Sarcoma treatment in the era of molecular medicine

Grünewald, Thomas G.P.; Alonso, Marta M.; Avnet, Sofia; Banito, Ana; Burdach, Stefan; Cidre‐Aranaz, Florencia; Pompo, Gemma Di; Distel, Martin; Dorado-Garcia, Heathcliff; García‐Castro, Javier; González-González, Laura; Grigoriadis, Agamemnon E.; Kasan, Merve; Koelsche, Christian; Krumbholz, Manuela; Lecanda, Fernando; Lemma, Silvia; Longo, Dario Livio; Madrigal-Esquivel, Claudia; Morales-Molina, Álvaro; Musa, Julian; Ohmura, Shunya; Ory, Benjamin; Pereira-Silva, Miguel; Perut, Francesca; Rodrı́guez, René; Seeling, Carolin; Shaaili, Nada Al; Shaabani, Shabnam; Shiavone, Kristina; Sinha, Snehadri; Tomazou, Eleni M.; Trautmann, Marcel; Vela, María; Versleijen-Jonkers, Yvonne M.H.; Visgauss, Julia D.; Zalacaín, Marta; Schober, Sebastian Johannes; Lissat, Andrej; English, William R.; Baldini, Nicola; Heymann, Dominique

doi:10.15252/emmm.201911131

Cited by 164 publications

(135 citation statements)

References 449 publications

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“…Interestingly, chemotherapy did not change immune cell expression, once again suggesting there may be a role for immunotherapy to generate a more favourable immune rich microenvironment. Taken together, this suggests a potential role for immunotherapy for at least a subset of patients with osteosarcoma [ 77 ].…”

Section: Does Genomic Heterogeneity Suggest Efficacy Of Immunothermentioning

confidence: 99%

Future Directions in the Treatment of Osteosarcoma

Smrke

Anderson

Gulia

et al. 2021

Cells

112

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Osteosarcoma is the most common primary bone sarcoma and is often diagnosed in the 2nd–3rd decades of life. Response to the aggressive and highly toxic neoadjuvant methotrexate-doxorubicin-cisplatin (MAP) chemotherapy schedule is strongly predictive of outcome. Outcomes for patients with osteosarcoma have not significantly changed for over thirty years. There is a need for more effective treatment for patients with high risk features but also reduced treatment-related toxicity for all patients. Predictive biomarkers are needed to help inform clinicians to de-escalate or add therapy, including immune therapies, and to contribute to future clinical trial designs. Here, we review a variety of approaches to improve outcomes and quality of life for patients with osteosarcoma with a focus on incorporating toxicity reduction, immune therapy and molecular analysis to provide the most effective and least toxic osteosarcoma therapy.

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Section: Does Genomic Heterogeneity Suggest Efficacy Of Immunothermentioning

confidence: 99%

Future Directions in the Treatment of Osteosarcoma

Smrke

Anderson

Gulia

et al. 2021

Cells

112

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“…Although some predisposing genetic factors such as p53 mutations have been discovered, the precise etiology of this pediatric disease remains undetermined [ 1 , 4 ]. The standard treatment of OS is complete surgical resection combined with neo-adjuvant and adjuvant chemotherapies [ 5 , 6 , 7 , 8 ]. Unfortunately, OS is a particularly chemotherapy-resistant tumor [ 9 ] and resistance to treatment remains one of the leading causes of death in OS patients, with a 5-year survival rate of only around 20–25% [ 7 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…The standard treatment of OS is complete surgical resection combined with neo-adjuvant and adjuvant chemotherapies [ 5 , 6 , 7 , 8 ]. Unfortunately, OS is a particularly chemotherapy-resistant tumor [ 9 ] and resistance to treatment remains one of the leading causes of death in OS patients, with a 5-year survival rate of only around 20–25% [ 7 , 10 , 11 ]. The lack of response to conventional treatments underlines the urgency of developing new therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

The YAP/TEAD Axis as a New Therapeutic Target in Osteosarcoma: Effect of Verteporfin and CA3 on Primary Tumor Growth

