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Review

Investigational IGF1R inhibitors in early stage clinical trials for cancer therapy

, &
Pages 1101-1112 | Received 26 Aug 2019, Accepted 14 Nov 2019, Published online: 23 Nov 2019

References

  • Collins FS, Morgan M, Patrinos A. The human genome project: lessons from large-scale biology. Science. 2003;300:286–290.
  • Green ED, Watson JD, Collins FS. Human genome project: twenty-five years of big biology. Nature. 2015;526:29–31.
  • Saadeh C, Bright D, Rustem D. Precision medicine in oncology pharmacy practice. Acta Med Acad. 2019;48:90–104.
  • Jorgensen JT. A paradigm shift in biomarker guided oncology drug development. Ann Transl Med. 2019;7:148.
  • Werner H, Wood T. Editorial: personalized medicine in cancer research. Front Endocrinol (Lausanne). 2018;9:692.
  • Pierobon M, Wulfkuhle J, Liotta LA, et al. Utilization of proteomic technologies for precision oncology applications. Cancer Treat Res. 2019;178:171–187.
  • Yakar S, Adamo ML. Insulin-like growth factor 1 physiology: lessons from mouse models. Endocrinol Metab Clin North Am. 2012;41:231–247.
  • LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor-1. Nat Clin Pract Endocrinol Metab. 2007;3:302–310.
  • Yakar S, Werner H, Rosen CJ. Insulin-like growth factors: actions on the skeleton. J Mol Endocrinol. 2018;61:T115–T137.
  • Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nature Rev Cancer. 2012;12:159–169.
  • Maki RG. Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J Clin Oncol. 2010;28:4985–4995.
  • Samani AA, Yakar S, LeRoith D, et al. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007;28:20–47.
  • Bentov I, Werner H. IGF, IGF receptor and overgrowth syndromes. Pediatr Endocrinol Rev. 2004;1:352–360.
  • Salmon WD, Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med. 1957;49:825–836.
  • Baserga R, Rubin R. Cell cycle and growth control. Crit Rev Eukar Genet Exp. 1993;3:47–61.
  • Lu K, Campisi J. Ras proteins are essential and selective for the action of insulin-like growth factor 1 late in the G1 phase of the cell cycle in BALB/c murine fibroblasts. Proc Natl Acad Sci USA. 1992;89:3889–3893.
  • Clayton P, Banerjee I, Murray PG, et al. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol. 2011;7:11–24.
  • Chitnis MM, Yuen JSP, Protheroe AS, et al. The type I insulin-like growth factor-I receptor pathway. Clin Cancer Res. 2008;14:6364–6370.
  • LeRoith D, Werner H, Beitner-Johnson D, et al. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 1995;16:143–163.
  • Allard JB, Duan C. IGF-binding proteins: why do they exist and why are there so many? Front Endocrinol (Lausanne). 2018;9:117.
  • Bach L. Insulin-like growth factor binding proteins–an update. Pediatr Endocrinol Rev. 2015;13:521–530.
  • Werner H, Woloschak M, Adamo M, et al. Developmental regulation of the rat insulin-like growth factor I receptor gene. Proc Natl Acad Sci USA. 1989;86:7451–7455.
  • Bondy CA, Werner H, Roberts CT Jr, et al. Cellular pattern of insulin-like growth factor I (IGF-I) and type I IGF receptor gene expression in early organogenesis: comparison with IGF-II gene expression. Mol Endocrinol. 1990;4:1386–1398.
  • Adamo ML, Ben-Hur H, Roberts CT Jr, et al. Regulation of start site usage in the two leader exons of the rat insulin-like growth factor I gene by development, fasting and diabetes. Mol Endocrinol. 1991;5:1677–1686.
  • Werner H, Bruchim I. The insulin-like growth factor-I receptor as an oncogene. Arch Physiol Biochem. 2009 May;115(2):58–71.
  • Bondy CA, Werner H, Roberts CT Jr, et al. Cellular pattern of type I insulin-like growth factor receptor gene expression during maturation of the rat brain: comparison with insulin-like growth factors I and II. Neuroscience. 1992;46:909–923.
  • Werner H, Adamo M, Roberts CT Jr. Molecular and cellular aspects of insulin-like growth factor action. In: Litwack G, editor. Vitamins and hormones. Vol. 48. San Diego, CA: Academic Press; 1994. p. 1–58.
  • Liu J-P, Baker J, Perkins AS, et al. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 1993;75:59–72.
  • Baker J, Liu J-P, Robertson EJ, et al. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993;75:73–82.
  • Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer. 2003;107:873–877.
