vivo analysis of insulin-like growth factor type 1 receptor humanized monoclonal antibody MK-0646 and small molecule kinase inhibitor OSI-906 in colorectal cancer. Oncol. Rep. 2014, 31, 87–94.
- Beltran, P.J.; Calzone, F.J.; Mitchell, P.; Chung, Y.A.; Cajulis, E.; Moody, G.; Belmontes, B.; Li, C.M.; Vonderfecht, S.; Velculescu, V.E.; et al. Ganitumab (AMG 479) inhibits IGF-II-dependent ovarian cancer growth and potentiates platinum-based chemotherapy. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2014, 20, 2947–2958.
- Wang, Y.; Lipari, P.; Wang, X.; Hailey, J.; Liang, L.; Ramos, R.; Liu, M.; Pachter, J.A.; Bishop, W.R.; Wang, Y. A fully human insulin-like growth factor-I receptor antibody SCH 717454 (Robatumumab) has antitumor activity as a single agent and in combination with cytotoxics in pediatric tumor xenografts. Mol. Cancer Ther. 2010, 9, 410–418.
- Schmitz, S.; Kaminsky-Forrett, M.C.; Henry, S.; Zanetta, S.; Geoffrois, L.; Bompas, E.; Moxhon, A.; Mignion, L.; Guigay, J.; Knoops, L.; et al. Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Clinical activity and molecular response (GORTEC 2008-02). Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2012, 23, 2153–2161.
- Pandini, G.; Wurch, T.; Akla, B.; Corvaia, N.; Belfiore, A.; Goetsch, L. Functional responses and in vivo anti-tumour activity of h7C10: A humanised monoclonal antibody with neutralising activity against the insulin-like growth factor-1 (IGF-1) receptor and insulin/IGF-1 hybrid receptors. Eur. J. Cancer 2007, 43, 1318–1327.
- Buck, E.; Gokhale, P.C.; Koujak, S.; Brown, E.; Eyzaguirre, A.; Tao, N.; Rosenfeld-Franklin, M.; Lerner, L.; Chiu, M.I.; Wild, R.; et al. Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): Rationale for cotargeting IGF-1R and IR in cancer. Mol. Cancer Ther. 2010, 9, 2652–2664.
- Desbois-Mouthon, C.; Baron, A.; Blivet-Van Eggelpoel, M.J.; Fartoux, L.; Venot, C.; Bladt, F.; Housset, C.; Rosmorduc, O. 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. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2009, 15, 5445–5456.
- Liu, R.; Tang, W.; Han, X.; Geng, R.; Wang, C.; Zhang, Z. Hepatocyte growth factor-induced mesenchymal-epithelial transition factor activation leads to insulin-like growth factor 1 receptor inhibitor unresponsiveness in gastric cancer cells. Oncol. Lett. 2018, 16, 5983–5991.
- Solomon, V.R.; Alizadeh, E.; Bernhard, W.; Makhlouf, A.; Hartimath, S.V.; Hill, W.; El-Sayed, A.; Barreto, K.; Geyer, C.R.; Fonge, H. Development and preclinical evaluation of cixutumumab drug conjugates in a model of insulin growth factor receptor I (IGF-1R) positive cancer. Sci. Rep. 2020, 10, 18549.
- Akla, B.; Broussas, M.; Loukili, N.; Robert, A.; Beau-Larvor, C.; Malissard, M.; Boute, N.; Champion, T.; Haeuw, J.F.; Beck, A.; et al. Efficacy of the Antibody-Drug Conjugate W0101 in Preclinical Models of IGF-1 Receptor Overexpressing Solid Tumors. Mol. Cancer Ther. 2020, 19, 168–177.
- Favelyukis, S.; Till, J.H.; Hubbard, S.R.; Miller, W.T. Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat. Struct. Biol. 2001, 8, 1058–1063.
- Mulvihill, M.J.; Cooke, A.; Rosenfeld-Franklin, M.; Buck, E.; Foreman, K.; Landfair, D.; O’Connor, M.; Pirritt, C.; Sun, Y.; Yao, Y.; et al. Discovery of OSI-906: A selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med. Chem. 2009, 1, 1153–1171.
- Awasthi, N.; Zhang, C.; Ruan, W.; Schwarz, M.A.; Schwarz, R.E. BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor, enhances gemcitabine response in pancreatic cancer. Mol. Cancer Ther. 2012, 11, 2644–2653.
- Carrasco-Garcia, E.; Martinez-Lacaci, I.; Mayor-Lopez, L.; Tristante, E.; Carballo-Santana, M.; Garcia-Morales, P.; Ventero Martin, M.P.; Fuentes-Baile, M.; Rodriguez-Lescure, A.; Saceda, M. PDGFR and IGF-1R Inhibitors Induce a G2/M Arrest and Subsequent Cell Death in Human Glioblastoma Cell Lines. Cells 2018, 7, 131.
- George, B.; George, S.K.; Shi, W.; Haque, A.; Shi, P.; Eskandari, G.; Axelson, M.; Larsson, O.; Kaseb, A.O.; Amin, H.M. Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK(+) T-cell lymphoma. J. Hematol. Oncol. 2019, 12, 80.
- Aiken, R.; Axelson, M.; Harmenberg, J.; Klockare, M.; Larsson, O.; Wassberg, C. Phase I clinical trial of AXL1717 for treatment of relapsed malignant astrocytomas: Analysis of dose and response. Oncotarget 2017, 8, 81501–81510.
- Bergqvist, M.; Holgersson, G.; Bondarenko, I.; Grechanaya, E.; Maximovich, A.; Andor, G.; Klockare, M.; Thureson, M.; Jerling, M.; Harmenberg, J. Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer. Acta Oncol. 2017, 56, 441–447.
- Gao, J.; Chesebrough, J.W.; Cartlidge, S.A.; Ricketts, S.A.; Incognito, L.; Veldman-Jones, M.; Blakey, D.C.; Tabrizi, M.; Jallal, B.; Trail, P.A.; et al. Dual IGF-I/II-neutralizing antibody MEDI-573 potently inhibits IGF signaling and tumor growth. Cancer Res. 2011, 71, 1029–1040.
- Zhong, H.; Fazenbaker, C.; Chen, C.; Breen, S.; Huang, J.; Yao, X.; Ren, P.; Yao, Y.; Herbst, R.; Hollingsworth, R.E. Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies. Oncogene 2017, 36, 797–806.
- Haluska, P.; Menefee, M.; Plimack, E.R.; Rosenberg, J.; Northfelt, D.; LaVallee, T.; Shi, L.; Yu, X.Q.; Burke, P.; Huang, J.; et al. Phase I dose-escalation study of MEDI-573, a bispecific, antiligand monoclonal antibody against IGFI and IGFII, in patients with advanced solid tumors. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2014, 20, 4747–4757.
- Chen, Y.M.; Qi, S.; Perrino, S.; Hashimoto, M.; Brodt, P. Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug. Cells 2020, 9, 1098.
- Vaniotis, G.; Moffett, S.; Sulea, T.; Wang, N.; Elahi, S.M.; Lessard, E.; Baardsnes, J.; Perrino, S.; Durocher, Y.; Frystyk, J.; et al. Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties. Sci. Rep. 2018, 8, 17361.