Morice

Mullard

Brion

et al. 2020

Cancers

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Although some studies suggested that disruption of the Hippo signaling pathway is associated with osteosarcoma progression, the molecular mechanisms by which YAP regulates primary tumor growth is not fully clarified. In addition, the validation of YAP as a therapeutic target through the use of inhibitors in a preclinical model must be demonstrated. RNA-seq analysis and Kaplan–Meier assays identified a YAP signature in osteosarcoma patients and a correlation with patients’ outcomes. Molecular and cellular analysis (RNAseq, PLA, immunoprecipitation, promoter/specific gene, proliferation, cell cycle assays) using overexpression of mutated forms of YAP able or unable to interact with TEAD, indicate that TEAD is crucial for YAP-driven cell proliferation and in vivo tumor growth. In addition, in vivo experiments using an orthotopic mice model of osteosarcoma show that two YAP/TEAD inhibitors, verteporfin and CA3, reduce primary tumor growth. In this context, in vitro experiments demonstrate that these inhibitors decrease YAP expression, YAP/TEAD transcriptional activity and cell viability mainly by their ability to induce cell apoptosis. We thus demonstrate that the YAP/TEAD signaling axis is a central actor in mediating primary tumor growth of osteosarcoma, and that the use of YAP inhibitors may be a promising therapeutic strategy against osteosarcoma tumor growth.

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“…Given the rather simple genetic make-up of EwS, this disease may constitute an ideal model to study how perturbation of a transcriptional network by a dominant oncogene can mediate stemness and metastasis features. Although several groups identified particular EWSR1-ETSdriven genes or pathways that likely play a role in maintenance of stemness, and hence in the establishment of a more metastatic phenotype 20 , a systematic understanding of this process and of its clinical implications is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Systems biology analysis identifies TCF7L1 as a key regulator of metastasis in Ewing sarcoma

Cidre‐Aranaz

Hölting³

et al. 2021

Preprint

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Identification of cancer stemness genes is crucial to understanding the underlying biology of therapy resistance, relapse, and metastasis. Ewing sarcoma (EwS) is the second most common bone tumor in children and adolescents. It is a highly aggressive cancer associated with a dismal survival rate (<30%) for patients with metastatic disease at diagnosis (~25% of cases). Hence, deciphering the underlying mechanisms of metastasis is imperative. EwS tumors are characterized by a remarkably 'silent' genome with a single driver mutation generating an oncogenic fusion transcription factor (EWSR1-ETS). Thus, EwS constitutes an ideal model to study how perturbation of a transcriptional network by a dominant oncogene can mediate metastasis, even though canonical metastasis-associated genes are not mutated. Here, through the implementation of an integrative systems biology approach, we identified transcription factor 7 like 1 (TCF7L1, alias TCF3) as a prognostically-relevant and EWSR1-ETS suppressed determinant of metastasis in EwS. We demonstrated that conditional TCF7L1 re-expression significantly reduces EwS single-cell migration, invasion and anchorage-independent growth in 3D assays in vitro, and tumorigenesis in vivo mediated by its DNA binding domain. In primary EwS tumors as well as in functional orthotopic in vivo models, low TCF7L1 expression was associated with pro-metastatic gene signatures and a much higher migratory and metastatic capacity of EwS cells, which correlated with poor outcome of EwS patients. Collectively, our findings establish TCF7L1 as a major regulator of metastasis in EwS, which may be utilized as a prognostic biomarker and open inroads to future therapeutic intervention.

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Sarcoma treatment in the era of molecular medicine

Cited by 164 publications

References 449 publications

Future Directions in the Treatment of Osteosarcoma

Future Directions in the Treatment of Osteosarcoma

The YAP/TEAD Axis as a New Therapeutic Target in Osteosarcoma: Effect of Verteporfin and CA3 on Primary Tumor Growth

Systems biology analysis identifies TCF7L1 as a key regulator of metastasis in Ewing sarcoma

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