  • Christofori G, Naik P, Hanahan D. A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature. 1994;369:414–418.
  • Liao Y, Abel U, Grobholz R, et al. Up-regulation of insulin-like growth factor axis components in human primary prostate cancer correlates with tumor grade. Human Pathol. 2005;36:1186–1196.
  • Schnarr B, Strunz K, Ohsam J, et al. Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Int J Cancer. 2000;89:506–513.
  • Maor S, Yosepovich A, Papa MZ, et al. Elevated insulin-like growth factor-I receptor (IGF-IR) levels in primary breast tumors associated with BRCA1 mutations. Cancer Lett. 2007;257:236–243.
  • Aleem E, Nehrbass D, Klimek F, et al. Upregulation of the insulin receptor and type I insulin-like growth factor receptor are early events in hepatocarcinogenesis. Toxicol Pathol. 2011;39:524–543.
  • Werner H. Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer. Oncogene. 2012;31:2703–2714.
  • Baserga R. The decline and fall of the IGF-I receptor. J Cell Physiol. 2013;28:675–679.
  • Sarfstein R, Belfiore A, Werner H. Identification of insulin-like growth factor-I receptor gene promoter-binding proteins in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. Cancers (Basel). 2010;2:233–261.
  • Werner H, Stannard B, Bach MA, et al. Cloning and characterization of the proximal promoter region of the rat insulin-like growth factor I (IGF-I) receptor gene. Biochem Biophys Res Comm. 1990;169:1021–1027.
  • Cooke DW, Bankert LA, Roberts CT Jr, et al. Analysis of the human type I insulin-like growth factor receptor promoter region. Biochem Biophys Res Comm. 1991;177:1113–1120.
  • Beitner-Johnson D, Werner H, Roberts CT Jr, et al. Regulation of insulin-like growth factor I receptor gene expression by Sp1: physical and functional interactions of Sp1 at GC boxes and at a CT element. Mol Endocrinol. 1995;9:1147–1156.
  • Werner H, Bach MA, Stannard B, et al. Structural and functional analysis of the insulin-like growth factor I receptor gene promoter. Mol Endocrinol. 1992;6:1545–1558.
  • Aiello A, Pandini G, Sarfstein R, et al. HMGA1 protein is a positive regulator of the insulin-like growth factor-I receptor gene. Eur J Cancer. 2010;46:1919–1926.
  • Werner H, Shalita-Chesner M, Abramovitch S, et al. Regulation of the insulin-like growth factor-I receptor gene by oncogenes and antioncogenes: implications in human cancer. Mol Genet Metab. 2000;71:315–320.
  • Oren M. p53: the ultimate tumor suppressor gene? FASEB J. 1992;6:3169–3176.
  • Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014;14:359–370.
  • Harris CC, Hollstein M. Clinical implications of the p53 tumor suppressor gene. New Eng J Med. 1993;329:1318–1327.
  • Werner H, Karnieli E, Rauscher FJ III, et al. Wild type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. Proc Natl Acad Sci USA. 1996;93:8318–8323.
  • Ohlsson C, Kley N, Werner H, et al. p53 regulates IGF-I receptor expression and IGF-I induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1. Endocrinology. 1998;139:1101–1107.
  • Werner H, Sarfstein R, LeRoith D, et al. Insulin-like growth factor 1 signaling axis meets p53 genome protection pathways. Front Oncol. 2016;6:159.
  • Holt JT, Thompson ME, Szabo C, et al. Growth retardation and tumour inhibition by BRCA1. Nature Genet. 1996;12:298–301.
  • Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.
  • Futreal PA, Liu Q, Shattuck-Eidens D, et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994;266:120–122.
  • Wang Q, Zhang H, Fishel R, et al. BRCA1 and cell signaling. Oncogene. 2000;19:6152–6158.
  • Maor SB, Abramovitch S, Erdos MR, et al. BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1. Mol Genet Metab. 2000;69:130–136.
  • Abramovitch S, Glaser T, Ouchi T, et al. BRCA1-Sp1 interactions in transcriptional regulation of the IGF-IR gene. FEBS Lett. 2003;541:149–154.
  • Werner H, Bruchim I. IGF-1 and BRCA1 signalling pathways in familial cancer. Lancet Oncol. 2012;13:e53744.
  • Abuzzahab MJ, Schneider A, Goddard A, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. New Eng J Med. 2003;349:2211–2222.
  • Baserga R. The insulin-like growth factor I receptor: a key to tumor growth? Cancer Res. 1995;55:249–252.
