Publications by authors named "Enrique de Alava"

115 Publications

E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor.

Oncogene 2021 Oct 7. Epub 2021 Oct 7.

Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

KIT/PDGFRA oncogenic tyrosine kinase signaling is the central oncogenic event in most gastrointestinal stromal tumors (GIST), which are human malignant mesenchymal neoplasms that often feature myogenic differentiation. Although targeted inhibition of KIT/PDGFRA provides substantial clinical benefit, GIST cells adapt to KIT/PDGFRA driver suppression and eventually develop resistance. The specific molecular events leading to adaptive resistance in GIST remain unclear. By using clinically representative in vitro and in vivo GIST models and GIST patients' samples, we found that the E3 ubiquitin ligase Atrogin-1 (FBXO32)-the main effector of muscular atrophy in cachexia-resulted in the most critical gene derepressed in response to KIT inhibition, regardless the type of KIT primary or secondary mutation. Atrogin-1 in GISTs is transcriptionally controlled by the KIT-FOXO3a axis, thus indicating overlap with Atrogin-1 regulation mechanisms in nonneoplastic muscle cells. Further, Atrogin-1 overexpression was a GIST-cell-specific pro-survival mechanism that enabled the adaptation to KIT-targeted inhibition by apoptosis evasion through cell quiescence. Buttressed on these findings, we established in vitro and in vivo the preclinical proof-of-concept for co-targeting KIT and the ubiquitin pathway to maximize the therapeutic response to first-line imatinib treatment.
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http://dx.doi.org/10.1038/s41388-021-02049-0DOI Listing
October 2021

[Multidisciplinary consensus on optimizing the detection of NTRK gene alterations in tumours].

Rev Esp Patol 2021 Oct-Dec;54(4):250-262. Epub 2021 Jul 10.

Sociedad Española de Oncología Médica (SEOM), Hospital Universitario Ramón y Cajal, Universidad de Alcalá, IRYCIS, CIBERONC, Madrid, España.

The recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionized the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children and are either rare tumours with common NTRK fusions that may be diagnostic, or more common tumours with rare NTRK fusions. To assess the currently available evidence, 3key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathology (SEAP) and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical and therapeutic aspects of NTRK-fusion tumours. It also discusses the challenges related to the routine detection of these genetic alterations in a mostly public health care system.
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http://dx.doi.org/10.1016/j.patol.2021.05.003DOI Listing
July 2021

Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma.

Oncogene 2021 Sep 3;40(39):5843-5853. Epub 2021 Aug 3.

Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/University of Seville /CIBERONC, Seville, Spain.

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.
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http://dx.doi.org/10.1038/s41388-021-01974-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484017PMC
September 2021

Characterizing the Invasive Tumor Front of Aggressive Uterine Adenocarcinoma and Leiomyosarcoma.

Front Cell Dev Biol 2021 3;9:670185. Epub 2021 Jun 3.

Cancer CIBER (CIBERONC), Madrid, Spain.

The invasive tumor front (the tumor-host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.
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http://dx.doi.org/10.3389/fcell.2021.670185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209546PMC
June 2021

Ewing Sarcoma-Diagnosis, Treatment, Clinical Challenges and Future Perspectives.

J Clin Med 2021 Apr 14;10(8). Epub 2021 Apr 14.

Pediatrics III, University Hospital Essen, 45147 Essen, Germany.

Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.
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http://dx.doi.org/10.3390/jcm10081685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071040PMC
April 2021

Molecular diagnosis in non-small-cell lung cancer: expert opinion on and testing.

J Clin Pathol 2021 Apr 19. Epub 2021 Apr 19.

Department of Pathology, Hospital Universitario Virgen del Rocío, Sevilla, Spain.

The effectiveness of targeted therapies with tyrosine kinase inhibitors in non-small-cell lung cancer (NSCLC) depends on the accurate determination of the genomic status of the tumour. For this reason, molecular analyses to detect genetic rearrangements in some genes (ie, , , ) have become standard in patients with advanced disease. Since immunohistochemistry is easier to implement and interpret, it is normally used as the screening procedure, while fluorescence in situ hybridisation (FISH) is used to confirm the rearrangement and decide on ambiguous immunostainings. Although FISH is considered the most sensitive method for the detection of and rearrangements, the interpretation of results requires detailed guidelines. In this review, we discuss the various technologies available to evaluate and genomic rearrangements using these techniques. Other techniques such as real-time PCR and next-generation sequencing have been developed recently to evaluate and gene rearrangements, but some limitations prevent their full implementation in the clinical setting. Similarly, liquid biopsies have the potential to change the treatment of patients with advanced lung cancer, but further research is required before this technology can be applied in routine clinical practice. We discuss the technical requirements of laboratories in the light of quality assurance programmes. Finally, we review the recent updates made to the guidelines for the determination of molecular biomarkers in patients with NSCLC.
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http://dx.doi.org/10.1136/jclinpath-2021-207490DOI Listing
April 2021

Endoglin in the Spotlight to Treat Cancer.

