Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies

Simpson, Aaron D.; Petnga, Wilfride; Macaulay, Valentine M.; Weyer-Czernilofsky, Ulrike; Bogenrieder, Thomas

doi:10.1007/s11523-017-0514-5

Cited by 147 publications

(172 citation statements)

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“…Increased height is associated with elevated insulin-like growth factor 1 (IGF1), [55] which is a growth factor that drives cellular proliferation and survival and has thus been implicated in carcinogenesis of IGF responsive tissues. Notably therefore, and increased expression of IGF1 and its cellular receptors are present in cancer [56,57]. Dysregulation of IGF1 signalling axis in taller individuals may therefore be a driver in a wide range of cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulation of IGF1 signalling axis in taller individuals may therefore be a driver in a wide range of cancers. Therapeutic options exist with receptor tyrosine kinase inhibitors and monoclonal inhibitors, although clinical trials using such agents in treatment of cancers have thus far had disappointing results [57]. Further studies should strengthen the link between IGF-1 in cancer progression in taller individuals and the impact of such therapies in taller patients with IGF responsive tumours.…”

Section: Discussionmentioning

confidence: 99%

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Body size and composition and site-specific cancers in UK Biobank: a Mendelian randomisation study

Vithayathil

Carter

Kar

et al. 2020

Preprint

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word count: 299 Main text word count: 2,320 Number of Tables: 5 (supplementary) Number of Figures: 4 ABSTRACT Objectives To investigate the casual role of body mass index, body fat composition and height in cancer. DesignTwo stage mendelian randomisation study SettingPrevious genome wide association studies and the UK Biobank ParticipantsGenetic instrumental variables for body mass index (BMI), fat mass index (FMI), fat free mass index (FFMI) and height from previous genome wide association studies and UK Biobank .Cancer outcomes from 367 586 participants of European descent from the UK Biobank. Main outcome measuresOverall cancer risk and 22 site-specific cancers risk for genetic instrumental variables for BMI, FMI, FFMI and height. ResultsGenetically predicted BMI (per 1 kg/m 2 ) was not associated with overall cancer risk (OR 0.99; 95% confidence interval (CI) 0-98-1.00, p=0.105). Elevated BMI was associated with increased risk of stomach cancer (OR 1.15, 95% (CI) 1.05-1.26; p=0.003) and melanoma (OR 0.96, 95% CI 0.92-1.00; p=0.044). For sex-specific cancers, BMI was positively associated with uterine cancer (OR 1.08, 95% CI 1.01-1.14; p=0.015) but inversely associated with breast (OR 0.95, 95% CI 0.92-0.98; p=0.001), prostate (OR 0.95, 95% CI 0.92-0.99; p=0.007) and testicular cancer (OR 0.89, 95% CI 0.81-0.98; p=0.017). Elevated FMI (per 1 kg/m 2 ) was associated with gastrointestinal cancer (stomach cancer OR 4.23, 95% CI 1.18-15.13, p=0.027; colorectal cancer OR 1.94, 95% CI 1.23-3.07; p=0.004). Increased height (per 1 standard deviation, approximately 6.5cm) was associated with increased risk of overall cancer (OR 1.06; 95% 1.04-1.09; p = 2.9710 -8 ) and most site-specific cancers with the strongest estimates for kidney, non-Hodgkin lymphoma, colorectal, lung, melanoma and breast cancer. ConclusionsThere is little evidence for BMI as a casual risk factor for cancer. BMI may have a causal role for sexspecific cancers, although with inconsistent directions of effect, and FMI for gastrointestinal malignancies. Elevated height is a risk factor for overall cancer and multiple site cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Body size and composition and site-specific cancers in UK Biobank: a Mendelian randomisation study

Vithayathil

Carter

Kar

et al. 2020

Preprint

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“…All skeletal cells express IGF-1 and its receptor, IGF-1R, and require IGF-1 for normal development and function (19). IGF-1 and IGF-2 play an important role in regulating growth and development of normal human tissues by promoting cellular proliferation and differentiation via activation of IGF-1R and IGF-1R/insulin receptor (INSR) hybrids (4,20). In addition, IGF-2 binds to the A isoform of the INSR (INSR-A), a fetal variant of the classical metabolic INSR (INSR-B), which is frequently overexpressed in tumors (4).…”

