Cancer Research Meeting Calendar Frontiers in Basic Cancer Research
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Miller, B. S.
Right arrow Articles by Yee, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Miller, B. S.
Right arrow Articles by Yee, D.
Related Collections
Right arrow Therapeutics and Targets
Right arrow Therapeutics and Targets: Identification, Validation, and Markers
[Cancer Research 65, 10123-10127, November 15, 2005]
© 2005 American Association for Cancer Research

Reviews

Type I Insulin-like Growth Factor Receptor as a Therapeutic Target in Cancer

Bradley S. Miller1 and Douglas Yee2

Departments of 1 Pediatrics and 2 Medicine, University of Minnesota, Minneapolis, Minnesota

Requests for reprints: Douglas Yee, University of Minnesota Cancer Center, MMC 806, 420 Delaware Street Southeast, Minneapolis, MN 55455. Phone: 612-626-8487; Fax: 612-626-4842; E-mail: yeexx006{at}umn.edu.


   Abstract
Top
 Abstract
Why Target Type I...
 How Should We Target...
 What Should We Expect...
 Summary
 References
 
Data from experimental model systems and population studies have implicated type I insulin-like growth factor receptor (IGF1R) signaling in many different human cancers. Drugs to disrupt IGF1R function have been developed and are now entering clinical trial. This brief review will identify key areas to consider as these clinical trials move forward.

Any new therapy based on targeting a specific molecule must answer three questions: why should we believe that the molecule is a target, how should we target this molecule, and what should we expect from target inhibition?


   Why Target Type I Insulin-like Growth Factor Receptor?
Top
 Abstract
 Why Target Type I...
How Should We Target...
 What Should We Expect...
 Summary
 References
 
The first identified target for cancer therapy was the estrogen receptor-{alpha} (ER{alpha}). In 1896, Beatson recognized the important link between normal mammary gland development and breast cancer growth (1). Although Beatson did not appreciate the central role of ER{alpha} in mediating this response, the idea that factors regulating normal growth and development could also serve as a cancer target was postulated.

Type I insulin-like growth factor receptor (IGF1R) is clearly involved in normal growth and development. During puberty, serum IGF-I levels increase as pituitary-derived growth hormone increases liver igf-1 expression. Children with mutation in igf-1 and igf1r have been described. These children share common features and have poor in utero and postnatal growth, microcephaly, and neurodevelopmental delay (2, 3). In animal model systems, disruption of IGF1R signaling results in reduced breast and prostate gland growth, implying that IGF1R mediates normal organ development (4, 5).

It has also been recognized that some cancers have abnormal expression or function of specific molecules. For example, amplification of the HER-2 oncogene in breast cancer led to the development of trastuzumab as a specific therapy directed against the target (6, 7). Although igf1r causes transformation in vitro (8), amplification of igf1r in human cancer is uncommon (9), and mutation has not been reported. Despite a lack of evidence that igf1r functions as an oncogene, population studies suggest that factors associated with IGF1R function, such as height and diet, elevate breast cancer risk (10, 11). Moreover, elevated levels of IGF-I are associated with an increased risk of developing breast, prostate, and colon cancer (12–14). Thus, igf1r may not be an oncogene, but findings from model systems suggest that IGF1R must function normally in order for malignant transformation to occur (15).

In the transformed cell, there are abundant data showing that IGF1R regulates cancer cell proliferation, survival, and metastasis. Expression of IGF-I, IGF-II, and all of the IGF binding proteins have been documented in primary human cancer, suggesting that tumor biology may be regulated by this system (reviewed in ref. 16). Taken together, these findings support a role for IGF1R in malignant transformation and progression. In many ways, targeting of IGF1R is similar to targeting of ER{alpha} in breast cancer. Although er{alpha} is not an oncogene, it is involved in normal and malignant breast epithelial biology and represents an outstanding target for cancer prevention and treatment.


