Minireview: Were the IGF Signaling Inhibitors All Bad?

Overview

Journal Mol Endocrinol

Specialties Endocrinology
Molecular Biology

Date 2015 Sep 15

PMID 26366975

Citations 58

Authors

Heather Beckwith

Douglas Yee

Affiliations

Soon will be listed here.

Abstract

Preclinical studies in the 1980s defined a role for IGF signaling in the development and sustainability of the malignant process. Subsequently, antibody, tyrosine kinase, and ligand inhibitors of the IGF receptor were manufactured. In the past decade, numerous clinical trials have tested the efficacy of IGF receptor inhibitors in the treatment of advanced tumors. Early-phase trials in heavily pretreated populations showed promise with complete or partial responses in a few patients and stable disease in many more. Unfortunately, the results of the early-phase trials did not pan out to later-phase trials. The lack of use of biomarkers to define subsets of patients that may benefit from IGF receptor blockade and compensatory signaling via other growth factor receptors such as the insulin, GH, and epidermal growth factor receptors may have played a role in the lack of efficacy of IGF receptor inhibition in phase III trials. Although these trials failed to show benefit, the trials have revealed previously unknown knowledge regarding the complex nature of IGF signaling. The knowledge obtained from these trials will be useful in designing future trials studying inhibitors of growth factor signaling.

Citing Articles

Haploinsufficiency of miR-143 and miR-145 reveal targetable dependencies in resistant del(5q) myelodysplastic neoplasm.

Gharaee N, Wegrzyn-Woltosz J, Jiang J, Akhade V, Bridgers J, Stubbins R Leukemia. 2025; .

PMID: 40000845 DOI: 10.1038/s41375-025-02537-2.

Hepatocellular carcinoma: signaling pathways and therapeutic advances.

Zheng J, Wang S, Xia L, Sun Z, Chan K, Bernards R Signal Transduct Target Ther. 2025; 10(1):35.

PMID: 39915447 PMC: 11802921. DOI: 10.1038/s41392-024-02075-w.

β-integrin controls IGF-1R internalization and intracellular signaling.

McDermott N, OShea S, Rieger L, Cox O, OConnor R J Biol Chem. 2024; 301(1):108021.

PMID: 39608716 PMC: 11732470. DOI: 10.1016/j.jbc.2024.108021.

The Impact of Pdcd4, a Translation Inhibitor, on Drug Resistance.

Wang Q, Yang H Pharmaceuticals (Basel). 2024; 17(10).

PMID: 39459035 PMC: 11510623. DOI: 10.3390/ph17101396.

Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer.

Basu R, Kulkarni P, Swegan D, Duran-Ortiz S, Ahmad A, Caggiano L Int J Mol Sci. 2024; 25(13).

PMID: 39000545 PMC: 11242728. DOI: 10.3390/ijms25137438.

References

Sachdev D . Regulation of breast cancer metastasis by IGF signaling. J Mammary Gland Biol Neoplasia. 2008; 13(4):431-41. DOI: 10.1007/s10911-008-9105-5. View

Karp D, Paz-Ares L, Novello S, Haluska P, Garland L, Cardenal F . Phase II study 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. 2009; 27(15):2516-22. DOI: 10.1200/JCO.2008.19.9331. View

Zhang H, Fagan D, Zeng X, Freeman K, Sachdev D, Yee D . Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation. Oncogene. 2010; 29(17):2517-27. PMC: 2861724. DOI: 10.1038/onc.2010.17. View

Fagan D, Uselman R, Sachdev D, Yee D . Acquired resistance to tamoxifen is associated with loss of the type I insulin-like growth factor receptor: implications for breast cancer treatment. Cancer Res. 2012; 72(13):3372-80. PMC: 4520534. DOI: 10.1158/0008-5472.CAN-12-0684. View

Pavlicek A, Lira M, Lee N, Ching K, Ye J, Cao J . Molecular predictors of sensitivity to the insulin-like growth factor 1 receptor inhibitor Figitumumab (CP-751,871). Mol Cancer Ther. 2013; 12(12):2929-39. DOI: 10.1158/1535-7163.MCT-13-0442-T. View

