Ewing sarcoma: prognostic criteria, outcomes and future treatment

Leavey, Patrick J.; Collier, Anderson B.

doi:10.1586/14737140.8.4.617

Cited by 59 publications

(48 citation statements)

References 67 publications

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“…Activation of the IGF-IR signaling pathway is involved in the growth, invasion, and metastasis of Ewing's sarcoma (31). More than 85% of Ewing's family tumors harbor a translocation between the EWS gene and the FLI1 transcription factor, and silencing the expression of this transcription factor increases the susceptibility of Ewing's sarcoma cells to apoptosis (32 -34).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

Sabbatini

Rowand

Groy

et al. 2009

Clinical Cancer Research

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Purpose: Dysregulation of the insulin-like growth factor-I receptor (IGF-IR) signaling pathway has been implicated in the development of many types of tumors, including prostate, colon, breast, pancreatic, ovarian, and sarcomas. Agents that inhibit IGF-IR activity may be useful in treatment of patients with various cancers. Experimental Design: Kinase assays were used to identify a selective small-molecule inhibitor of IGF-IR activity. The effects of this compound on IGF-IR signaling, cell proliferation, and the cell cycle were determined using a panel of cell lines. Antitumor activity was evaluated in human tumor xenografts growing in athymic mice. Inhibition of IGF-IR and the closely related insulin receptor (IR) was measured in vivo, and the effect on glucose metabolism was evaluated. Results: GSK1904529A selectively inhibits IGF-IR and IR with IC 50 s of 27 and 25 nmol/L, respectively. GSK1904529A blocks receptor autophosphorylation and downstream signaling, leading to cell cycle arrest. It inhibits the proliferation of cell lines derived from solid and hematologic malignancies, with multiple myeloma and Ewing's sarcoma cell lines being most sensitive. Oral administration of GSK1904529A decreases the growth of human tumor xenografts in mice, consistent with a reduction of IGF-IR phosphorylation in tumors. Despite the potent inhibitory activity of GSK1904529A on IR in vitro and in vivo, minimal effects on blood glucose levels are observed in animals at doses that show significant antitumor activity. Conclusion: GSK1904529A is a promising candidate for therapeutic use in IGF-IR^dependent tumors.

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Section: Discussionmentioning

confidence: 99%

Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

Sabbatini

Rowand

Groy

et al. 2009

Clinical Cancer Research

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“…• Whereas chemotherapy often enables patients with localized disease to be cured, in those with metastatic spread its benefit is more often limited to extending progression-free survival [51,52]. Durable responses remain elusive.…”

Section: Recurrent or Metastatic Diseasementioning

confidence: 99%

Ewing’s Sarcoma: Standard and Experimental Treatment Options

Subbiah

Anderson

Lazar

et al. 2009

Curr. Treat. Options in Oncol.

131

103

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Ewing sarcoma family tumors (EWS), which include classic Ewing's sarcoma in addition to primitive neuroectodermal tumor and Askin tumor, are the second most common variety of primary bone cancer to afflict adolescents and young adults. Multi-disciplinary care incorporating advances in diagnosis, surgery, chemotherapy, and radiation has substantially improved the survival rate of patients with localized Ewing sarcoma to nearly 70%. Unfortunately, those advances have not significantly changed the long-term outcome for those with metastatic or recurrent disease; 5-year survival remains less than 25%. This apparent therapeutic plateau exists despite extensive effort during the last four decades to optimize the efficacy of cytotoxic chemotherapy through combination of chemotherapies of mechanistically diverse action, dose-dense scheduling (provided as frequently as every 2 weeks), increased adjuvant treatment duration, and higher dosage per cycle (facilitated with parallel strides in supportive care incorporating growth factors). As has already occurred for malignancies such as breast or colon cancer, the "-omics-based" revolution has enhanced our understanding of the molecular changes responsible for Ewing's tumor formation and identified a number of potential targets (such as IGF-1R or mTOR) amenable to biological therapy. It has also created both a challenge and an opportunity to develop predictive biomarkers capable of selecting patients most likely to benefit from targeted therapy. In this review, we discuss current standard-of-care for patients with Ewing's sarcoma and highlight the most promising experimental therapies in early-phase clinical trials.

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“…Patients with nonmetastatic ES have improved outcomes, however, 30-40% of recovering ES patients experience recurrence or relapse (2). Traditional therapeutic approaches include local control of the primary lesion by surgery and/or radiation therapy, and treatment of disseminated disease with multiagent cytotoxic chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-301a promotes cell proliferation via PTEN targeting in Ewing's sarcoma cells

Kawano

Tanaka

Itonaga

et al. 2016

International Journal of Oncology

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Abstract. MicroRNAs (miRNAs) regulate cell proliferation and differentiation by affecting gene expression at the posttranscriptional level by binding to complementary sequences within mRNAs in cancer cells, indicating that miRNAs can function as tumor suppressors or oncogenes. Recent studies showed that dysregulation of miRNA expression was associated with increased tumorigenicity and poor prognosis in several types of cancers, including Ewing's sarcoma (ES). To explore possible oncogenic factors in ES, we conducted microarray-based investigation and profiled the changes in miRNA expression and their effects on downstream mRNAs in five ES cell lines and human mesenchymal stem cells (hMSCs). miR-301a was significantly upregulated, while the phosphatase and tensin homolog (PTEN) expression was significantly downregulated in all tested ES cells as compared to hMSCs. When anti-miR-301a was transfected into ES cell lines, PTEN expression was significantly enhanced, suggesting that PTEN might be a target of miR-301a in ES cells. The expression of protein kinase B (Akt), which is inversely correlated with PTEN expression, was significantly downregulated in antimiR-301a-transfected cells. Additionally, the transfection of anti-miR-301a inhibited ES cell proliferation and cell cycle progression. Furthermore, downregulation of miR-301a in ES cells significantly suppressed tumor growth in vivo. Our results demonstrated the novel mechanism controlling PTEN expression via miR-301a in ES cells. Given that PTEN is a pivotal phosphatase factor that regulates cell cycle progression, apoptosis, and proliferation, these results might lead to development of new ES-related therapeutic targets.

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Ewing sarcoma: prognostic criteria, outcomes and future treatment

Cited by 59 publications

References 67 publications

Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

Ewing’s Sarcoma: Standard and Experimental Treatment Options

MicroRNA-301a promotes cell proliferation via PTEN targeting in Ewing's sarcoma cells

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