   How Should We Target Type I Insulin-like Growth Factor Receptor?
Top
 Abstract
 Why Target Type I...
 How Should We Target...
What Should We Expect...
 Summary
 References
 
The IGF1R is highly homologous to insulin receptor, and this has important implications into the targeting of this receptor system (17, 18). Experimental model systems have shown that insulin receptor stimulates mitogenic signaling in cancer cells (19). Because both insulin and IGF-II (20, 21) may activate insulin receptor signaling, inhibition of IGF1R alone may be insufficient. Both insulin receptor and IGF1R require ligand stimulation for activation. Unlike members of the epidermal growth factor receptor family, overexpression alone is insufficient to trigger biochemical activation of the receptor. Thus, inhibition of ligand-receptor interactions could be a strategy to disrupt IGF1R action. The tyrosine kinase domains of IGF1R and insulin receptor are highly homologous. Development of a specific IGF1R inhibitor might be necessary, as type II diabetes, a disease of disrupted insulin receptor signaling, is a major health problem. However, if insulin receptor has a major role in regulating insulin or IGF-II action in cancer cells, then a highly specific IGF1R antagonist may be insufficient to disrupt insulin receptor action in cancer cells.

IGF1R signaling could be disrupted at many levels as shown in Fig. 1. Because serum IGF-I levels are regulated by growth hormone, disruption of the growth hormone/IGF-I axis could be a strategy to disrupt IGF1R signaling by removing the ligand. Antagonists of growth hormone–releasing hormone (22–24) or growth hormone (25) could be used to lower serum IGF-I levels. Interestingly, these drugs may directly affect tumor cells independently of their effects on serum IGF-I levels. It is notable that the growth hormone antagonist pegvisomant is already approved for treatment (26) of growth hormone excess (acromegaly), and it would not be difficult to test this drug as a cancer therapy.



View larger version (23K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. IGF system. Serum IGF-I is regulated by growth hormone (GH). Disruption of the hypothalamic/pituitary axis by growth hormone–releasing hormone (GHRH) antagonists or growth hormone receptor on the liver by pegvisomant would result in lowered IGF-I levels. Both IGF-I and IGF-II could be neutralized by monoclonal antibodies. IGF1R function may be disrupted by monoclonal antibodies or tyrosine kinase inhibitors. However, multiple receptors may participate in tumor cell biology, and disruption of multiple signals may be necessary.

 
However, methods to lower growth hormone–stimulated IGF-I serum levels do not account for paracrine expression of IGF-I nor do they address serum IGF-II. To address this concern, Goya et al. used an IGF-I- and IGF-II-neutralizing antibody to inhibit the growth of prostate cancer cells in human bone (27). By implanting human bone into a xenograft model, the authors showed that this approach could disrupt endocrine and paracrine sources of IGF-I and IGF-II. This method of disrupting IGF action should not affect insulin receptor signaling, which could have an important therapeutic advantage.

Most of the anti-IGF1R strategies have been directed against the receptor itself. A number of monoclonal antibodies have been developed, which block ligand binding and down-regulate receptor levels over time (28–31). Down-regulation of IGF1R may be common to all of the antibodies and may be an important aspect of the observed effects. A single-chain antibody directed against IGF1R acts as a full agonist of the receptor yet retains its ability to down-regulate receptor levels over time and inhibits tumor growth (32, 33). Thus, the ligand blocking effect of the antibodies may be less important than the monoclonal antibodies' ability to down-regulate receptor levels as suggested by Wu et al. (34). None of the antibodies have cross-reactivity with insulin receptor and should not disrupt insulin interaction with its receptor.

Several tyrosine kinase inhibitors have also been developed (35–37). Although these molecules have higher affinity for IGF1R than insulin receptor, there is still some cross-inhibition due to the high degree of homology between the tyrosine kinase domains of the two receptors. In addition, the tyrosine kinase inhibitors have not been reported to down-regulate IGF1R levels.

Thus, both classes of antagonists, monoclonal antibodies and tyrosine kinase inhibitors, disrupt IGF1R signaling via different mechanisms of actions. Because one of the antibodies (CP-751,871) is currently in phase I clinical trial for the treatment of multiple myeloma, we should soon have the initial results from IGF1R signal disruption as a platform to develop strategies in other diseases.


