Precision medicine approaches for the management of Ewing sarcoma: current perspectives

Rizk, Victoria T.; Walko, Christine M.; Brohl, Andrew S.

doi:10.2147/pgpm.s170612

Cited by 9 publications

(11 citation statements)

References 58 publications

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“…[148][149][150] A randomized phase III trial lead by the Children's Oncology group (COG) studied the use of ganitumab, a monoclonal antibody against IGF-1R as part of the upfront therapy for metastatic ES along with conventional chemotherapy (NCT02306161). 151 Unfortunately, the study was closed in the spring of 2019, and ganitumab was discontinued in patients who had been randomized to the ganitumab arm based on a lack of benefit as well as the potential for increased toxicities such as pneumonitis. Several other monoclonal antibodies 22 The tyrosine kinase-like orphan receptor 1 (ROR1) has been demonstrated to harbor a key role in tumor cell migration and invasiveness in ES, and it was initially thought that its presence on healthy adults tissues was limited to B cell precursors and adipose tissue, [152][153][154][155] making it a desirable immunotherapeutic target.…”

Section: The Search For Tumor Targets: Surface Antigensmentioning

confidence: 99%

“… 148–150 A randomized phase III trial lead by the Children’s Oncology group (COG) studied the use of ganitumab, a monoclonal antibody against IGF-1R as part of the upfront therapy for metastatic ES along with conventional chemotherapy (NCT02306161). 151 Unfortunately, the study was closed in the spring of 2019, and ganitumab was discontinued in patients who had been randomized to the ganitumab arm based on a lack of benefit as well as the potential for increased toxicities such as pneumonitis. Several other monoclonal antibodies targeting IGF-1R have been explored including robatumumab, cixutumumab and figitumumab, all with limited clinical efficacy in ES.…”

Section: The Search For Tumor Targets: Surface Antigensmentioning

confidence: 99%

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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: The Search For Tumor Targets: Surface Antigensmentioning

confidence: 99%

Section: The Search For Tumor Targets: Surface Antigensmentioning

confidence: 99%

Role of immunotherapy in Ewing sarcoma

Morales

Olson

Iglesias

et al. 2020

J Immunother Cancer

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“…The most commonly found is the chimeric protein EWSR1-FLI1 t(11;22)(q24;q12), which is detected in almost 90% of the cases, while EWSR1-ERG t(21;22)(q22;q12) accounts for only 10% of the cases [ 7 ]. Targeted therapeutic approaches have been recently developed, such as drugs that work against the oncogenic protein EWSR1-FLI1 and the Insulin-like Growth Factor 1 Receptor (IGF-1R) [ 8 , 9 ], which are currently in clinical trials (clinical trial numbers: NCT02657005 and NCT02306161, respectively).…”

Section: Introductionmentioning

confidence: 99%

PDX-Derived Ewing’s Sarcoma Cells Retain High Viability and Disease Phenotype in Alginate Encapsulated Spheroid Cultures

Domenici

Eduardo

Castillo‐Ecija

et al. 2021

Cancers

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Ewing’s Sarcoma (ES) is the second most frequent malignant bone tumour in children and young adults and currently only untargeted chemotherapeutic approaches and surgery are available as treatment, although clinical trials are on-going for recently developed ES-targeted therapies. To study ES pathobiology and develop novel drugs, established cell lines and patient-derived xenografts (PDX) are the most employed experimental models. Nevertheless, the establishment of ES cell lines is difficult and the extensive use of PDX raises economic/ethical concerns. There is a growing consensus regarding the use of 3D cell culture to recapitulate physiological and pathophysiological features of human tissues, including drug sensitivity. Herein, we implemented a 3D cell culture methodology based on encapsulation of PDX-derived ES cell spheroids in alginate and maintenance in agitation-based culture systems. Under these conditions, ES cells displayed high proliferative and metabolic activity, while retaining the typical EWSR1-FLI1 chromosomal translocation. Importantly, 3D cultures presented reduced mouse PDX cell contamination compared to 2D cultures. Finally, we show that these 3D cultures can be employed in drug sensitivity assays, with results similar to those reported for the PDX of origin. In conclusion, this novel 3D cell culture method involving ES-PDX-derived cells is a suitable model to study ES pathobiology and can assist in the development of novel drugs against this disease, complementing PDX studies.

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“…New therapeutic approaches are needed to improve patient survival. Molecular target therapies are a very promising but challenging option, mainly because ES is characterized by a low mutation burden [11][12][13]. This is due to the oncogenic driving translocation between the EWSR1 gene and ETS family transcription factors that dominated the ES genetic landscape [11].…”

Section: Introductionmentioning

confidence: 99%

Mutational landscape of primary and recurrent Ewing sarcoma

Jagodzińska-Mucha¹,

Sobczuk²,

Mikula³

et al. 2021

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Introduction: Ewing sarcoma (ES) is a highly aggressive malignancy of bone and soft tissues characterized by the presence of a genetic fusion involving the EWSR1 gene. More than one-third of patients develop distant metastases, which are associated with unfavorable prognosis. Knowledge about the disease's genetic landscape may help foster progress in using targeted therapies in the treatment of ES. Aim of the study: The objective is to assess the mutational landscape of ES in pretreatment samples, tumor samples after neoadjuvant chemotherapy, and in metastatic/recurrent tumors in children and adults Material and methods: DNA from 39 for malin-fixed paraffin-embedded tumor samples of 22 patients (17 adults, 5 children) were analyzed by targeted next generation sequencing (NGS) using the Oncomine Comprehensive Assay v3gene panel. Additional functional analyses were performed between patient subgroups. Results: All samples were characterized by low tumor mutation burden (< 10 mut/Mb). The most commonly mutated genes were PIK3R1 (59%) and POLE (50%). The most widely detected variants in biopsy samples were PIK3R1 T369I (50%), FGFR1 E159K, and TP53 at codon 72 (both in 27.3%). Additionally, the ATR, BRCA1, RAD50, ATM, CHEK1, and NBN genes showed a significantly higher number of mutations in ES. Mutations in PIK3R1 were significantly more frequent in adults, while mutations in the pathways responsible for cell cycle control, DNA repair, and transcriptional regulation were more frequent in children. Conclusions: Besides EWSR1 fusion, ES is characterized by numerous point mutations that are potential targets for precision medicine. There is high genomic heterogeneity that may explain differences in outcomes between patient subgroups.

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Precision medicine approaches for the management of Ewing sarcoma: current perspectives

Cited by 9 publications

References 58 publications

Role of immunotherapy in Ewing sarcoma

Role of immunotherapy in Ewing sarcoma

PDX-Derived Ewing’s Sarcoma Cells Retain High Viability and Disease Phenotype in Alginate Encapsulated Spheroid Cultures

Mutational landscape of primary and recurrent Ewing sarcoma

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