Targeting of Insulin-Like Growth Factor Type 1 Receptor in Ewing Sarcoma: Unfulfilled Promise or a Promising Beginning?

Ho, Alan L.; Schwartz, Gary K.

doi:10.1200/jco.2011.38.2374

Cited by 27 publications

(27 citation statements)

References 21 publications

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“…Beyond its role in transporting IGFs, IGFBP3 is a tumor suppressor, controlling cell proliferation and survival through interacting with pericellular and intracellular compartments (36). In EWS, EWS-FLI1 binds to the IGFBP3 promoter and transcriptionally represses its expression, which in turn enhances IGF-1 signaling (35). In this study, we discovered that EWS-FLI1 is a novel target of CRM1 in several EWS cell lines (TC32, SKES1, and EW8).…”

Section: Discussionmentioning

confidence: 84%

“…Therefore, the inhibitory effect of KPT-330 on different cells might not only depend on the expression level of CRM1, but also rely on its downstream targets. IGF-1R is a promising target in EWS, and several monoclonal antibodies and chemical inhibitors have been developed (35). Linsitinib (OSI-906) is a potent, selective IGF-1R inhibitor under evaluation in a phase II trial (ORPHA394629) of EWS (42,43).…”

Section: Discussionmentioning

confidence: 99%

“…3H; Supplementary Table S5). IGFBP3 is an important EWS-FlLI1 transcriptionally repressed gene, which has been shown to bind and inhibit IGF-1 (35). Constitutive activation of the IGF-1 pathway in EWS was partly attributable to the downregulation of IGFBP3 by EWS-FLI1 (36).…”

Section: Inhibition Of Crm1 Induced Cytotoxicity By Repressing Ews-flmentioning

confidence: 99%

“…Development of EWS relies on activation of the IGF-1 pathway (35). As an important IGF-1 signaling partner, IGF-1R is recognized as a promising target against this disease (41).…”

Section: Combination Of Kpt-330 With Linsitinib Synergistically Inhibmentioning

confidence: 99%

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CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling

et al. 2016

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Ewing sarcoma (EWS) is an aggressive bone malignancy that mainly affects children and young adults. The mechanisms by which EWS (EWSR1) fusion genes drive the disease are not fully understood. CRM1 (XPO1) traffics proteins from the nucleus, including tumor suppressors and growth factors, and is overexpressed in many cancers. A small-molecule inhibitor of CRM1, KPT-330, has shown therapeutic promise, but has yet to be investigated in the context of EWS. In this study, we demonstrate that CRM1 is also highly expressed in EWS. shRNA-mediated or pharmacologic inhibition of CRM1 in EWS cells dramatically decreased cell growth while inducing apoptosis, cell-cycle arrest, and protein expression alterations to several cancer-related factors. Interestingly, silencing of CRM1 markedly reduced EWS-FLI1 fusion protein expression at the posttranscriptional level and upregulated the expression of the well-established EWS-FLI1 target gene, insulin-like growth factor binding protein 3 (IGFBP3), which inhibits IGF-1. Accordingly, KPT-330 treatment attenuated IGF-1-induced activation of the IGF-1R/AKT pathway. Furthermore, knockdown of IGFBP3 increased cell growth and rescued the inhibitory effects on IGF-1 signaling triggered by CRM1 inhibition. Finally, treatment of EWS cells with a combination of KPT-330 and the IGF-1R inhibitor, linsitinib, synergistically decreased cell proliferation both in vitro and in vivo. Taken together, these findings provide a strong rationale for investigating the efficacy of combinatorial inhibition of CRM1 and IGF-1R for the treatment of EWS. Cancer Res; 76(9);

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Inhibition Of Crm1 Induced Cytotoxicity By Repressing Ews-flmentioning

confidence: 99%

“…Development of EWS relies on activation of the IGF-1 pathway (35). As an important IGF-1 signaling partner, IGF-1R is recognized as a promising target against this disease (41).…”

Section: Combination Of Kpt-330 With Linsitinib Synergistically Inhibmentioning

confidence: 99%

See 2 more Smart Citations

CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling

et al. 2016

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“…Despite a strong scientific rationale and evidence for an additive effect for the ganitumab/conatumumab combination in a xenograft model, this clinical trial did not show evidence for activity of the combination in any of the tumor types tested, though one patient with sarcoma had a PR, and several patients with colorectal cancer ( n =2), sarcoma ( n =2), and NSCLC ( n =1) experienced prolonged stable disease. Of note, recent review articles summarizing the trial data from multiple candidates have concluded that both IGF1R-directed [41, 42, 35] and DR5 agonist agents [43] have shown modest activity as single agents in the clinical setting. Results from a prior single-agent study with ganitumab were encouraging, with responses observed in 2 of 12 patients with Ewing’s sarcoma (1 durable CR and 1 PR), and 2 of 5 patients with neuroendocrine tumors (1 PR and 1 durable minor response) [3].…”

Section: Discussionmentioning

confidence: 99%

Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab

et al. 2014

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Agents targeting the insulin-like growth factor receptor type 1 (IGF1R) have shown antitumor activity. Based on the evidence for interaction between the IGF-1 and TRAIL pathways, we hypothesized that the combination of ganitumab (monoclonal antibody to IGF1R) with the pro-apoptotic death receptor 5 agonist, conatumumab, might increase antitumor response. Ganitumab and conatumumab were tested in combination in a Colo-205 xenograft model. Part 1 of the clinical study was a phase Ib program of three doses of conatumumab (1, 3, 15 mg/kg) in combination with 18 mg/kg ganitumab to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. Part 2 was conducted in six cohorts with advanced non-small cell lung cancer (squamous or nonsquamous histology), colorectal cancer, sarcoma, pancreatic cancer, or ovarian cancer, treated at the recommended doses of the combination. The combination was significantly more active in the Colo-205 xenograft model than either single agent alone (p<0.0015). In part 1 of the clinical study, no dose-limiting toxicities were observed and the MTD of conatumumab was 15 mg/kg in combination with 18 mg/kg ganitumab. In part 2, 78 patients were treated and there were no objective responses but 28 patients (36 %) had stable disease (median 46 days, range 0–261). The combination was well-tolerated with no new toxicities. In conclusion, the combination of ganitumab and conatumumab was well-tolerated but had no objective responses in the population tested. The successful future application of this combination of antitumor mechanisms may rely on the identification of predictive biomarkers.

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Ewing’s Sarcoma Family of Tumors: Targeting Molecular Pathways and the Race for a Cure

Ahmed

Samuel

Fulbright

2013

Pediatric Cancer, Volume 4

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Targeting of Insulin-Like Growth Factor Type 1 Receptor in Ewing Sarcoma: Unfulfilled Promise or a Promising Beginning?

Cited by 27 publications

References 21 publications

CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling

CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling

Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab

Ewing’s Sarcoma Family of Tumors: Targeting Molecular Pathways and the Race for a Cure

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