The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link

Bowers, Laura W.; Rossi, Emily L.; O’Flanagan, Ciara H.; deGraffenried, Linda A.; Hursting, Stephen D.

doi:10.3389/fendo.2015.00077

Cited by 130 publications

(130 citation statements)

References 196 publications

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“…Consequently, many drug development programs targeting the IGF-IR have been discontinued. Several possible explanations have been suggested for the failure of IGF-IR therapy, as reviewed in [187–189]. Firstly, most past clinical trials failed to incorporate the use of predictive biomarkers for the selection of probable responders.…”

Section: Lessons Learned From Previous Clinical Trialsmentioning

confidence: 99%

“…To limit these adverse effects and prevent treatment failure it can therefore be hypothesized that next to lifestyle changes insulin sensitizers (e.g. metformin) should be combined with the IGF system inhibitors [187]. In addition, more efforts should be made to identify more selective targets to improve tumor cell selectivity and avoid IGF system related toxicity.…”

Section: Lessons Learned From Previous Clinical Trialsmentioning

confidence: 99%

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The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

et al. 2016

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Multiple myeloma (MM) is a highly heterogeneous plasma cell malignancy. The MM cells reside in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, proliferation, and drug resistance. As in most cancers, the insulin-like growth factor (IGF) system has been demonstrated to play a key role in the pathogenesis of MM. The IGF system consists of IGF ligands, IGF receptors, IGF binding proteins (IGFBPs), and IGFBP proteases and contributes not only to the survival, proliferation, and homing of MM cells, but also MM-associated angiogenesis and osteolysis. Furthermore, increased IGF-I receptor (IGF-IR) expression on MM cells correlates with a poor prognosis in MM patients. Despite the prominent role of the IGF system in MM, strategies targeting the IGF-IR using blocking antibodies or small molecule inhibitors have failed to translate into the clinic. However, increasing preclinical evidence indicates that IGF-I is also involved in the development of drug resistance against current standard-of-care agents against MM, including proteasome inhibitors, immunomodulatory agents, and corticoids. IGF-IR targeting has been able to overcome or revert this drug resistance in animal models, enhancing the efficacy of standard-of-care agents. This finding has generated renewed interest in the therapeutic potential of IGF-I targeting in MM. The present review provides an update of the impact of the different IGF system components in MM and discusses the diagnostic and therapeutic potentials.

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Section: Lessons Learned From Previous Clinical Trialsmentioning

confidence: 99%

Section: Lessons Learned From Previous Clinical Trialsmentioning

confidence: 99%

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

et al. 2016

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“…This signaling pathway has been identified as a critical determinant of colorectal cancer (CRC) development 2, 3 , and many evidences showed hyperinsulinemia as determinant of CRC risk as well as possible prognostic factors 4–7 .…”

Section: Introductionmentioning

confidence: 99%

“…The Insulin Growth Factor-1 (IGF)-/Insulin-like Growth Factor-Receptor1 (IGF-1R) pathway is a key mediator of the response of tumor cells to the metabolic microenvironment and the regulation of tumor cell metabolism, proliferation, survival and angiogenesis. [1][2][3] This signaling pathway has been identified as a critical determinant of colorectal cancer (CRC) development, 2,3 and many evidences showed hyperinsulinemia as determinant of CRC risk as well as possible prognostic factor. [4][5][6][7] Insulin receptor substrate (IRS) 1 and IRS2 are scaffolding proteins regulating downstream signaling of IGF/IGF-1R.…”

mentioning

confidence: 99%

Single nucleotide polymorphisms in the IGF‐IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE‐3 trial

Schirripa

Heinemann

et al. 2017

Intl Journal of Cancer

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The Insulin-like growth factor (IGF)/IGF-receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF-1R SNPs in mCRC patients enrolled in the FIRE-3 trial. Four SNPs of IRS (IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and 4 SNPs of IGF1-IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct-sequencing in the FIRE-3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/- carriers (N= 105) achieved significantly worse OS compared to T/T (N=464) in univariate (HR=1.32 [95%CI 1.03–1.70], p=0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/- variant (N= 280) achieved improved PFS compared to C/C (N=257) in univariate (HR=0.77 [95%CI 0.64–0.92], p=0.004) and in multivariable. In the RAS wild-type subgroup IGF1 rs2946834 T/- carriers showed better PFS and OS compared to C/C (univariate HR for PFS=0.65 [95%CI 0.51–0.81], p<0.001; multivariable HR for PFS=0.63 [95%CI 0.50–0.81], p<0.001). IRS1 rs1801123 SNP was identified as a new prognostic marker for mCRC. IGF1 rs2946834 was confirmed as prognostic factor in the overall population and in RAS wild type patients. Our findings underline the importance of IGF downstream signaling pathway in RAS wild-type mCRC patient.

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“…Insulin resistance appears to play a central role in endometrial carcinogenesis. Therefore, treatment with insulin-sensitizing agents that act through reducing insulin levels could offer a general approach to prevent the development of cancer and reduce metastasis (10,11).…”

Section: Introductionmentioning

confidence: 99%

Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment

et al. 2016

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Abstract. In order to improve our understanding of the potential preventive and therapeutic role of metformin, the present study aimed to investigate the capability of low-dose metformin in the efficient inhibition of cancer development and the reduction of the metastasis of endometrial adenocarcinoma type I and primary endometrial epithelial cells (eEPs), with the drug acting as a treatment in a hyperinsulinemic environment exposed to high and normal glucose conditions. The Ishikawa endometrial adenocarcinoma cell line and primary eEPs were exposed to an environment with high (17 mM) or normal glucose (5 mM) and treated with insulin, low-dose metformin (0.1 mM) or a combined treatment. Metastatic potential was assessed by migration and invasion assays, and relative cell proliferation was determined. Metformin at a low dose potently inhibited the insulin action, decreasing the ability of the endometrial cancer (EC) cell line to migrate and invade in a high and normal glucose environment, and decreasing the migration ability of the primary eEPs. In the EC cell line, the insulin treatment increased the proliferation, without any subsequent reduction of proliferation by the addition of 0.1 mM metformin; however, relative cell proliferation sensitivity to metformin was observed in the range between 1 and 5 mM regardless of the glucose concentration present. Overall, metformin at 0.1 mM is not efficient enough to decrease the proliferation in an EC cell line. However, at this concentration, metformin can inhibit the insulin action in endometrial epithelial cancer cells, demonstrating an anti-metastatic effect in high and normal glucose environments.

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The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link

Cited by 130 publications

References 196 publications

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

Single nucleotide polymorphisms in the IGF‐IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE‐3 trial

Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment

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