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Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions

Abstract

Preclinical evidence that targeting the insulin-like growth factor receptor (IGF-IR) is effective in cancer treatment has been accumulating for almost two decades. Efforts to develop drugs began in the late 1990s, and initial data from clinical trials were reported in 2006. The biological rationale for IGF-IR targeting has potential relevance to many tumor types, and early results have justified expanded programs to evaluate IGF-IR-targeting agents in many areas of clinical need. More than two dozen drug candidates have been developed and clinical trials are underway for at least 12 of these. Early clinical trials reveal an acceptable safety profile together with pharmacodynamic evidence that the receptor can be successfully targeted. It is premature to draw conclusions regarding efficacy, but well-documented instances of single-agent activity were noted during phase I evaluations, and recent evidence from a phase II study suggests that co-administration of an anti-IGF-IR antibody with chemotherapy for non-small-cell lung cancer improves objective response rate and progression-free survival. With more than 70 trials involving a variety of drug candidates underway, the IGF-IR is becoming one of the most intensively investigated molecular targets in oncology. Early results justify the continuation of ongoing research across a broad range of cancer indications.

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Abbreviations

ACC:

adrenocortical carcinoma

ALL:

acute lymphocytic leukemia

CML:

chronic myeloid leukaemia

CTCs:

circulating tumor cells

DLT:

dose-limiting toxicity

GH:

growth hormone

IGFBP-3:

insulin-like growth factor-binding protein

IGF-IR:

insulin-like growth factor I receptor

IR:

insulin receptor

NSCLC:

non-small cell lung cancer

q2weeks:

every 2 weeks

q3weeks:

every 3 weeks

q4weeks:

every 4 weeks

References

  • Adelaide J, Finetti P, Bekhouche I, Repellini L, Geneix J, Sircoulomb F et al. (2007). Integrated profiling of basal and luminal breast cancers. Cancer Res 67: 11565–11575.

    Article  CAS  PubMed  Google Scholar 

  • Ahlgren M, Melbye M, Wohlfahrt J, Sorensen TI . (2004). Growth patterns and the risk of breast cancer in women. N Engl J Med 351: 1619–1626.

    CAS  PubMed  Google Scholar 

  • Allen GW, Saba C, Armstrong EA, Huang SM, Benavente S, Ludwig DL et al. (2007). Insulin-like growth factor-I receptor signaling blockade combined with radiation. Cancer Res 67: 1155–1162.

    CAS  PubMed  Google Scholar 

  • Arteaga CL, Kitten LJ, Coronado EB, Jacobs S, Kull Jr FC, Allred DC et al. (1989). Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J Clin Invest 84: 1418–1423.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Attard G, Fong PC, Molife R, Reade S, Shaw H, Reid A et al. (2006). Phase I trial involving the pharmacodynamic (PD) study of circulating tumour cells, of CP-751,871 (C), a monoclonal antibody against the insulin-like growth factor 1 receptor (IGF-1R), with docetaxel (D) in patients (p) with advanced cancer. J Clin Oncol 24: 126s.

    Google Scholar 

  • Atzori F, Tabernero J, Cervantes A, Botero M, Hsu K, Brown H et al. (2008). A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly (qW) MK-0646, an insulin-like growth factor-1 receptor (IGF1R) monoclonal antibody (MAb) in patients (pts) with advanced solid tumors. J Clin Oncol 26: 157s.

    Google Scholar 

  • Barr S, Buck E, Thomson S, Haley J, Gibson N, Ji Q et al. (2007). The combination of small molecule inhibitors of EGFR and IGF-1R is synergistic in HNSCC and ovarian cancer cell lines. Proc Am Assoc Cancer Res 48: 608.

    Google Scholar 

  • Baserga R, Peruzzi F, Reiss K . (2003). The IGF-1 receptor in cancer biology. Int J Cancer 107: 873–877.

    CAS  PubMed  Google Scholar 

  • Belfiore A . (2007). The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des 13: 671–686.