   What Should We Expect from Target Inhibition?
Top
 Abstract
 Why Target Type I...
 How Should We Target...
 What Should We Expect...
Summary
 References
 
Targeted therapies increasingly depend on the measurement of biomarkers that can be used to predict response. Clinical development of tamoxifen and trastuzumab underscore this point; in the absence of the target, these drugs are ineffective. For IGF1R targeting, development of predictive biomarkers may present a problem. First, virtually every tumor studied has some level of IGF1R expression. Defining a minimum number of IGF1Rs required for biological effects has not been defined in preclinical systems. Second, biomarkers for IGF1R action have not been well characterized. In most xenograft model systems, it is difficult to show IGF1R phosphorylation without supplying ligand to the host. Even in humans with well-characterized mutation of IGF1R, in vitro isolation of fibroblasts was necessary to show defective ligand-dependent signaling (3). Pretreatment biopsies may not be useful to distinguish IGF-driven tumors from IGF-independent tumors. Third, IGF1R may regulate several different cancer cell phenotypes. IGF1R has been linked to tumor cell invasion and metastasis. Blocking IGF1R may result in inhibition of signaling but may have no effect on primary tumor growth. In some model systems, disruption of IGF1R regulates metastatic potential independently of tumor growth (38, 39). Indeed, as cells become more aggressive, levels of IGF1R decline (40, 41), suggesting that the function of IGF1R may differ in early-stage tumors versus late-stage tumors. Although it is possible that suppression of IGF1R levels leads to dedifferentiation and more aggressive tumor biology, there are no preclinical data to show that a decline in IGF1R is the cause of tumor progression. Phase II studies only measure changes in tumor growth; even careful measurement of biomarkers would be unable to show changes in tumor invasion or metastasis.

Most targeted therapies eventually will be combined with conventional cytotoxic chemotherapy. For example, trastuzumab and chemotherapy are clearly synergistic (42). Initial preclinical studies suggest that IGF1R enhances response to chemotherapy (30), but the effects of IGF1R inhibition may differ between tumor types and even between cell lines within a single tumor type (34). Although initial trials of tamoxifen in combination with chemotherapy suggested synergistic benefit (43), it took 20 years to show that inhibition of ER{alpha} actually interfered with cytotoxic chemotherapy (44). Careful attention to the clinical trial design of IGF1R combination chemotherapy will be necessary to determine if disruption of IGF1R function will synergize or antagonize the effects of specific cytotoxic drugs.

Perhaps the most concerning aspect of blocking IGF1R is potential toxicity. Because of the ubiquitous nature of IGF1R expression and action, blockade of IGF1R signaling could affect multiple tissues. An increase in the dependence of malignant tissues on IGF1R function could provide a therapeutic window of tolerable IGF1R signal inhibition. However, IGF1R inhibition could preferentially affect tissues with rapid turnover, such as gastrointestinal and hematopoietic cells, similar to other chemotherapy agents.

Because of the importance of IGF signaling in many tissues during growth and development (45, 46), children receiving aggressive IGF1R blockade would be expected to have poor growth and may have other developmental delays. The effect of postnatal IGF1R blockade would be expected to have a lesser but age-related effect on neurodevelopment. Throughout life, IGFs play an important role in neuronal survival (47, 48). As such, systemic blockade of IGF signaling could have toxic effects on the central and peripheral nervous systems. IGF1R has also been implicated in cardiac myocyte survival, and signaling in this organ likely plays an important role in maintaining normal cardiac function (49). Disruption of IGF1R action in the heart could have cardiac effects.

Although the importance of expression and function of the IGF1R in the adult is unknown, the effect of aggressive IGF1R blockade in individuals might be clinically similar to the signs and symptoms of severe growth hormone deficiency. Adults with severe growth hormone deficiency who are not receiving supplementation have an increased risk of osteoporosis, hyperlipidemia, visceral adiposity, cardiac events, and impaired physical performance and psychological complaints (50). Whether any of these signs and symptoms are solely due to diminished IGF1R signaling may require an extended period of IGF1R inhibition to discern.

It is expected that disruption of IGF-I feedback at the hypothalamic IGF1R will result in a reflex increase in growth hormone secretion, similar to the reflex increase in serum estradiol seen in premenopausal women receiving tamoxifen (51). The metabolic effect of excessive growth hormone in the absence of IGF-I action has not been determined. One could imagine that IGF-independent effects of growth hormone, such as lipolysis, may be increased under this therapeutic paradigm.