  • Schayek H, Haugk K, Sun S, et al. Tumor suppressor BRCA1 is expressed in prostate cancer and control IGF1-R gene transcription in an androgen receptor-dependent manner. Clin Cancer Res. 2009;15:1558–1565.
  • Eshet R, Werner H, Klinger B, et al. Up-regulation of insulin-like growth factor-I (IGF-I) receptor gene expression in patients with reduced serum IGF-I levels. J Mol Endocrinol. 1993;10:115–120.
  • Steuerman R, Shevah O, Laron Z. Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol. 2011;164:485–489.
  • Hernandez-Sanchez C, Werner H, Roberts CT Jr, et al. Differential regulation of IGF-I receptor gene expression by IGF-I and basic fibroblast growth factor. J Biol Chem. 1997;272:4663–4670.
  • Rubini M, Werner H, Gandini E, et al. Platelet-derived growth factor increases the activity of the promoter of the IGF-I receptor gene. Exp Cell Res. 1994;211:374–379.
  • Sell C, Rubini M, Rubin R, et al. Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc Natl Acad Sci USA. 1993;90:11217–11221.
  • Sell C, Dumenil G, Deveaud C, et al. Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol Cell Biol. 1994;14:3604–3612.
  • Yerushalmi R, Gelmon KA, Leung S, et al. Insulin-like growth factor receptor (IGF-IR) in breast subtypes. Breast Cancer Res Treat. 2012;132:131–142.
  • Pearson OH, Ray BS. Results of hypophysectomy in the treatment of metastatic mammary carcinoma. Cancer. 1959;12:85–92.
  • Hankinson SE, Willett WC, Colditz GA, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998;351:1393–1396.
  • Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998;279:563–566.
  • Allen NE, Roddam AW, Allen DS, et al. A prospective study of serum insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 and breast cancer risk. Br J Cancer. 2005;92:1283–1287.
  • Petridou E, Koukoulomatis P, Alexe DM, et al. Endometrial cancer and the IGF system: a case-control study in Greece. Oncology. 2003;64:341–345.
  • Ma J, Pollack MN, Giovannucci E, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst. 1999;91:620–625.
  • Palmqvist R, Hallmans G, Rinaldi S, et al. Plasma insulin-like growth factor 1, insulin-like growth factor binding protein 3, and risk of colorectal cancer: a prospective study in northern Sweden. Gut. 2002;50:642–646.
  • Yu H, Spitz MR, Mistry J, et al. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst. 1999;91:151–156.
  • Zhao H, Grossman HB, Spitz MR, et al. Plasma levels of insulin-like growth factor-I and binding protein-3, and their association with bladder cancer risk. J Urol. 2003;169:714–717.
  • Renehan AG, Zwahlen M, Minder C, et al. Insulin-like growth factor-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004;363:1346–1353.
  • Kull FC, Jacobs S, Su Y-F, et al. Monoclonal antibodies to receptors for insulin and somatomedin-c. J Biol Chem. 1983;258:6561–6566.
  • Arteaga CL, Kitten LJ, Coronado EB, et al. Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J Clin Invest. 1989;84:1418–1423.
  • Andrews DW, Resnicoff M, Flanders AE, et al. Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. J Clin Oncol. 2001;19:2189–2200.
  • Simpson A, Petnga W, Macaulay VM, et al. 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.
  • Osher E, Macaulay VM. Therapeutic targeting of the IGF axis. Cells. 2019;8:E895.
  • Crudden C, Girnita A, Girnita L. Targeting the IGF-1R: the tale of the tortoise and the hare. Front Endocrinol. 2015;6:64.
  • Bruchim I, Werner H. Targeting IGF-1 signaling pathways in gynecologic malignancies. Expert Opin Ther Targets. 2013;17:307–320.
  • Hofmann F, Garcia-Echeverria C. Blocking the insulin-like growth factor-I receptor as a strategy for targeting cancer. Drugs Discovery Today. 2005;10:1041–1047.
  • Beckwith H, Yee D. Were the IGF signaling inhibitors all bad? Mol Endocrinol. 2015;29:1549–1557.
  • Yee D. Insulin-like growth factor receptor inhibitors: baby or the bathwater? J Natl Cancer Inst. 2012;104:975–981.
  • Olmos D, Martins AS, Jones RL, et al. Targeting the insulin-like growth factor 1 receptor in Ewing’s sarcoma: reality and expectations. Sarcoma. 2011;2011:402508.
  • Yap TA, Olmos D, Molife LR, et al. Targeting the insulin-like growth factor signaling pathway: figitumumab and other novel anticancer strategies. Expert Opin Investig Drugs. 2011;20:1293–1304.
