Insulin-like growth factor type 1 (IGF-1) and IGF binding protein-3 in patients with Ewing sarcoma family of tumors

Toretsky, Jeffrey A.; Steinberg, Seth M.; Thakar, Manjusha; Counts, Debra; Pironis, Baiba; Parente, B.; Eskenazi, Allen E.; Helman, Lee J.; Wexler, Leonard H.

doi:10.1002/1097-0142(20011201)92:11<2941::aid-cncr10072>3.0.co;2-c

Cited by 55 publications

(33 citation statements)

References 18 publications

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“…The role of EWS-FLI1 inactivation in slowing/arresting tumor growth has been demonstrated in vitro [122]. In a recent multicenter trial, use of IGF1 receptor antisense agents in nude mice resulted in improved survival in the mice treated with the agent as compared with mice that did not receive the IGF1 receptor antisense agent [123].…”

Section: Novel Biologic Therapiesmentioning

confidence: 99%

Current treatment for Ewing’s sarcoma

Thacker¹,

Temple²,

Scully³

2005

Expert Review of Anticancer Therapy

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Ewing's sarcoma is the second most common primary bone tumor seen in children and adolescents, and was described by James Ewing in 1921 as a diffuse endothelioma of bone. It is one of the differential diagnoses of pediatric small round blue cell tumors. This is not a single condition, but a group of morphologically and clinically closely related disorders with similar molecular biology -- expression of tumor-specific chimeric oncoproteins through balanced chromosomal translocations involving the EWS gene -- often referred to as the Ewing family of tumors. This includes Ewing's sarcoma of bone, extra-osseous Ewing's sarcoma, Askin tumor and peripheral neuroectodermal tumor. These are aggressive neoplasms with almost 25% of patients having clinically evident metastases at presentation. Ewing's sarcoma has therefore been considered as a systemic disease necessitating local as well as systemic treatment. An aggressive multidisciplinary approach has resulted in significant improvement in prognosis for patients with these tumors. Despite aggressive treatment, 20-40% of patients with localized disease and almost 80% of patients with metastatic disease at presentation succumb to the illness. Advances in understanding the molecular biology of these tumors will hopefully result in the development of novel treatment approaches. The aim of this article is to review the existing treatment methods and to highlight the more recent approaches to the treatment of this condition.

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Section: Novel Biologic Therapiesmentioning

confidence: 99%

Current treatment for Ewing’s sarcoma

Thacker¹,

Temple²,

Scully³

2005

Expert Review of Anticancer Therapy

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“…Although previously it had been shown that in NIH3T3 cells rapamycin does not inhibit activation of MAPKs (2), there are anecdotal reports that rapamycin can influence activation of MAPK pathways (36). We were interested in the possible role of mTORC1 in coordinating both translational initiation and MAPK activation after stimulation by growth factors reported to be mitogenic in sarcoma cells (37)(38)(39)(40). Cell Lines and Growth Conditions-Culture conditions in serum-containing and serum-free, antibiotic-free media have been described for the human cell lines previously (40,41).…”

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confidence: 99%

mTORC1 Signaling Can Regulate Growth Factor Activation of p44/42 Mitogen-activated Protein Kinases through Protein Phosphatase 2A