    CAS  PubMed  Google Scholar 

  • Benini S, Manara MC, Baldini N, Cerisano V, Massimo S, Mercuri M et al. (2001). Inhibition of insulin-like growth factor I receptor increases the antitumor activity of doxorubicin and vincristine against Ewing's sarcoma cells. Clin Cancer Res 7: 1790–1797.

    CAS  PubMed  Google Scholar 

  • Benyoucef S, Surinya KH, Hadaschik D, Siddle K . (2007). Characterization of insulin/IGF hybrid receptors: contributions of the insulin receptor L2 and Fn1 domains and the alternatively spliced exon 11 sequence to ligand binding and receptor activation. Biochem J 403: 603–613.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Best CJ, Ludwig DL, Steeg PS . (2006). Breast cancer cell lines resistant to either tamoxifen or Herceptin exhibit sensitivity to the anti-IGF receptor antibody A12 in vitro. Proc Am Assoc Cancer Res 47: 290.

    Google Scholar 

  • Britten C, Smith D, Bui L, Clary D, Hurwitz H . (2008). A phase I dose de-escalation study of XL228, a potent IGFIR/src inhibitor in patients with advanced malignancies. Presented at the 20th EORTC-NCI-AACR symposium on Molecular Targets and Cancer Therapeutics Congress, 21–24 October 2008, Geneva, Switzerland.

  • Buck E, Eyzaguirre A, Rosenfeld-Franklin M, Thomson S, Mulvihill M, Barr S et al. (2008). Feedback mechanisms promote cooperativity for small molecule inhibitors of epidermal and insulin-like growth factor receptors. Cancer Res 68: 8322–8332.

    CAS  PubMed  Google Scholar 

  • Cao L, Yu Y, Darko I, Currier D, Mayeenuddin LH, Wan X et al. (2008). Addiction to elevated insulin-like growth factor I receptor and initial modulation of the AKT pathway define the responsiveness of rhabdomyosarcoma to the targeting antibody. Cancer Res 68: 8039–8048.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ceda GP, Dall’Aglio E, Maggio M, Lauretani F, Bandinelli S, Falzoi C et al. (2005). Clinical implications of the reduced activity of the GH-IGF-I axis in older men. J Endocrinol Invest. 28 (11 Suppl): 96–100.

    CAS  PubMed  Google Scholar 

  • Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P et al. (1998). Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279: 563–566.

    CAS  PubMed  Google Scholar 

  • Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM . (2008). The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res 14: 6364–6370.

    CAS  PubMed  Google Scholar 

  • Cohen BD, Baker DA, Soderstrom C, Tkalcevic G, Rossi AM, Miller PE et al. (2005). Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin Cancer Res 11: 2063–2073.

    CAS  PubMed  Google Scholar 

  • Cortes J, Paquette R, Talpaz M, Pinilla J, Asatiani E, Wetzler M et al. (2008). Preliminary clinical activity in a phase I trial of the BCR-ABL/IGF-1R/aurora kinase inhibitor XL228 in patients with Ph+ leukemias with either failure to multiple TKI therapies or with T315I mutation. Presented at the 50th ASH Annual Meeting and Exposition, San Francisco, USA, 6–9 December 2008, http://ash.confex.com/ash/2008/webprogram/Paper13204.html.

  • Cox ME, Gleave ME, Zakikhani M, Bell RH, Piura E, Vickers E et al. (2009). Insulin receptor expression by human prostate cancers. Prostate 69: 33–40.

    CAS  PubMed  Google Scholar 

  • De Bono JS, Attard G, Adjei A, Pollak MN, Fong PC, Haluska P et al. (2007). Potential applications for circulating tumor cells expressing the insulin-like growth factor-I receptor. Clin Cancer Res 13: 3611–3616.

    CAS  PubMed  Google Scholar 

  • De Bono JS, Attard G, Adjei A, Pollak MN, Fong PC, Haluska P et al. (2008). Activity of the anti-IGF-IR antibody CP-751,871 in combination with docetaxel as first-line treatment for castration-resistant prostate cancer in a randomized phase II trial. Presented at the Molecular Targets and Cancer Therapeutics Congress, 21–24 October 2008, Geneva, Switzerland.

