Limits...
Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours.

Kelleher FC, Thomas DM - Clin Sarcoma Res (2012)

Bottom Line: Molecularly targeted treatments offer the potential to further improve treatment outcomes.A PUBMED search was performed from 1997 to 2011.Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Oncology, St, Vincent's University Hospital, Dublin, Ireland. fergalkelleher@hotmail.com.

ABSTRACT

Background: Ewing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes.

Methods: A PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced.

Results: Insulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-β receptor II allowing TFF-β signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET.

Conclusion: Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances.

No MeSH data available.


Related in: MedlinePlus

Diagram of t(11;22)(q24;q12) and the EWS-FLI1 gene fusion. Adapted from; Enrique de Alava, William L. Gerald, Biology of Sarcoma/Primitive Neuroectodermal Tumor Family, Journal of Clinical Oncology, Vol 18, Issue 1(January), 2000: 204.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3351706&req=5

Figure 1: Diagram of t(11;22)(q24;q12) and the EWS-FLI1 gene fusion. Adapted from; Enrique de Alava, William L. Gerald, Biology of Sarcoma/Primitive Neuroectodermal Tumor Family, Journal of Clinical Oncology, Vol 18, Issue 1(January), 2000: 204.

Mentions: Members of the Ewing sarcoma/PNET family of tumours are characterized by rearrangements involving the EWS gene on chromosome 22q12 and fusion partners from the ETS oncogene family, most frequently FLI1 on chromosome 11q24 (85%) as demonstrated in Figure 1, or ERG on chromosome 21q22 (10%). The EWS gene also has 3 other ETS family gene partners leading to the chimeric gene transcripts. The five most common gene rearrangements are detailed in table 1 however other rarer fusions have been described. Ninety-five percent of ESFT have fusion of the central exons of the EWSR1 gene (Ewing Sarcoma Breakpoint Region 1) to the central exons of an ETS gene family member and fusion occurs between the NH2 end of the EWS gene and the -COOH end of the ETS gene family partner. In Ewing sarcoma/PNET tumours it was previously considered that one particular rearrangement was specific for the malignancy and that no molecular shift occurs during progression. However a case has been described of a patient, in whom two separate Ewing sarcoma/PNET tumours arose after a 56 month remission interval, initially involving a EWS/ERG fusion transcript followed by a EWS/FLI1 fusion [12]. As Ewing sarcoma/PNET tumours have variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and protein architecture. The effect of EWS-ETS fusion type on disease progression in Ewing sarcoma/PNET tumours was evaluated prospectively from the co-operative Euro-E.W.I.N.G. 99 trial [13]. Variants in the genomic breakpoint location lead to the transcription of varying RNA's. In most cases rearrangements occur with EWS intron 7 or 8: FLI1 introns 5 or 4 leading to either fusion of EWS intron 7 to Fli1 exon 6 (type I fusion [EF1]) documented in 51% of cases or exon 5 (type 2 fusion [EF2]) recorded in 27% of cases.


Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours.

Kelleher FC, Thomas DM - Clin Sarcoma Res (2012)

Diagram of t(11;22)(q24;q12) and the EWS-FLI1 gene fusion. Adapted from; Enrique de Alava, William L. Gerald, Biology of Sarcoma/Primitive Neuroectodermal Tumor Family, Journal of Clinical Oncology, Vol 18, Issue 1(January), 2000: 204.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351706&req=5

Figure 1: Diagram of t(11;22)(q24;q12) and the EWS-FLI1 gene fusion. Adapted from; Enrique de Alava, William L. Gerald, Biology of Sarcoma/Primitive Neuroectodermal Tumor Family, Journal of Clinical Oncology, Vol 18, Issue 1(January), 2000: 204.
Mentions: Members of the Ewing sarcoma/PNET family of tumours are characterized by rearrangements involving the EWS gene on chromosome 22q12 and fusion partners from the ETS oncogene family, most frequently FLI1 on chromosome 11q24 (85%) as demonstrated in Figure 1, or ERG on chromosome 21q22 (10%). The EWS gene also has 3 other ETS family gene partners leading to the chimeric gene transcripts. The five most common gene rearrangements are detailed in table 1 however other rarer fusions have been described. Ninety-five percent of ESFT have fusion of the central exons of the EWSR1 gene (Ewing Sarcoma Breakpoint Region 1) to the central exons of an ETS gene family member and fusion occurs between the NH2 end of the EWS gene and the -COOH end of the ETS gene family partner. In Ewing sarcoma/PNET tumours it was previously considered that one particular rearrangement was specific for the malignancy and that no molecular shift occurs during progression. However a case has been described of a patient, in whom two separate Ewing sarcoma/PNET tumours arose after a 56 month remission interval, initially involving a EWS/ERG fusion transcript followed by a EWS/FLI1 fusion [12]. As Ewing sarcoma/PNET tumours have variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and protein architecture. The effect of EWS-ETS fusion type on disease progression in Ewing sarcoma/PNET tumours was evaluated prospectively from the co-operative Euro-E.W.I.N.G. 99 trial [13]. Variants in the genomic breakpoint location lead to the transcription of varying RNA's. In most cases rearrangements occur with EWS intron 7 or 8: FLI1 introns 5 or 4 leading to either fusion of EWS intron 7 to Fli1 exon 6 (type I fusion [EF1]) documented in 51% of cases or exon 5 (type 2 fusion [EF2]) recorded in 27% of cases.

Bottom Line: Molecularly targeted treatments offer the potential to further improve treatment outcomes.A PUBMED search was performed from 1997 to 2011.Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Oncology, St, Vincent's University Hospital, Dublin, Ireland. fergalkelleher@hotmail.com.

ABSTRACT

Background: Ewing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes.

Methods: A PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced.

Results: Insulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-β receptor II allowing TFF-β signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET.

Conclusion: Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances.

No MeSH data available.


Related in: MedlinePlus