Schmidt J, Wehde B, Sakamoto K, Triplett A, Anderson S, Tsichlis P . Stat5 regulates the phosphatidylinositol 3-kinase/Akt1 pathway during mammary gland development and tumorigenesis. Mol Cell Biol. 2014; 34(7):1363-77. PMC: 3993568. DOI: 10.1128/MCB.01220-13. View

Ludovini V, Bellezza G, Pistola L, Bianconi F, Di Carlo L, Sidoni A . High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients. Ann Oncol. 2009; 20(5):842-9. DOI: 10.1093/annonc/mdn727. View

Haluska P, Shaw H, Batzel G, Yin D, Molina J, Molife L . 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. 2007; 13(19):5834-40. DOI: 10.1158/1078-0432.CCR-07-1118. View

Zeng X, Sachdev D, Zhang H, Gaillard-Kelly M, Yee D . Sequencing of type I insulin-like growth factor receptor inhibition affects chemotherapy response in vitro and in vivo. Clin Cancer Res. 2009; 15(8):2840-9. PMC: 2720270. DOI: 10.1158/1078-0432.CCR-08-1401. View

10.

Sachdev D, Yee D . The IGF system and breast cancer. Endocr Relat Cancer. 2001; 8(3):197-209. DOI: 10.1677/erc.0.0080197. View

11.

Puzanov I, Lindsay C, Goff L, Sosman J, Gilbert J, Berlin J . 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. 2014; 21(4):701-11. DOI: 10.1158/1078-0432.CCR-14-0303. View

12.

Fuchs C, Azevedo S, Okusaka T, Van Laethem J, Lipton L, Riess H . 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(5):921-927. PMC: 4804122. DOI: 10.1093/annonc/mdv027. View

13.

Lovly C, McDonald N, Chen H, Ortiz-Cuaran S, Heukamp L, Yan Y . Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med. 2014; 20(9):1027-34. PMC: 4159407. DOI: 10.1038/nm.3667. View

14.

Buck E, Gokhale P, Koujak S, Brown E, Eyzaguirre A, Tao N . 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(10):2652-64. DOI: 10.1158/1535-7163.MCT-10-0318. View

15.

Guevara-Aguirre J, Rosenbloom A . Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency. Diabetologia. 2014; 58(1):37-42. DOI: 10.1007/s00125-014-3397-3. View

16.

Vilmar A, Santoni-Rugiu E, Cillas J, Huarriz M, Sorensen J . Insulin-like growth factor receptor 1 mRNA expression as a prognostic marker in advanced non-small cell lung cancer. Anticancer Res. 2014; 34(6):2991-6. View

17.

Thariat J, Bensadoun R, Etienne-Grimaldi M, Grall D, Penault-Llorca F, Dassonville O . Contrasted outcomes to gefitinib on tumoral IGF1R expression in head and neck cancer patients receiving postoperative chemoradiation (GORTEC trial 2004-02). Clin Cancer Res. 2012; 18(18):5123-33. DOI: 10.1158/1078-0432.CCR-12-1518. View

18.

Yee D . Insulin-like growth factor receptor inhibitors: baby or the bathwater?. J Natl Cancer Inst. 2012; 104(13):975-81. PMC: 3634550. DOI: 10.1093/jnci/djs258. View

19.

Karp D, Pollak M, Cohen R, Eisenberg P, Haluska P, Yin D . Safety, pharmacokinetics, and pharmacodynamics of the insulin-like growth factor type 1 receptor inhibitor figitumumab (CP-751,871) in combination with paclitaxel and carboplatin. J Thorac Oncol. 2009; 4(11):1397-403. PMC: 2941876. DOI: 10.1097/JTO.0b013e3181ba2f1d. View

20.

McCaffery I, Tudor Y, Deng H, Tang R, Suzuki S, Badola S . Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor. Clin Cancer Res. 2013; 19(15):4282-9. DOI: 10.1158/1078-0432.CCR-12-1840. View