Tissue-specific deletion of the igf-1, igf-1r, and irs-2 genes in mice have provided some insight into the potential metabolic effect of IGF1R inhibition (reviewed in ref. 52). Disruption of IGF1R signaling has led to some degree of insulin resistance in most model systems studied. Although this phenotype may be exacerbated by the formation of nonfunctional hybrids of mutant IGF1R and normal insulin receptor, a less severe version of these effects may be expected if a specific IGF-I inhibitor is used. Liver-specific knockout of igf-I in mice also results in a phenotype of insulin resistance (53). It is unclear whether the insulin resistance in these experiments is due to growth hormone overproduction or due to an IGF-dependent event. Deletion of the igf1r, irs-1, and irs-2 in pancreatic ß cells has been shown to reduce ß cell mass and increase ß cell apoptosis (54–56). The combination of insulin resistance and reduction of ß cell mass, perhaps caused by igf1r blockade, could result in clinical diabetes. Although temporary induction of insulin resistance could be managed, a permanent effect on pancreatic islet cells would obviously be undesired.

The development of IGF1R antagonists has focused on non–cross-reactivity with insulin receptor. The reason specificity is desired is due to the understanding of the biology and pathology associated with insulin receptor inhibition. The most extreme example of such insulin receptor inhibition is illustrated in individuals with leprechaunism caused by mutations of the insulin receptor (57). Individuals with leprechaunism have severe insulin-resistant diabetes associated with acanthosis nigricans, lipodystrophy, hypertrichosis, and acral hypertrophy (enlarged ears, nose, chin, and fingertips). Again, blockade of insulin signaling by cross-inhibition would be expected to produce a much milder phenotype.

In preclinical model systems, currently published animal data show that short-term inhibition of IGF1R by tyrosine kinase inhibitors (35, 36) or by a monoclonal antibody with significant murine cross-reactivity (34) does not result in substantial weight loss. However, the affinity for these reagents to mouse IGF1R has not been shown, and long-term, more potent inhibition in humans may have other toxicities. There is currently little or no human data regarding the potential short-term and long-term side effects of IGF1R blockade. As therapeutic agents that block IGF1R signaling are developed, special attention needs to be paid to the design of preclinical and clinical trials to collect appropriate safety end points for these therapies alone or in combination with other drugs.


   Summary
Top
 Abstract
 Why Target Type I...
 How Should We Target...
 What Should We Expect...
 Summary
References
 
One perceived disadvantage of targeting IGF1R in cancer is the substantial preclinical understanding of the role this receptor family has in normal physiology. Despite the potential negative side effects of blocking IGF1R signaling, some of which may be permanent, this class of reagents holds promise for the treatment of a number of different cancer types. The negative effects of these agents will be determined by the potency and duration of IGF1R blockade; their ability to cross-inhibit other tyrosine kinases, particularly the insulin receptor; and the individual properties of each drug. As clinical trial designs move forward, careful attention must be paid to these potential side effects. It is likely that long-term IGF1R inhibition may not be tolerated, but alterations in dose or schedule could potentially ameliorate any observed toxicity. One thing is clear, after many years of hypothesizing a role for IGF1R signaling in cancer, the hypothesis can finally be tested in human clinical trials.

Received 8/ 4/05. Revised 9/21/05. Accepted 10/ 5/05.


   References
Top
 Abstract
 Why Target Type I...
 How Should We Target...
 What Should We Expect...
 Summary
 References
 