  • del Rincon JP, Iida K, Gaylinn BD, McCurdy CE, Leitner JW, Barbour LA et al. (2007). Growth hormone regulation of p85alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. Diabetes 56: 1638–1646.

    CAS  PubMed  Google Scholar 

  • Diorio C, Pollak M, Byrne C, Masse B, Hebert-Croteau N, Yaffe M et al. (2005). Insulin-like growth factor-I, IGF-binding protein-3, and mammographic breast density. Cancer Epidemiol Biomarkers Prev 14: 1065–1073.

    CAS  PubMed  Google Scholar 

  • Dong MQ, Venable JD, Au N, Xu T, Park SK, Cociorva D et al. (2007). Quantitative mass spectrometry identifies insulin signaling targets in C. elegans. Science 317: 660–663.

    CAS  PubMed  Google Scholar 

  • Feng Y, Dimitrov DS . (2008). Monoclonal antibodies against components of the IGF system for cancer treatment. Curr Opin Drug Discov Devel 11: 178–185.

    CAS  PubMed  Google Scholar 

  • Gebre-Medhin M, Kindblom LG, Wennbo H, Tornell J, Meis-Kindblom JM . (2001). Growth hormone receptor is expressed in human breast cancer. Am J Pathol 158: 1217–1222.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Girnita A, Girnita L, del PF, Bartolazzi A, Larsson O, Axelson M . (2004). Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res 64: 236–242.

    CAS  PubMed  Google Scholar 

  • Glait C, Tencer L, Ravid D, Sarfstein R, Liscovitch M, Werner H . (2006). Caveolin-1 up-regulates IGF-I receptor gene transcription in breast cancer cells via Sp1- and p53-dependent pathways. Exp Cell Res 312: 3899–3908.

    CAS  PubMed  Google Scholar 

  • Goodin S. (2008). Development of monoclonal antibodies for the treatment of colorectal cancer. Am J Health Syst Pharm 65: S3–S7.

    CAS  PubMed  Google Scholar 

  • Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y et al. (2002). Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20: 42–51.

    CAS  PubMed  Google Scholar 

  • Gualberto A, Karp DD . (2008). Development of a monoclonal antibody against the IGF-IR for the treatment of non small cell lung cancer (CP-751,871). Clin Lung Cancer June 2009 (in press).

  • Gualberto A, Melvin CL, Dean A, Ang AL, Reynolds JM, Lee AV et al. (2008a). Characterization of NSCLC patients responding to anti-IGF-IR therapy. J Clin Oncol 26: 424s.

    Google Scholar 

  • Gualberto A, Melvin CL, Dean A, Ang AL, Reynolds JM, Lee AV et al. (2008b). IGF-IR markers in NSCLC patients on anti-IGF-IR therapy. Ann Oncol 19: viii62.

    Google Scholar 

  • Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S et al. (2008). Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 118: 2609–2619.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Haluska P, Shaw HM, Batzel GN, Yin D, Molina JR, Molife LR et al. (2007). Phase I dose escalation study of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Clin Cancer Res 13: 5834–5840.

    CAS  PubMed  Google Scholar 

  • Hartog H, Wesseling J, Boezen HM, van der Graaf WT . (2007). The insulin-like growth factor 1 receptor in cancer: old focus, new future. Eur J Cancer 43: 1895–1904.

    CAS  PubMed  Google Scholar 

  • Hidalgo M, Tirado Gomez M, Lewis N, Vuky JL, Taylor G, Hayburn JL et al. (2008). A phase I study of MK-0646, a humanized monoclonal antibody against the insulin-like growth factor receptor type 1 (IGF1R) in advanced solid tumor patients in a q2 wk schedule. J Clin Oncol 26: 158s.

    Google Scholar 

  • Higano CS, Yu EY, Whiting SH, Gordon MS, Lorusso P, Fox F et al. (2007). A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors. Presented at the 2007 Prostate Cancer Symposium, Orlando, USA, 22–24 February, 2007 (Abstract 269) http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=46&abstractID=20331.

