Expression of insulin-like growth factor 2 in mesenchymal neoplasms

Steigen, Sonja Eriksson; Schaeffer, David F.; West, Robert B.; Nielsen, Torsten O.

doi:10.1038/modpathol.2009.48

Cited by 75 publications

(49 citation statements)

References 52 publications

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“…5,23,24 Previous studies have indicated another potential factor in the Akt/mTOR pathway: the activation of receptor tyrosine kinases or cytokine receptors. Epidermal growth factor receptor (EGFR), 14,25,26 insulin-like growth factor-1 receptor (IGF1R), 14,27 and plateletderived growth factor receptor a (PDGFRa) 6,28,29 have been proven responsible for Akt/mTOR pathway activation in SS, and some preclinical studies have lent credence to targeting this pathway. 6,29 Clinical trials of molecular targeting drugs also have been undertaken in STS.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Setsu

Kohashi

Fushimi

et al. 2013

Cancer

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BACKGROUND:The Akt/mammalian target of rapamycin (mTOR) pathway, downstream from phosphatidylinositol 3-kinase (PI3K), mediates cell survival and proliferation. Although this pathway reportedly contributes to the progression of synovial sarcoma, its prognostic impact has not been clarified. METHODS: The authors analyzed clinicopathologic data and phosphorylation status of Akt (a serine/threonine kinase also known as protein kinase B), mTOR, the eukaryotic translation initiation factor 4E binding protein (4E-BP1), and the S6 ribosomal protein by immunohistochemical analysis of 120 formalin-fixed, paraffin-embedded samples and by Western blot analysis of 24 frozen samples from 112 patients with synovial sarcoma. RESULTS: Akt, mTOR, 4E-BP1, and S6 were activated in 76.5%, 67.6%, 59.6%, and 42.6% of samples, respectively. Immunohistochemically positive phosphorylated (p) mTOR (pmTOR) and p4E-BP1 results were correlated with higher mitotic activity, and positive p4E-BP1 results were correlated with greater necrosis. No mutations around the hot spots in the PI3K catalytic subunit a (PI3KCA) and Akt1 genes were observed. In multivariate analysis of clinicopathologic parameters, frequent mitosis was a risk factor for shorter overall survival; and male sex, visceral location, larger tumor size, and frequent mitosis were identified as risk factors for shorter event-free survival. Positive pmTOR and p4E-BP1 results were correlated significantly with shorter overall survival, and positive p4E-BP1 results were correlated with shorter event-free survival in univariate analysis. Positive pAkt results were associated significantly with shorter event-free survival in multivariate analysis. CONCLUSIONS: In this study, the Akt/mTOR pathway was activated and was associated with worse clinical and pathologic behavior in patients with synovial sarcoma. The authors propose that this pathway may have potential as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Setsu

Kohashi

Fushimi

et al. 2013

Cancer

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“…They underline the frequent expression of platelet-derived growth factor receptor (PDGFR) family members (PDGFRB, 86.5%; PDGFRA, 97.7%), MET (96.6%; ref. 15), as well as IGF2 (16). Sporadically missense mutations involving PDGFRB were described (i.e., 2 cases of 88 examined; ref.…”

Section: Introductionmentioning

confidence: 99%

“…15). Interestingly, among the 50+ bone and soft tissue tumors, SFT is the one with the most prominent expression of IGF2, in terms of frequency (20 of 25 cases) and magnitude (16). Furthermore, in a series of eight surgical specimens, the constitutive activation of insulin receptor (IR), mainly represented by the IR-A isoform, and its downstream signaling, was shown through immunoprecipitation (IP), Western blotting (WB), and reverse transcription-PCR (RT-PCR; ref.…”

Section: Introductionmentioning

confidence: 99%

Sunitinib Malate and Figitumumab in Solitary Fibrous Tumor: Patterns and Molecular Bases of Tumor Response

