Exploiting Signaling Pathways and Immune Targets Beyond the Standard of Care for Ewing Sarcoma

Casey, Dana L.; Lin, Tsung-Yi; Cheung, Nai‐Kong V.

doi:10.3389/fonc.2019.00537

Cited by 24 publications

(40 citation statements)

References 194 publications

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“…[19][20][21] However, there is not a drug available that can directly inhibit the fusion protein. 22 There has been some promise with strategies targeted to inactivate or reduce the expression or function of the EWS-FLI1 oncoprotein; some of these approaches include inhibitory oligonucleotides and small-molecule inhibitors that can disrupt its transcriptional complex. 22 23 Moreover, these inhibitory oligonucleotides have been designed for ES to bind to certain sequences coding for the EWS-FLI1 fusion protein in preclinical models and has led to decreased expression of the fusion protein and subsequently lead to a reduction in tumor growth.…”

Section: Introductionmentioning

confidence: 99%

Role of immunotherapy in Ewing sarcoma

Morales

Olson

Iglesias

et al. 2020

J Immunother Cancer

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Ewing sarcoma (ES) is thought to arise from mesenchymal stem cells and is the second most common bone sarcoma in pediatric patients and young adults. Given the dismal overall outcomes and very intensive therapies used, there is an urgent need to explore and develop alternative treatment modalities including immunotherapies. In this article, we provide an overview of ES biology, features of ES tumor microenvironment (TME) and review various tumor-associated antigens that can be targeted with immune-based approaches including cancer vaccines, monoclonal antibodies, T cell receptor-transduced T cells, and chimeric antigen receptor T cells. We highlight key reasons for the limited efficacy of various immunotherapeutic approaches for the treatment of ES to date. These factors include absence of human leukocyte antigen class I molecules from the tumor tissue, lack of an ideal surface antigen, and immunosuppressive TME due to the presence of myeloid-derived suppressor cells, F2 fibrocytes, and M2-like macrophages. Lastly, we offer insights into strategies for novel therapeutics development in ES. These strategies include the development of gene-modified T cell receptor T cells against cancer–testis antigen such as XAGE-1, surface target discovery through detailed profiling of ES surface proteome, and combinatorial approaches. In summary, we provide state-of-the-art science in ES tumor immunology and immunotherapy, with rationale and recommendations for future therapeutics development.

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Section: Introductionmentioning

confidence: 99%

Role of immunotherapy in Ewing sarcoma

Morales

Olson

Iglesias

et al. 2020

J Immunother Cancer

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“…ES is one of the most malignant childhood cancers and its prognosis has not improved over the past two decades (Casey et al 2019 ; Vornicova and Bar-Sela 2016 ). There thus is an urgent need for the development of new therapeutic approaches (Bailey et al 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…The standard of care is a treatment combination consisting of cytotoxic chemotherapy, surgery and radiation (Balamuth and Womer 2010 ). Of note, the prognosis for patients with ES has reached a plateau over the last two decades, as no further therapy improvement by optimising treatment protocols could be achieved (Casey et al 2019 ). It is thus imperative to identify druggable targets to improve the outcome for ES patients.…”

Section: Introductionmentioning

confidence: 99%

Anticancer effects of the PLK4 inhibitors CFI-400945 and centrinone in Ewing’s sarcoma cells

Kerschner-Morales

Kühne

Becker

et al. 2020

J Cancer Res Clin Oncol

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Purpose Polo-like kinase 4 (PLK4) inhibitors, such as CFI-400945 and centrinone, are emerging as promising antineoplastic agents. However, their effectiveness against Ewing’s sarcoma, a highly aggressive childhood cancer, remains to be established. Methods CFI-400945 and centrinone were tested in three Ewing’s sarcoma cell lines with different TP53 status. Effects were assessed by flow-cytometric analyses of cell death, dissipation of the mitochondrial transmembrane potential and cell cycle distribution, by cell viability assay as well as by caspase 3/7 activity measurement, by immunoblotting and by immunofluorescence microscopy. Results CFI-400945 and centrinone elicited cell death in p53 wild-type and mutant Ewing’s sarcoma cells. Both agents induced mitochondrial membrane depolarisation, caspase 3/7 activation, PARP1 cleavage and DNA fragmentation, indicating an apoptotic form of cell death. In addition, the PLK4 inhibitors induced a G2/M cell cycle arrest, particularly when cell killing was attenuated by the pan-caspase inhibitor z-VAD-fmk. Moreover, CFI-400945 treatment produced polyploidy. Conclusion Our findings show that PLK4 inhibitors were effective against Ewing’s sarcoma cells in vitro and thus provide a rationale for their evaluation in vivo.

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“…Ewing sarcoma has been studied for disialoganglioside GD2 expression, and the results ranged from no detectable surface expression to diffuse and/or intense staining in some tumors (46). More specifically, GD2 expression levels ranged from 40 to 90% from diagnostic biopsy samples of Ewing sarcoma (47). Kailayangiri et al detected disialoganglioside GD2 expression by immunofluorescence staining in 10 of 10 Ewing sarcoma cell lines and 3 of 3 primary cell cultures, concluding that surface expression of disialoganglioside GD2 is a characteristic of Ewing sarcoma and that GD2 provides an appropriate target antigen for therapeutic strategies to eradicate micrometastases and reduce the risk of recurrence in patients with high-risk disease (48).…”

Section: Ewing Sarcomamentioning

confidence: 99%