  • Hochberg Z . (2002). Mechanisms of steroid impairment of growth. Horm Res 58 (Suppl 1): 33–38.

    CAS  PubMed  Google Scholar 

  • Huang F, Greer A, Hurlburt W, Han X, Hafezi R, Wittenberg GM et al. (2009). The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors. Cancer Res 69: 161–170.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hyun T, Yam A, Pece S, Xie X, Zhang J, Miki T et al. (2000). Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood. 96: 3560–3568.

    CAS  PubMed  Google Scholar 

  • Ji QS, Mulvihill MJ, Rosenfeld-Franklin M, Cooke A, Feng L, Mak G et al. (2007). A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor dependent tumor growth in vivo. Mol Cancer Ther 6: 2158–2167.

    CAS  PubMed  Google Scholar 

  • Karp DD, Paz-Ares LG, Novello S, Haluska P, Garland L, Cardenal F et al. (2009). Phase II study of the efficacy of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer. J Clin Oncol 27: 2516–2522.

    CAS  PubMed  Google Scholar 

  • Klinakis A, Szabolcs M, Chen G, Xuan S, Hibshoosh H, Efstratiadis A . (2009). Igf1r as a therapeutic target in a mouse model of basal-like breast cancer. Proc Natl Acad Sci USA 106: 2359–2364.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kopchick JJ, Parkinson C, Stevens EC, Trainer PJ . (2002). Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly. Endocr Rev 23: 623–646.

    CAS  PubMed  Google Scholar 

  • Lacy MQ, Alsina M, Fonseca R, Paccagnella ML, Melvin CL, Yin D et al. (2008). Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulinlike growth factor type 1 Receptor monoclonal antibody CP-751,871 in patients with multiple myeloma. J Clin Oncol 26: 3196–3203.

    CAS  PubMed  Google Scholar 

  • Lammers R, Gray A, Schlessinger J, Ullrich A . (1989). Differential signalling potential of insulin- and IGF-1-receptor cytoplasmic domains. EMBO J. 8: 1369–1375.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL et al. (2008). Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68: 10238–10246.

    CAS  PubMed  Google Scholar 

  • Leong S, Gore L, Benjamin R, Warren TL, Eckhardt SG, Camidge DR et al. (2007). A phase I study of R1507, a human monoclonal antibody IGF-1R (insulin-like growth factor receptor) antagonist given weekly inpatients with advanced solid tumors. Presented at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting, San Francisco, USA, 22–26 October 2007, http://www.aacr.org/Uploads/DocumentRepository/2007conf/moltar/mt07_postera.pdf.

  • Lindsay CR, Chan E, Evans TR, Campbell S, Bell P, Stephens AW et al. (2009). Phase I dose escalation study of continuous oral dosing of OSI-906, an insulin like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 27: 15s (suppl; abstr 2559).

    Google Scholar 

  • Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. (2001). Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93: 1852–1857.

    CAS  PubMed  Google Scholar 

  • Ma J, Li H, Giovannucci E, Mucci L, Qiu W, Nguyen PL et al. (2008). Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol 9: 1039–1047.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Majeed N, Blouin MJ, Kaplan-Lefko PJ, Barry-Shaw J, Greenberg NM, Gaudreau P et al. (2005). A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model. Oncogene 24: 4736–4740.

    CAS  PubMed  Google Scholar 

  • Martin MJ, Melnyk N, Pollard M, Bowden M, Leong H, Podor TJ et al. (2006). The insulin-like growth factor I receptor is required for Akt activation and suppression of anoikis in cells transformed by the ETV6-NTRK3 chimeric tyrosine kinase. Mol Cell Biol 26: 1754–1769.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mendelsohn J, Baselga J . (2006). Epidermal growth factor receptor targeting in cancer. Semin Oncol 33: 369–385.