Section: The Role Of Igf In Normal Bone Development and Remodelingmentioning

confidence: 99%

“…The failure of IGF-1Rinhibitory drugs to impact tumor growth in unselected patients may be attributable to compensatory activation of other signaling pathways, including those involving the epidermal growth factor receptor (EGFR; ref. 76) and Wnt (77), and by the lack of a validated biomarker for patient selection (4). Further, IGF-1R inhibitors are commonly associated with hyperglycemia, due to coinhibition of INSR-B (71,72,(78)(79)(80)(81)(82)(83)(84)(85), which may preclude their use at therapeutic doses; consequently, most agents targeting IGF-1R are no longer in clinical development.…”

Section: Clinical Studies Of Igf Axis Inhibition and Implications Formentioning

confidence: 99%

“…3). Research suggests that IGFs play a fundamental role in bone development, remodeling, and repair, and contribute to key hallmarks of primary cancers, via alteration of stem-cell renewal/differentiation, epithelial-mesenchymal transition (EMT), and treatment resistance (4). In this review, we discuss the clinical significance of bone metastases, review the normal physiologic role of IGFs in bone development and homeostasis, and consider the potential role of the IGF axis in the metastasis of primary tumors to bone.…”

Section: Introductionmentioning

confidence: 99%

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Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

Rieunier

Macaulay

et al. 2019

Clinical Cancer Research

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Bone metastases are a frequent complication of cancer that are associated with considerable morbidity. Current treatments may temporarily palliate the symptoms of bone metastases but often fail to delay their progression. Bones provide a permissive environment because they are characterized by dynamic turnover, secreting factors required for bone maintenance but also stimulating the establishment and growth of metastases. Insulin-like growth factors (IGF) are the most abundant growth factors in bone and are required for normal skeletal development and function. Via activation of the IGF-1 receptors (IGF-1R) and variant insulin receptors, IGFs promote cancer progression, aggressiveness, and treatment resistance. Of specific relevance to bone biology, IGFs contribute to the homing, dormancy, colonization, and expansion of bone metastases. Furthermore, preclinical evidence suggests that tumor cells can be primed to metastasize to bone by a high IGF-1 environment in the primary tumor, suggesting that bone metastases may reflect IGF dependency. Therapeutic targeting of the IGF axis may therefore provide an effective method for treating bone metastases. Indeed, anti-IGF-1R antibodies, IGF-1R tyrosine kinase inhibitors, and anti-IGF-1/2 antibodies have demonstrated antitumor activity in preclinical models of prostate and breast cancer metastases, either alone or in combination with other agents. Several studies suggest that such treatments can inhibit bone metastases without affecting growth of the primary tumor. Although previous trials of anti-IGF-1R drugs have generated negative results in unselected patients, these considerations suggest that future clinical trials of IGF-targeted agents may be warranted in patients with bone metastases.

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Systematic review of antitumour efficacy and mechanism of metformin activity in prostate cancer models

et al. 2022

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Metformin, the first line pharmacotherapy for type 2 diabetes has demonstrated favourable effects in prostate cancer (PCa) across a range of studies evaluating PCa patient outcomes amongst metformin users. However, a lack of rigorously conducted prospective studies has stalled clinical use in this setting. Despite multiple studies evaluating the mechanisms underpinning antitumour effects of metformin in PCa, to date, no reviews have compared these findings. This systematic review and meta‐analysis consolidates the mechanisms accounting for the antitumour effect of metformin in PCa and evaluates the antitumour efficacy of metformin in preclinical PCa studies. Data were obtained through Medline and EMBASE, extracted by two independent assessors. Risk of bias was assessed using the TOXR tool. Meta‐analysis compared in vivo reductions of PCa tumour volume with metformin. In total, 447 articles were identified with 80 duplicates, and 261 articles excluded based on eligibility criteria. The remaining 106 articles were assessed and 71 excluded, with 35 articles included for systematic review, and eight included for meta‐analysis. The mechanisms of action of metformin regarding tumour growth, viability, migration, invasion, cell metabolism, and activation of signalling cascades are individually discussed. The mechanisms by which metformin inhibits PCa cell growth are multimodal. Metformin regulates expression of multiple proteins/genes to inhibit cellular proliferation, cell cycle progression, and cellular invasion and migration. Published in vivo studies also conclusively demonstrate that metformin inhibits PCa growth. This highlights the potential of metformin to be repurposed as an anticancer agent, warranting further investigation of metformin in the setting of PCa.

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Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies

Cited by 147 publications

References 220 publications

Body size and composition and site-specific cancers in UK Biobank: a Mendelian randomisation study

Body size and composition and site-specific cancers in UK Biobank: a Mendelian randomisation study

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

Systematic review of antitumour efficacy and mechanism of metformin activity in prostate cancer models

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