  1. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma. Suggestions for a new method of treatment with illustrative cases. Lancet 1896;2:104–7.
  2. Woods KA, Camachohubner C, Savage MO, Clark AJL. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 1996;335:1363–7.[Free Full Text]
  3. Abuzzahab MJ, Schneider A, Goddard A, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003;349:2211–22.[Abstract/Free Full Text]
  4. Ruan WF, Newman CB, Kleinberg DL. Intact and amino-terminally shortened forms of insulin-like growth factor-I induce mammary gland differentiation and development. Proc Natl Acad Sci U S A 1992;89:10872–6.[Abstract/Free Full Text]
  5. Ruan WF, PowellBraxton L, Kopchick JJ, Kleinberg DL. Evidence that insulin-like growth factor I and growth hormone are required for prostate gland development. Endocrinology 1999;140:1984–9.[Abstract/Free Full Text]
  6. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–82.[Abstract/Free Full Text]
  7. Vogel C, Cobleigh MA, Tripathy D, et al. First-line, single-agent Herceptin (trastuzumab) in metastatic breast cancer: a preliminary report. Eur J Cancer 2001;37 Suppl 1:25–9.
  8. Kaleko M, Rutter WJ, Miller AD. Overexpression of the human insulin-like growth factor I receptor promotes ligand-dependent neoplastic transformation. Mol Cell Biol 1990;10:464–73.[Abstract/Free Full Text]
  9. Berns EMJJ, Klign JGM, van Staveren IL, Portengen H, Foekens JA. Sporadic amplification of the insulin-like growth factor I receptor gene in human breast tumors. Cancer Res 1992;52:1036–9.[Abstract/Free Full Text]
  10. Ahlgren M, Melbye M, Wohlfahrt J, Sorensen TI. Growth patterns and the risk of breast cancer in women. N Engl J Med 2004;351:1619–26.[Abstract/Free Full Text]
  11. Voskuil DW, Vrieling A, van't Veer LJ, Kampman E, Rookus MA. The insulin-like growth factor system in cancer prevention: potential of dietary intervention strategies. Cancer Epidemiol Biomarkers Prev 2005;14:195–203.[Abstract/Free Full Text]
  12. Giovannucci E, Pollak M, Platz EA, et al. Insulin-like growth factor I (IGF-I), IGF-binding protein-3 and the risk of colorectal adenoma and cancer in the Nurses' Health Study. Growth Horm IGF Res 2000;10 Suppl A:S30–1.
  13. Hankinson SE, Willett WC, Colditz GA, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 1998;351:1373–5.[CrossRef][Medline]
  14. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279:563–5.[Abstract/Free Full Text]
  15. Baserga R, Sell C, Porcu P, Rubini M. The role of the IGF-I receptor in the growth and transformation of mammalian cells. Cell Prolif 1994;27:63–71.[Medline]
  16. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004;4:505–18.[CrossRef][Medline]
  17. Ullrich A, Gray A, Tam AW, et al. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define hormonal specificity. EMBO J 1986;5:2503–12.[Medline]
  18. Steele-Perkins G, Turner J, Edman JC, et al. Expression and characterization of a functional human insulin-like growth factor I receptor. J Biol Chem 1988;263:11486–92.[Abstract/Free Full Text]
  19. Osborne CK, Bolan G, Monaco ME, Lippman ME. Hormone responsive human breast cancer in long-term tissue culture: effect of insulin. Proc Natl Acad Sci U S A 1976;73:4536–40.[Abstract/Free Full Text]
  20. Sciacca L, Costantino A, Pandini G, et al. Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism. Oncogene 1999;18:2471–9.[CrossRef][Medline]
  21. Frasca F, Pandini G, Scalia P, et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 1999;19:3278–88.[Abstract/Free Full Text]
  22. Szereday Z, Schally AV, Varga JL, et al. Antagonists of growth hormone-releasing hormone inhibit the proliferation of experimental non-small cell lung carcinoma. Cancer Res 2003;63:7913–9.[Abstract/Free Full Text]
  23. Braczkowski R, Schally AV, Plonowski A, et al. Inhibition of proliferation in human MNNG/HOS osteosarcoma and SK-ES-1 Ewing sarcoma cell lines in vitro and in vivo by antagonists of growth hormone-releasing hormone: effects on insulin-like growth factor II. Cancer 2002;95:1735–45.[CrossRef][Medline]
  24. Letsch M, Schally AV, Busto R, Bajo AM, Varga JL. Growth hormone-releasing hormone (GHRH) antagonists inhibit the proliferation of androgen-dependent and -independent prostate cancers. Proc Natl Acad Sci U S A 2003;100:1250–5.[Abstract/Free Full Text]
  25. McCutcheon IE, Flyvbjerg A, Hill H, et al. Antitumor activity of the growth hormone receptor antagonist pegvisomant against human meningiomas in nude mice. J Neurosurg 2001;94:487–92.[Medline]
  26. van der Lely AJ, Hutson RK, Trainer PJ, et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 2001;358:1754–9.[CrossRef][Medline]
  27. Goya M, Miyamoto S, Nagai K, et al. Growth inhibition of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth factors. Cancer Res 2004;64:6252–8.[Abstract/Free Full Text]
  28. Burtrum D, Zhu Z, Lu D, et al. A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 2003;63:8912–21.[Abstract/Free Full Text]