Harwood

Shu

Houghton

2008

Journal of Biological Chemistry

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. 1). The mTORC1 complex comprises mTOR, raptor, mLST8, PRAS40, and controls initiation of translation of ribosomal proteins and several proteins that regulate cell cycle. Activation of ribosomal S6K1 after mitogen stimulation is dependent on mTORC1 (2). Cap-dependent translation is facilitated by mTORC1's phosphorylation and inactivation of 4E-BP1, the suppressor of eukaryotic initiation factor 4E (3, 4). The emerging picture places mTORC1 in a central role in which it senses mitogenic stimuli and amino acid (5) nutrient (6) conditions or AMP levels (7,8) and coordinates many cellular processes related to growth and proliferation. Rapamycin, a macrocyclic lactone antibiotic, is a potent and highly selective inhibitor of mTORC1 (9).The mTORC2 complex (mTOR, rictor, mSIN1, and mLST8) is thought to control actin cytoskeleton organization and protein kinase C (reviewed in Refs. 9 -12). The mTORC2 complex also phosphorylates Akt(Ser 473 ), required for full activation (13) and negative regulation of FOXO1A (14). Activation of mTORC1 by insulin and insulin-like growth factors occurs through activation of phosphatidylinositol 3-kinase and Akt. Akt negatively regulates the tuberous sclerosis complex (TSC) composed of harmartin and tuberin that acts as a GTPase-activating protein to maintain Rheb in the GDP (inactive) form (15). Exactly how Rheb activates mTOR is unknown. The activity of TSC is regulated by hypoxia, increases in AMP that activate AMP-PK, a positive regulator of TSC activity, and by MAPKs p44/42 that phosphorylate and inactivate TSC, thus promoting mTORC1 activation (16 -20). Akt also phosphorylates and inactivates PRAS40, another negative regulator of mTOR (21).To date, there is no clear evidence of the exact mechanism by which mTORC1 controls growth-related cellular processes. In vitro, mTORC1 phosphorylates at least two residues (Thr 37 and Thr 46 ) of 22,23). Direct phosphorylation of S6K1 has also been reported (24). However, an alternative mechanism has been proposed in which mTOR kinase activity

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“…Additionally, lower levels of IGF-1 were reported in five patients with metastatic disease compared to patients with localized disease 26. Toretsky et al27 also reported that Ewing sarcoma patients with metastatic disease had lower circulating IGF-1 levels than patients with localized disease, suggesting that more severe illness downregulates IGF-1 production in the liver. In keeping with these reports, we observed lower levels of serum IGF-1 in patients with metastatic disease compared to localized disease, but the difference was not statistically significant, perhaps because of the small population size.…”

Section: Discussionmentioning

confidence: 99%

Serum levels of IGF-1 and IGF-BP3 are associated with event-free survival in adult Ewing sarcoma patients treated with chemotherapy

Groot¹,

Gelderblom²,

Fiocco³

et al. 2017

OTT

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BackgroundActivation of the insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis, tumor progression, and therapy resistance in solid tumors. We examined whether variability in serum levels of IGF-1, IGF-2, and IGF-binding protein 3 (IGF-BP3) can predict event-free survival (EFS) and overall survival (OS) in Ewing sarcoma patients treated with chemotherapy.Patients and methodsSerum levels of IGF-1, IGF-2, and IGF-BP3 of 22 patients with localized or metastasized Ewing sarcoma treated with six cycles of vincristine/ifosfamide/doxorubicin/etoposide (VIDE) chemotherapy were recorded. Baseline levels were compared with presixth cycle levels using paired t-tests and were tested for associations with EFS and OS. Continuous variables were dichotomized according to the Contal and O’Quigley procedure. Survival analyses were performed using Cox regression analysis.ResultsHigh baseline IGF-1 and IGF-BP3 serum levels were associated with EFS (hazard ratio [HR] 0.075, 95% confidence interval [CI] 0.009–0.602 and HR 0.090, 95% CI 0.011–0.712, respectively) in univariate and multivariate analyses (HR 0.063, 95% CI 0.007–0.590 and HR 0.057, 95% CI 0.005–0.585, respectively). OS was improved, but this was not statistically significant. IGF-BP3 and IGF-2 serum levels increased during treatment with VIDE chemotherapy (P=0.055 and P=0.023, respectively).ConclusionHigh circulating serum levels of IGF-1 and IGF-BP3 and the molar ratio of IGF-1:IGF-BP3 serum levels were associated with improved EFS and a trend for improved OS in Ewing sarcoma patients treated with VIDE chemotherapy. These findings suggest the need for further investigation of the IGF-1 pathway as a biomarker of disease progression in patients with Ewing sarcoma.

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Insulin-like growth factor type 1 (IGF-1) and IGF binding protein-3 in patients with Ewing sarcoma family of tumors

Cited by 55 publications

References 18 publications

Current treatment for Ewing’s sarcoma

Current treatment for Ewing’s sarcoma

mTORC1 Signaling Can Regulate Growth Factor Activation of p44/42 Mitogen-activated Protein Kinases through Protein Phosphatase 2A

Serum levels of IGF-1 and IGF-BP3 are associated with event-free survival in adult Ewing sarcoma patients treated with chemotherapy

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