    CAS  PubMed  Google Scholar 

  • Moreau P, Hulin C, Facon T, Boccadoro M, Mery-Mignard D, Deslandes A et al. (2007). Phase I study of AVE1642 anti IGF-1R monoclonal antibody in patients with advanced multiple myeloma. Blood. ASH Annual Meeting Abstracts, http://abstracts.hematologylibrary.org/cgi/content/abstract/110/11/1166?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=AVE1642&searchid=1&FIRSTINDEX=0&volume=110&issue=11&resourcetype=HWCIT.

  • Morrow LA, O’Brien MB, Moller DE, Flier JS, Moses AC . (1994). Recombinant human insulin-like growth factor-I therapy improves glycemic control and insulin action in the type A syndrome of severe insulin resistance. J Clin Endocrinol Metab 79: 205–210.

    CAS  PubMed  Google Scholar 

  • Myal Y, Shiu RP, Bhaumick B, Bala M . (1984). Receptor binding and growth-promoting activity of insulin-like growth factors in human breast cancer cells (T-47D) in culture. Cancer Res 44: 5486–5490.

    CAS  PubMed  Google Scholar 

  • Natrajan R, Reis-Filho JS, Little SE, Messahel B, Brundler MA, Dome JS et al. (2006). Blastemal expression of type I insulin-like growth factor receptor in Wilms’ tumors is driven by increased copy number and correlates with relapse. Cancer Res 66: 11148–11155.

    CAS  PubMed  Google Scholar 

  • O’Reilly KE, Molife R, Okuno S, Worden F, Hammer G, Yap T et al. (2006). mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66: 1500–1508.

    PubMed  PubMed Central  Google Scholar 

  • Olmos D, Molife R, Okuno S, Worden F, Hammer G, Yap T et al. (2007). Safety, tolerability and preliminary efficacy of the anti-IGF-IR monoclonal antibody CP-751,871 in patients with sarcomas and adrenocortical tumors. Presented at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting, San Francisco, USA, 22–26, October 2007, http://www.aacr.org/Uploads/DocumentRepository/2007conf/moltar/mt07_postera.pdf.

  • Olmos D, Okuno S, Schuetze SM, Pacagnella ML, Yin D, Gualberto A et al. (2008). Safety, pharmacokinetics and preliminary activity of the anti-IGF-IR antibody CP-751,871 in patients with sarcoma. J Clin Oncol 26: 553s.

    Google Scholar 

  • Plymate SR, Haugk K, Coleman I, Woodke L, Vessella R, Nelson P et al. (2007). An antibody targeting the type I insulin-like growth factor receptor enhances the castration-induced response in androgen-dependent prostate cancer. Clin Cancer Res 13: 6429–6439.

    CAS  PubMed  Google Scholar 

  • Pollak M . (2008a). Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8: 915–928.

    CAS  PubMed  Google Scholar 

  • Pollak M. (2008b). Targeting insulin and insulin-like growth factor signalling in oncology. Curr Opin Pharmacol 8: 384–392.

    CAS  PubMed  Google Scholar 

  • Pollak M, Blouin MJ, Zhang JC, Kopchick JJ. (2001). Reduced mammary gland carcinogenesis in transgenic mice expressing a growth hormone antagonist. Br J Cancer 85: 428–430.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pollak M, Eisenberg P, Karp D, Cohen R, Kreisman H, Adjei A et al. (2007). Safety and tolerability of the anti-IGF-I receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in patients with advanced solid tumors. AACR Meeting Abstracts (abstract LB-343), http://www.aacrmeetingabstracts.org/cgi/content/meeting_abstract/2007/1_Annual_Meeting/LB-343?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1=Pollak&title=paclitaxel+carboplatin&andorexacttitle=and&andorexacttitleabs=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&fdate=1/1/2007&tdate=12/31/2007&resourcetype=HWCIT.

  • Pollak MN, Perdue JF, Margolese RG, Baer K, Richard M. (1987). Presence of somatomedin receptors on primary human breast and colon carcinomas. Cancer Lett 38: 223–230.

    CAS  PubMed  Google Scholar 

  • Pollak MN, Schernhammer ES, Hankinson SE. (2004). Insulin-like growth factors and neoplasia. Nat Rev Cancer 4: 505–518.