  • Gualberto A, Pollak M. Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene. 2009;28:3009–3021.
  • Gualberto A, Hixon ML, Karp DD, et al. Pre-treatment levels of circulating free IGF-1 identify NSCLC patients who derive clinical benefit from figitumumab. Br J Cancer. 2011;104:68–74.
  • Asmane I, Watkin E, Alberti L, et al. Insulin-like growth factor type 1 receptor (IGF-1R) exclusive nuclear staining: a predictive biomarker for IGF-1R monoclonal antibody (Ab) therapy in sarcomas. Eur J Cancer. 2012;48:3027–3035.
  • Codony-Servat J, Cuatrecasas M, Asensio E, et al. Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer. Br J Cancer. 2017;117:1777–1786.
  • Pollak MN. The insulin receptor/insulin-like growth factor receptor family as a therapeutic target in oncology. Clin Cancer Res. 2012;18:40–50.
  • Nahor I, Abramovitch S, Engeland K, et al. The p53-family members p63 and p73 inhibit insulin-like growth factor-I receptor gene expression in colon cancer cells. Growth Hormone IGF Res. 2005;15:388–396.
  • Abramovitch S, Werner H. Functional and physical interactions between BRCA1 and p53 in transcriptional regulation of the IGF-IR gene. Horm Metab Res. 2003;35:758–762.
  • Attias-Geva Z, Bentov I, Kidron D, et al. p53 Regulates insulin-like growth factor-I receptor gene expression in uterine serous carcinoma and predicts responsiveness to an insulin-like growth factor-I receptor-directed targeted therapy. Eur J Cancer. 2012;48:1570–1580.
  • Cohen-Sinai T, Cohen Z, Werner H, et al. Identification of BRCA1 as a potential biomarker for insulin-like growth factor-1 receptor targeted therapy in breast cancer. Front Endocrinol. 2017;8:148.
  • Beltran PJ, Mitchell P, Chung YA, et al. AMG 479, a fully human anti-insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells. Mol Cancer Ther. 2009;8:1095–1105.
  • Kindler HL, Richards DA, Garbo LE, et al. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann Oncol. 2012;23:2834–2842.
  • Fuchs CS, Azevedo S, Okusaka T, et al. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015;26:921–927.
  • Molife LR, Fong PC, Paccagnella L, et al. The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study. Br J Cancer. 2010;103:332–339.
  • Gao J, Chang YS, Jallal B, et al. Targeting the insulin-like growth factor axis for the development of novel therapeutics in oncology. Cancer Res. 2012;72:3–12.
  • Rajan A, Carter CA, Berman A, et al. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. Lancet Oncol. 2014;15:191–200.
  • Abou-Alfa GK, Capanu M, O’Reilly EM, et al. A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma. J Hepatol. 2014;60:319–324.
  • Hussain M, Rathkopf D, Liu G, et al. A randomised non-comparative phase II trial of cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone in men with metastatic docetaxel-pretreated castration-resistant prostate cancer. Eur J Cancer. 2015;51:1714–1724.
  • Atzori F, Tabernero J, Cervantes A, et al. A phase I pharmacokinetic and pharmacodynamic study of Dalotuzumab (MK-0646), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2011;17:6304–6312.
  • Becker MA, Hou X, Tienchaianada P, et al. Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer. BMC Cancer. 2016;16:814.
  • Sclafani F, Kim TY, Cunningham D, et al. A randomized phase II/III study of Dalotuzumab in combination with cetuximab and irinotecan in chemorefractory, KRAS wild-type, metastatic colorectal cancer. J Natl Cancer Inst. 2015;107:djv258.
  • Puzanov I, Lindsay CR, Goff L, et al. A phase I study of continuous oral dosing of OSI-906, a dual inhibitor of insulin-like growth factor-1 and insulin receptors, in patients with advanced solid tumors. Clin Cancer Res. 2015;21:701–711.
  • Macaulay VM, Middleton MR, Eckhardt SG, et al. Phase I dose-escalation study of linsitinib (OSI-906) and erlotinib in patients with advanced solid tumors. Clin Cancer Res. 2016;22:2897–2907.
  • Fassnacht M, Berruti A, Baudin E, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol. 2015;16:426–435.
  • Ekman S, Harmenberg J, Frödin JE, et al. A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: a phase I clinical trial. Acta Oncol. 2016;55:140–148.
  • Haluska P, Menefee M, Plimack ER, 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. 2014;20:4747–4757.
