Targeting insulin-like growth factor type 1 receptor in cancer therapy

Atzori, Francesco; Traina, Tiffany A.; Ionta, Maria Teresa; Massidda, B.

doi:10.1007/s11523-009-0123-z

Cited by 35 publications

(30 citation statements)

References 64 publications

(43 reference statements)

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“…This resembles our data in man and is possibly due to the secretion of small amounts of GH. Further support for our hypothesis that IGF deficiency tends to protect against cancer is the successful use in oncology of IGF1R-blocking drugs (12).…”

Section: Discussionmentioning

confidence: 57%

“…There is also evidence that most tumors and transformed cells display increased IGF1 receptor (IGF-1R) concentration and high IGF1R mRNA, causing enhanced IGF1 binding (9,10), leading to the axiom that overexpression of IGF1R is a pre-requirement for acquisition or progress of malignant tumors (11). Further evidence for the link between GH, IGF1 and cancer is the successful use of GH and IGF-1R-blocking agents in the treatment of malignancy (12). The above findings led us to investigate the reverse situation, namely whether congenital defects of GH and IGF1 action would diminish or prevent the development of cancer.…”

Section: Introductionmentioning

confidence: 99%

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Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

Steuerman

Shevah²,

Laron

2011

European Journal of Endocrinology

188

109

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Objective: To investigate whether congenital IGF1 deficiency confers protection against development of malignancies, by comparing the prevalence of malignancies in patients with congenital (secondary) deficiency of IGF1 with the prevalence of cancer in their family members. Method: Only patients with an ascertained diagnosis of either Laron syndrome (LS), congenital IGHD, congenital multiple pituitary hormone deficiency (cMPHD) including GH or GHRHR defect were included in this study. In addition to our own patients, we performed a worldwide survey and collected data on a total of 538 patients, 752 of their first-degree family members, of which 274 were siblings and 131 were further family members. Results: We found that none of the 230 LS patients developed cancer and that only 1 out of 116 patients with congenital IGHD, also suffering from xeroderma pigmentosum, had a malignancy. Out of 79 patients with GHRHR defects and out of 113 patients with congenital MPHD, we found three patients with cancer in each group. Among the first-degree family members (most heterozygotes) of LS, IGHD and MPHD, we found 30 cases of cancer and 1 suspected. In addition, 31 malignancies were reported among 131 further relatives. Conclusions: Our findings bear heavily on the relationship between GH/IGF1 and cancer. Homozygous patients with congenital IGF1 deficiency and insensitivity to GH such as LS seem protected from future cancer development, even if treated by IGF1. Patients with congenital IGHD also seem protected.

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Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

Steuerman

Shevah²,

Laron

2011

European Journal of Endocrinology

188

109

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“…As a result, several strategies to inhibit it with antibodies, antisense, siRNAs, IGF binding proteins, dominant-negative receptors, and small-molecule inhibitors have been explored to date (36,37). In fact, some clinical efficacy has also been reported.…”

Section: Discussionmentioning

confidence: 99%

Molecular Target Characterization and Antimyeloma Activity of the Novel, Insulin-like Growth Factor 1 Receptor Inhibitor, GTx-134

Liang

Yang

Trieu

et al. 2011

Clinical Cancer Research

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Purpose: Therapeutic strategies that target insulin-like growth factor 1 receptor (IGF-1R) hold promise in a wide variety of cancers including multiple myeloma (MM). In this study, we describe GTx-134, a novel small-molecule inhibitor of IGF-1R and insulin receptor (IR) and characterized its antitumor activity in preclinical models of MM. Experimental Design: The activity of GTx-134 as a single agent and in combination was tested in MM cell lines and primary patient samples. Downstream effector proteins and correlation with apoptosis was evaluated. Cytotoxcity in bone marrow stroma coculture experiments was assessed. Finally, the in vivo efficacy was evaluated in a human myeloma xenograft model. Results: GTx-134 inhibited the growth of 10 of 14 myeloma cell lines (<5 μmol/L) and induced apoptosis. Sensitivity to GTx-134 correlated with IGF-1R signal inhibition. Expression of MDR-1 and CD45 were associated with resistance to GTx-134. Coculture with insulin-growth factor-1 (IGF-1) or adherence to bone marrow stroma conferred modest resistance, but did not overcome GTx-134–induced cytotoxicity. GTx-134 showed in vitro synergies when combined with dexamethasone or lenalidomide. Further, GTx-134 enhanced the activity of PD173074, a fibroblast growth factor receptor 3 (FGFR3) inhibitor, against t(4;14) myeloma cells. Therapeutic efficacy of GTx-134 was shown against primary cells and xenograft tumors. Although dysregulation of glucose homeostasis was observed in GTx-134–treated mice, impairment of glucose tolerance was modest. Conclusions: These studies support the potential therapeutic efficacy of GTx-134 in MM. Further, they provide a rationale for clinical application in combination with established antimyeloma treatments and novel targeted therapies. Clin Cancer Res; 17(14); 4693–704. ©2011 AACR.

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“…This provides a rationale for combination therapies with rapalogs and either IGFR antagonists or PI3K inhibitors which may be an appropriate strategy to enhance mTOR-targeted anticancer therapy. Recent preclinical studies could show that IGF-1R antibody in combination with rapamycin displays additive inhibition of cell growth and survival versus either alone [68,69]. This approach is now in early phases of clinical development.…”

Section: Defining the Role Of Mtor In Cancermentioning

confidence: 99%

Targeting mTOR in cancer: renal cell is just a beginning

Azim

Escudier

2010

Targ Oncol

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The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and proliferation. The mTOR pathway integrates signals from nutrients, energy status and extracellular growth factors to regulate many processes, including cell cycle progression, angiogenesis, ribosome biogenesis, and metabolism. Growth factors such as insulin-like growth factor, epidermal growth factor and vascular endothelial growth factor bind to and activate their corresponding tyrosine kinase receptors (TKR) located on the cell surface, to induce signal transduction to the nucleus. TKR induces intracellular signaling cascades via the phosphorylation of the phosphatidylinositol 3-kinase, which in turn phosphorylates Akt. Of particular interest among the Akt targets is the downstream effect on mTOR, which is responsible for protein synthesis of molecules necessary for nutrient uptake, angiogenesis, ribosome biogenesis, cell growth, and proliferation. Growing evidence suggests that mTOR deregulation is associated with many types of human cancer. The importance of mTOR signaling in tumor biology is now widely accepted. Consequently, a number of agents that selectively target mTOR are being developed for cancer treatment and currently temsirolimus and everolimus are approved for the treatment of advanced renal cell cancer. However, the therapeutic benefit of mTOR inhibitors in the clinic may vary depending on the activation state of the different components of the mTOR pathway in a given case. Therefore it seems clear that predicting sensitivity to rapamycins in different cancers will likely require assessing multiple molecular markers related to mTOR signaling pathway, such as phosphatase and tensin homolog (PTEN), phospho-Akt, cytoplasmic p27, and phospho-S6 kinase.

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Targeting insulin-like growth factor type 1 receptor in cancer therapy

Cited by 35 publications

References 64 publications

Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

Molecular Target Characterization and Antimyeloma Activity of the Novel, Insulin-like Growth Factor 1 Receptor Inhibitor, GTx-134

Targeting mTOR in cancer: renal cell is just a beginning

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