  29. Maloney EK, McLaughlin JL, Dagdigian NE, et al. An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation. Cancer Res 2003;63:5073–83.[Abstract/Free Full Text]
  30. Goetsch L, Gonzalez A, Leger O, et al. A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts. Int J Cancer 2005;113:316–28.[CrossRef][Medline]
  31. Cohen BD, Baker DA, Soderstrom C, et al. 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 2005;11:2063–73.[Abstract/Free Full Text]
  32. Li SL, Liang SJ, Guo N, Wu AM, Fujita-Yamaguchi Y. Single-chain antibodies against human insulin-like growth factor I receptor: expression, purification, and effect on tumor growth. Cancer Immunol Immunother 2000;49:243–52.[CrossRef][Medline]
  33. Sachdev D, Li SL, Hartell JS, Fujita-Yamaguchi Y, Miller JS, 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;63:627–35.[Abstract/Free Full Text]
  34. Wu JD, Odman A, Higgins LM, et al. 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 2005;11:3065–74.[Abstract/Free Full Text]
  35. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 2004;5:221–30.[CrossRef][Medline]
  36. Garcia-Echeverria C, Pearson MA, Marti A, et al. In vivo antitumor activity of NVP-AEW541: a novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 2004;5:231–9.[CrossRef][Medline]
  37. Carboni JM, Lee AV, Hadsell DL, et al. Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res 2005;65:3781–7.[Abstract/Free Full Text]
  38. Dunn SE, Ehrlich M, Sharp NJH, et al. A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion; invasion; and metastasis of breast cancer. Cancer Res 1998;58:3353–61.[Abstract/Free Full Text]
  39. Sachdev D, Hartell JS, Lee AV, Zhang X, Yee D. A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells. J Biol Chem 2004;279:5017–24.[Abstract/Free Full Text]
  40. Plymate SR, Bae VL, Maddison L, Quinn LS, Ware JL. Reexpression of the type 1 insulin-like growth factor receptor inhibits the malignant phenotype of simian virus 40 T antigen immortalized human prostate epithelial cells. Endocrinology 1997;138:1728–35.[Abstract/Free Full Text]
  41. Bartucci M, Morelli C, Mauro L, Ando S, Surmacz E. Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA- MB-231 breast cancer cells. Cancer Res 2001;61:6747–54.[Abstract/Free Full Text]
  42. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–92.[Abstract/Free Full Text]
  43. Kiang DT, Gay J, Goldman A, Kennedy BJ. A randomized trial of chemotherapy and hormonal therapy in advanced breast cancer. N Engl J Med 1985;313:1241–6.[Abstract]
  44. Albain KS, Green SJ, Ravdin PM, et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). Proc ASCO 2002;21:143a.
  45. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 1993;75:73–82.[CrossRef][Medline]
  46. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. 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.[Medline]
  47. Feldman EL, Sullivan KA, Kim B, Russell JW. Insulin-like growth factors regulate neuronal differentiation and survival. Neurobiol Dis 1997;4:201–14.[CrossRef][Medline]
  48. Garcia-Segura LM, Cardona-Gomez GP, Chowen JA, Azcoitia I. Insulin-like growth factor-I receptors and estrogen receptors interact in the promotion of neuronal survival and neuroprotection. J Neurocytol 2000;29:425–37.[CrossRef][Medline]
  49. McMullen JR, Shioi T, Huang WY, et al. The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase (p110{alpha}) pathway. J Biol Chem 2004;279:4782–93.[Abstract/Free Full Text]
  50. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998;83:379–81.[Abstract/Free Full Text]
  51. Cohen I, Figer A, Tepper R, et al. Ovarian overstimulation and cystic formation in premenopausal tamoxifen exposure: comparison between tamoxifen-treated and nontreated breast cancer patients. Gynecol Oncol 1999;72:202–7.[CrossRef][Medline]
  52. Butler AA, LeRoith D. Minireview: tissue-specific versus generalized gene targeting of the igf1 and igf1r genes and their roles in insulin-like growth factor physiology. Endocrinology 2001;142:1685–8.[Abstract/Free Full Text]
  53. Yakar S, Setser J, Zhao H, et al. Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice. J Clin Invest 2004;113:96–105.[CrossRef][Medline]
  54. Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF. IRS-2 coordinates IGF-1 receptor-mediated ß-cell development and peripheral insulin signalling. Nat Genet 1999;23:32–40.[Medline]
  55. Kulkarni RN, Winnay JN, Daniels M, et al. Altered function of insulin receptor substrate-1-deficient mouse islets and cultured ß-cell lines. J Clin Invest 1999;104:R69–75.
  56. Zhang Q, Berggren PO, Hansson A, Tally M. Insulin-like growth factor-I-induced DNA synthesis in insulin-secreting cell line RINm5F is associated with phosphorylation of the insulin-like growth factor-I receptor and the insulin receptor substrate-2. J Endocrinol 1998;156:573–81.[Abstract]
  57. Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med 1976;294:739–45.[Abstract]