Stacchiotti

Negri

Palassini

et al. 2010

Molecular Cancer Therapeutics

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Antiangiogenic treatment activity has been reported in solitary fibrous tumor (SFT), a rare and little chemosensitive sarcoma. We explored the activity of sunitinib malate (SM) in SFT and studied receptor tyrosine kinase (RTK) activation profile. Eleven patients with progressive metastatic SFT resistant to chemotherapy were treated with continuous-dosing 37.5 mg/d SM on a named-use basis. One of them also received the insulin-like growth factor I receptor (IGFIR) inhibitor figitumumab after developing secondary resistance to SM. Besides, biochemical, molecular, and fluorescence in situ hybridization analyses were done in eight naïve SFTs whose cryopreserved material was available to clarify RTK upstream and downstream signaling. In two cases treated with SM and belonging to the naïve series, both pretreatment and posttreatment samples were available. Ten patients were evaluable for response to SM. The best response according to the Choi criteria was six partial response (all with Response Evaluation Criteria in Solid Tumors stable disease), one stable disease, and three progressive disease. Responses lasted >6 months in five patients. The eight naïve samples showed high expression/phosphorylation of PDGFRB, epidermal growth factor receptor, and IGFIR/IR, in the presence of their cognate ligands. Downstream pathways revealed expression/activation of Akt, extracellular signal-regulated kinase 1-2 and, closely related to SFT subtypes, of S6 and 4E-BP1. In two patients, whose pretreatment and posttreatment clinical and molecular status were available, biochemical data confirmed the activity of SM, although they also suggested a possible time-dependent shift of dominant RTK from PDGFRB to IGFIR/insulin receptor. A Response Evaluation Criteria in Solid Tumors partial response to figitumumab corroborated these findings. SM has antitumor activity in SFT, possibly through a PDGFRB-mediated mechanism, but treatments with IGFIR/ insulin receptor and possibly epidermal growth factor receptor inhibitors are worth testing. Mol Cancer Ther; 9(5); 1286-97. ©2010 AACR.

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“…Several strategies, such as using a monoclonal antibody (mAb), a dominant-negative mutant, or antisense oligonucleotides, all originally showed that interference of IGF-IR signaling can inhibit tumor growth in animal models (6)(7)(8). In humans, altered expression of IGF-IR, its ligands, and/or IGFBPs is frequently found in a variety of cancers (9)(10)(11)(12)(13), and elevated circulating levels of serum IGF-I are linked with increased risk of developing many cancers (14)(15)(16). In particular, IGF-II upregulation with loss of imprinting is a common event observed in several cancer types (17).…”

Section: Introductionmentioning

confidence: 99%

Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response

Dong

Demarest

Sereno

et al. 2010

Molecular Cancer Therapeutics

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The insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor tyrosine kinase that mediates cell survival signaling and supports tumor progression in multiple tumor types. We identified a spectrum of inhibitory IGF-IR antibodies with diverse binding epitopes and ligand-blocking properties. By binding distinct inhibitory epitopes, two of these antibodies, BIIB4 and BIIB5, block both IGF-I and IGF-II binding to IGF-IR using competitive and allosteric mechanisms, respectively. Here, we explored the inhibitory effects of combining BIIB4 and BIIB5. In biochemical assays, the combination of BIIB4 and BIIB5 improved both the potency and extent of IGF-I and IGF-II blockade compared with either antibody alone. In tumor cells, the combination of BIIB4 and BIIB5 accelerated IGF-IR downregulation and more efficiently inhibited IGF-IR activation as well as downstream signaling, particularly AKT phosphorylation. In several carcinoma cell lines, the antibody combination more effectively inhibited ligand-driven cell growth than either BIIB4 or BIIB5 alone. Notably, the enhanced tumor growth-inhibitory activity of the BIIB4 and BIIB5 combination was much more pronounced at high ligand concentrations, where the individual antibodies exhibited substantially reduced activity. Compared with single antibodies, the BIIB4 and BIIB5 combination also significantly further enhanced the antitumor activity of the epidermal growth factor receptor inhibitor erlotinib and the mTOR inhibitor rapamycin. Moreover, in osteosarcoma and hepatocellular carcinoma xenograft models, the BIIB4 and BIIB5 combination significantly reduced tumor growth to a greater degree than each single antibody. Taken together, our results suggest that targeting multiple distinct inhibitory epitopes on IGF-IR may be a more effective strategy of affecting the IGF-IR pathway in cancer. Mol Cancer Ther; 9(9); 2593-604. ©2010 AACR.

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Expression of insulin-like growth factor 2 in mesenchymal neoplasms

Cited by 75 publications

References 52 publications

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

Sunitinib Malate and Figitumumab in Solitary Fibrous Tumor: Patterns and Molecular Bases of Tumor Response

Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response

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