    CAS  PubMed  Google Scholar 

  • Postel-Vinay S, Okuno S, Schuetze SM, Pacagnella L, Yin D, Gualberto A et al. (2008). Safety, pharmacokinetics and preliminary activity of the anti-IGF-1R antibody CP-751,871 in patients with sarcoma. Presented at the 20th EORTC-NCI-AACR symposium on Molecular Targets and Cancer Therapeutics Congress, 21–24 October 2008, Geneva, Switzerland.

  • Rodon J, DeSantos V, Ferry Jr RJ, Kurzrock R. (2008). Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials. Mol Cancer Ther 7: 2575–2588.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rodon J, Patnaik A, Stein M, Tolcher A, Ng C, Dias C et al. (2007). A phase I study of q3w R1507, a human monoclonal antibody IGF-1R antagonist in patients with advanced cancer. J Clin Oncol 25: 160s.

    Google Scholar 

  • Rothenberg ML, Poplin E, Sandler AB, Rubin EH, Fox F, Schwartz J et al. (2007). Phase I dose-escalation study of the anti-IGF-IR recombinant human IgG1 monoclonal antibody (Mab) IMC-A12, administered every other week to patients with advanced solid tumors. Presented at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting, San Francisco, USA, 22–26 October 2007, http://www.aacr.org/Uploads/DocumentRepository/2007conf/moltar/mt07_posterc.pdf.

  • Russo VC, Gluckman PD, Feldman EL, Werther GA. (2005). The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev 26: 916–943.

    CAS  PubMed  Google Scholar 

  • Ryan PD, Neven P, Dirix LY, Barrios CH, Miller WH, Fenton D et al. (2008). Safety of the anti-IGF-1R antibody CP-751,871 in combination with exemestane in patients with advanced breast cancer. Presented at the 31st Annual San Antonio Breast Cancer Meeting, San Antonio, USA, 10–14 December 2008.

  • Sachdev D, Singh R, Fujita-Yamaguchi Y, Yee D. (2006). 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 66: 2391–2402.

    CAS  PubMed  Google Scholar 

  • Sachdev D, Yee D . (2007). Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 6: 1–12.

    CAS  PubMed  Google Scholar 

  • Samani AA, Yakar S, LeRoith D, Brodt P. (2007). The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28: 20–47.

    CAS  PubMed  Google Scholar 

  • Sarantopoulos J, Mita AC, Mulay M, Romero O, Lu J, Capilla F et al. (2008). A phase IB study of AMG 479, a type 1 insulin-like growth factor receptor (IGF1R) antibody, in combination with panitumumab (P) or gemcitabine (G). J Clin Oncol 26: 173s.

    Google Scholar 

  • Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R. (1993). 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 90: 11217–11221.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Seraj J, Tsai M, Seiberling M, Cutler D. (2007). Evaluation of safety and pharmacokinetics of a fully human IGF-1 receptor antibody, SCH 717454, in healthy volunteers. Presented at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting, San Francisco, USA, 22-26 October 2007, http://www.aacr.org/Uploads/DocumentRepository/2007conf/moltar/mt07_postera.pdf.

  • Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA et al. (2005). The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642–1646.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783–792.

    CAS  PubMed  Google Scholar 

  • Tabernero J. (2008). The role of the IGF-1R inhibitor in CRC. Presented at the 33rd ESMO congress, Stockholm, Sweden, 12–16 September, 2008, http://www.esmo.org/fileadmin/media/presentations/977/1976/Tabernero_ESMO%20symposium%202008_slide%20presentation_d02b.ppt.pdf.

  • Tao Y, Pinzi V, Bourhis J, Deutsch E. . (2007). Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway—therapeutic perspectives in cancer. Nat Clin Pract Oncol 4: 591–602.

    CAS  PubMed  Google Scholar 

  • Tarn C, Rink L, Merkel E, Flieder D, Pathak H, Koumbi D et al. (2008). Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci USA 105: 8387–8392.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tolcher AW, Rothenberg ML, Rodon J, Delbeke D, Patnaik A, Nguyen L et al. (2008). A phase I study of AVE1642, a humanized monoclonal antibody IGF-1R (insulin like growth factor1 receptor) antagonist, in patients (pts) with advanced solid tumor (ST). J Clin Oncol 26: 173s.