This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
M. Al Sorkhy, R. Craig, B. Market, R. Ard, and L. A. Porter
The Cyclin-dependent Kinase Activator, Spy1A, Is Targeted for Degradation by the Ubiquitin Ligase NEDD4
J. Biol. Chem., January 30, 2009; 284(5): 2617 - 2627.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Cao, Y. Yu, I. Darko, D. Currier, L. H. Mayeenuddin, X. Wan, C. Khanna, and L. J. Helman
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., October 1, 2008; 68(19): 8039 - 8048.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
C. Tarn, L. Rink, E. Merkel, D. Flieder, H. Pathak, D. Koumbi, J. R. Testa, B. Eisenberg, M. von Mehren, and A. K. Godwin
Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors
PNAS, June 17, 2008; 105(24): 8387 - 8392.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
W. Piao, Y. Wang, Y. Adachi, H. Yamamoto, R. Li, A. Imsumran, H. Li, T. Maehata, M. Ii, Y. Arimura, et al.
Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas
Mol. Cancer Ther., June 1, 2008; 7(6): 1483 - 1493.
[Abstract] [Full Text] [PDF]

Home page
 J BiochemHome page
Y. Kusada, T. Morizono, A. Matsumoto-Takasaki, K. Sakai, S. Sato, H. Asanuma, A. Takayanagi, and Y. Fujita-Yamaguchi
Construction and Characterization of Single-chain Antibodies Against Human Insulin-like Growth Factor-I Receptor from Hybridomas Producing 1H7 or 3B7 Monoclonal Antibody
J. Biochem., January 1, 2008; 143(1): 9 - 19.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
C. J. Barnes, K. Ohshiro, S. K. Rayala, A. K. El-Naggar, and R. Kumar
Insulin-like Growth Factor Receptor as a Therapeutic Target in Head and Neck Cancer
Clin. Cancer Res., July 15, 2007; 13(14): 4291 - 4299.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. M. Wilson and P. Rotwein
Selective Control of Skeletal Muscle Differentiation by Akt1
J. Biol. Chem., February 23, 2007; 282(8): 5106 - 5110.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Tanaka, M. Yamamoto, N. Hashimoto, M. Miyakoshi, S. Tamakawa, M. Yoshie, Y. Tokusashi, K. Yokoyama, Y. Yaginuma, and K. Ogawa
Hypoxia-Independent Overexpression of Hypoxia-Inducible Factor 1{alpha} as an Early Change in Mouse Hepatocarcinogenesis
Cancer Res., December 1, 2006; 66(23): 11263 - 11270.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. M. Wilson and P. Rotwein
Control of MyoD Function during Initiation of Muscle Differentiation by an Autocrine Signaling Pathway Activated by Insulin-like Growth Factor-II
J. Biol. Chem., October 6, 2006; 281(40): 29962 - 29971.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. Lu, D. Katsaros, A. Wiley, I. A. Rigault de la Longrais, H. A. Risch, M. Puopolo, and H. Yu
The Relationship of Insulin-Like Growth Factor-II, Insulin-Like Growth Factor Binding Protein-3, and Estrogen Receptor-{alpha} Expression to Disease Progression in Epithelial Ovarian Cancer
Clin. Cancer Res., February 15, 2006; 12(4): 1208 - 1214.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Miller, B. S.
Right arrow Articles by Yee, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Miller, B. S.
Right arrow Articles by Yee, D.
Related Collections
Right arrow Therapeutics and Targets
Right arrow Therapeutics and Targets: Identification, Validation, and Markers

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online