  • Friedbichler K, Hofmann MH, Kroez M, et al. Pharmacodynamic and antineoplastic activity of BI 836845, a fully human IGF ligand-neutralizing antibody, and mechanistic rationale for combination with rapamycin. Mol Cancer Ther. 2014;13:399–409.
  • Ireland L, Santos A, Campbell F, et al. Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer. Oncogene. 2018;37:2022–2036.
  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.
  • Bruchim I, Sarfstein R, Werner H. The IGF hormonal network in endometrial cancer: functions, regulation, and targeting approaches. Front Endocrinol. 2014;5:76.
  • Beauchamp MC, Yasmeen A, Knafo A, et al. Targeting insulin and insulin-like growth factor pathways in epithelial ovarian cancer. J Oncol. 2010;2010:257058.
  • An Y, Cai Y, Guan Y, et al. Inhibitory effect of small interfering RNA targeting insulin-like growth factor-I receptor in ovarian cancer OVCAR3 cells. Cancer Biotherm Radiopharm. 2010;25:545–552.
  • Gest C, Mirshahi P, Li H, et al. Ovarian cancer: Stat3, Rhoa and IGF-IR as therapeutic targets. Cancer Lett. 2012;317:207–217.
  • Shao M, Hollar S, Chambliss D, et al. Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer. Mol Cancer Ther. 2012;11:1576–1586.
  • Beltran PJ, Calzone FJ, Mitchell P, et al. Ganitumab (AMG 479) inhibits IGF-II-dependent ovarian cancer growth and potentiates platinum-based chemotherapy. Clin Cancer Res. 2014;20:2947–2958.
  • Du J, Shi HR, Ren F, et al. Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells. BMC Cancer. 2017;17:851.
  • Hirano S, Ito N, Takahashi S, et al. Clinical implications of insulin-like growth factors through the presence of their binding proteins and receptors expressed in gynecological cancers. Eur J Gynaecol Oncol. 2004;25:187–191.
  • Ayabe T, Tsutsumi O, Sakai H, et al. Increased circulating levels of IGF-I and decreased circulating levels of IGFBP1 in postmenopausal women with endometrial cancer. Endocr J. 1997;44:419–424.
  • Shafiee MN, Seedhouse C, Mongan N, et al. Up-regulation of genes involved in the insulin signalling pathway (IGF1, PTEN and IGFBP1) in the endometrium may link polycystic ovarian syndrome and endometrial cancer. Mol Cell Endocrinol. 2016;424:94–101.
  • Mendivil A, Zhou C, Cantrell LA, et al. AMG 479, a novel IGF-1-R antibody, inhibits endometrial cancer cell proliferation through disruption of the PI3K/Akt and MAPK pathways. Reprod Sci. 2011;18:832–841.
  • Attias-Geva Z, Bentov I, Fishman A, et al. Insulin-like growth factor-I receptor inhibition by specific tyrosine kinase inhibitor NVP-AEW541 in endometrioid and serous papillary endometrial cancer cell lines. Gynecol Oncol. 2011;121:383–389.
  • Attias-Geva Z, Bentov I, Ludwig DL, et al. Insulin-like growth factor-I receptor (IGF-IR) targeting with monoclonal antibody cixutumumab (IMC-A12) inhibits IGF-I action in endometrial cancer cells. Eur J Cancer. 2011;47:1717–1726.
  • Sarfstein R, Friedman Y, Attias-Geva Z, et al. Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners. PLoS One. 2013;8(4):e61537.
  • Zhang Y, Li MX, Wang H, et al. Metformin down-regulates endometrial carcinoma cell secretion of IGF-1 and expression of IGF-1R. Asian Pac J Cancer Prev. 2015;16:221–225.
  • Laskov I, Drudi L, Beauchamp MC, et al. Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer. Gynecol Oncol. 2014;134:607–614.
  • Shu S, Liu X, Xu M, et al. MicroRNA-320a acts as a tumor suppressor in endometrial carcinoma by targeting IGF-1R. Int J Mol Med. 2019;43:1505–1512.
  • Liefers-Visser JAL, Meijering RAM, Reyners AKL, et al. IGF system targeted therapy: therapeutic opportunities for ovarian cancer. Cancer Treat Rev. 2017;60:90–99.
  • Brana I, Berger R, Golan T, et al. A parallel-arm phase I trial of the humanised anti-IGF-1R antibody Dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours. Br J Cancer. 2014;111:1932–1944.
  • Oza A, Kaye S, Van Tornout J, et al. Phase 2 study evaluating intermittent and continuous linsitinib and weekly paclitaxel in patients with recurrent platinum resistant ovarian epithelial cancer. Gynecol Oncol. 2018;149:275–282.

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