    Google Scholar 

  • Tolcher AW, Patnaik A, Till E, Takimoto CH, Papadopoulos KP, Massard C et al. (2007). A phase I pharmacokinetic and pharmacodynamic study of AMG 479, a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R), in advanced solid tumors. J Clin Oncol 25: 118s.

    Google Scholar 

  • Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. (2007). Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26: 1932–1940.

    CAS  PubMed  Google Scholar 

  • Weroha SJ, Haluska P . (2008). IGF-1 receptor inhibitors in clinical trials--early lessons. J Mammary Gland Biol Neoplasia 13: 471–483.

    PubMed  PubMed Central  Google Scholar 

  • Wiseman LR, Johnson MD, Wakeling AE, Lykkesfeldt AE, May FE, Westley BR. (1993). Type I IGF receptor and acquired tamoxifen resistance in oestrogen-responsive human breast cancer cells. Eur J Cancer 29A: 2256–2264.

    CAS  PubMed  Google Scholar 

  • Witt K . (2008). OSI Pharmaceuticals Oncology Portfolio: R&D Strategy and Update on Pipeline. Securities and Exchange Commission OSI Pharmaceuticals Inc. 8-K form for 11/26/2008, Exhibit 99.1.

  • Wolpin BM, Meyerhardt JA, Chan AT, Ng K, Chan JA, Wu K et al. (2009). Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J Clin Oncol 27: 176–185.

    PubMed  PubMed Central  Google Scholar 

  • Wu JD, Haugk K, Coleman I, Woodke L, Vessella R, Nelson P et al. (2006). Combined in vivo effect of A12, a type 1 insulin-like growth factor receptor antibody, and docetaxel against prostate cancer tumors. Clin Cancer Res 12: 6153–6160.

    CAS  PubMed  Google Scholar 

  • Wu JD, Odman A, Higgins LM, Haugk K, Vessella R, Ludwig DL et al. (2005). in vivo effects of the human type I insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumors. Clin Cancer Res 11: 3065–3074.

    CAS  PubMed  Google Scholar 

  • Wu Y, Cui K, Miyoshi K, Hennighausen L, Green JE, Setser J et al. (2003). Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors. Cancer Res 63: 4384–4388.

    CAS  PubMed  Google Scholar 

  • Yee D. (2006). Targeting insulin-like growth factor pathways. Br J Cancer 94: 465–468.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yin D, Paccagnella ML, Lacy MQ, De Bono JS, Haluska P, Gualberto A et al. (2008). Population pharmacokinetics of CP-751,871, a monoclonal antibody against IGF-I receptor, in patients with multiple myeloma or solid tumors. J Clin Oncol 26: 118s.

    Google Scholar 

  • Yuen JS, Macaulay VM . (2008). Targeting the type 1 insulin-like growth factor receptor as a treatment for cancer. Expert Opin Ther Targets 12: 589–603.

    CAS  PubMed  Google Scholar 

  • Zhang H, Pelzer AM, Kiang DT, Yee D. (2007) Down-regulation of type I insulin-like growth factor receptor increases sensitivity of breast cancer cells to insulin. Cancer Res 67: 391–397.

    CAS  PubMed  Google Scholar 

  • Zhang L, Zhou W, Velculescu VE, Kern SE, Hruban RH, Hamilton SR et al. (1997). Gene expression profiles in normal and cancer cells. Science 276: 1268–1272.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank D Yee and numerous colleagues for constructive criticism and encouragement. Editorial assistance was provided by ACUMED, Tytherington, UK and was funded by Pfizer Inc. This study was supported by funding from Pfizer Inc.

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Gualberto, A., Pollak, M. Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene 28, 3009–3021 (2009). https://doi.org/10.1038/onc.2009.172

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  • DOI: https://doi.org/10.1038/onc.2009.172

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