Int J Mol Sci 2021 Mar 20;22(6). Epub 2021 Mar 20.

Molecular Pathology of Sarcomas, Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital, CSIC, University of Sevilla, CIBERONC, 41013 Seville, Spain.

A spotlight has been shone on endoglin in recent years due to that fact of its potential to serve as both a reliable disease biomarker and a therapeutic target. Indeed, endoglin has now been assigned many roles in both physiological and pathological processes. From a molecular point of view, endoglin mainly acts as a co-receptor in the canonical TGFβ pathway, but also it may be shed and released from the membrane, giving rise to the soluble form, which also plays important roles in cell signaling. In cancer, in particular, endoglin may contribute to either an oncogenic or a non-oncogenic phenotype depending on the cell context. The fact that endoglin is expressed by neoplastic and non-neoplastic cells within the tumor microenvironment suggests new possibilities for targeted therapies. Here, we aimed to review and discuss the many roles played by endoglin in different tumor types, as well as the strong evidence provided by pre-clinical and clinical studies that supports the therapeutic targeting of endoglin as a novel clinical strategy.
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http://dx.doi.org/10.3390/ijms22063186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003971PMC
March 2021

Sarcoma classification by DNA methylation profiling.

Nat Commun 2021 01 21;12(1):498. Epub 2021 Jan 21.

Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
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http://dx.doi.org/10.1038/s41467-020-20603-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819999PMC
January 2021

(Immuno)histological Analysis of Ewing Sarcoma.

Methods Mol Biol 2021 ;2226:49-64

Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Seville, Spain.

The diagnosis of Ewing sarcoma requires the integration of the information generated from numerous techniques, some of them being very sophisticated. However, the first steps of the diagnostic process are crucial to achieve the maximum possible diagnostic performance. In this chapter we will review how to handle the diagnostic specimen from its collection, how to prepare it for diagnosis, how to make a complete pathology report, and provide guidance for the reasonable use of immunohistochemical techniques in this malignancy.
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http://dx.doi.org/10.1007/978-1-0716-1020-6_5DOI Listing
April 2021

Both Epimutations and Chromosome Aberrations Affect Multiple Imprinted Loci in Aggressive Wilms Tumors.

Cancers (Basel) 2020 Nov 18;12(11). Epub 2020 Nov 18.

Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', 81100 Caserta, Italy.

The embryonal renal cancer Wilms tumor (WT) accounts for 7% of all children's malignancies. Its most frequent molecular defect is represented by DNA methylation abnormalities at the imprinted 11p15.5 region. Multiple imprinted methylation alterations dictated by chromosome copy-number variations have been recently demonstrated in adult cancers, raising the question of whether multiple imprinted loci were also affected in WT. To address this issue, we analyzed DNA methylation and chromosome profiles of 7 imprinted loci in 48 WT samples. The results demonstrated that methylation abnormalities of multiple imprinted loci occurred in 35% of the cases, but that they were associated with either chromosome aberrations or normal chromosome profiles. Multiple imprinted methylation changes were correlated with tumor stage and presence of metastasis, indicating that these epimutations were more frequent in highly aggressive tumors. When chromosome profiles were affected, these alterations were extended to flanking cancer driver genes. Overall, this study demonstrates the presence of multiple imprinted methylation defects in aggressive WTs and suggests that the mechanism by which they arise in embryonal and adult cancers is different.
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http://dx.doi.org/10.3390/cancers12113411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698742PMC
November 2020

Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.

J Immunother Cancer 2020 11;8(2)

Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.

Background: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).

Methods: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).

Results: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).

Conclusions: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.
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http://dx.doi.org/10.1136/jitc-2020-001561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674086PMC
November 2020

RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis.

Sci Adv 2020 Oct 23;6(43). Epub 2020 Oct 23.

Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain.

Ewing sarcoma (EwS) is an aggressive tumor that affects adolescents and young adults. EwS is defined by a chromosomal translocation, EWSR1-FLI1 being the most common, that causes genome reprogramming through remodeling of enhancers. Here, we describe an unexpected function of RING1B, which is highly expressed in EwS. While retaining its repressive activity at Polycomb developmental regulated genes, RING1B colocalizes with EWSR1-FLI1 at active enhancers. We demonstrate that RING1B is necessary for the expression of key EWSR1-FLI1 targets by facilitating oncogene recruitment to their enhancers. Knockdown of RING1B impairs growth of tumor xenografts and expression of genes regulated by EWSR1-FLI1 bound enhancers. Pharmacological inhibition of AURKB with AZD1152 increases H2Aub levels causing down-regulation of RING1B/EWSR1-FLI1 common targets. Our findings demonstrate that RING1B is a critical modulator of EWSR1-FLI1-induced chromatin remodeling, and its inhibition is a potential therapeutic strategy for the treatment of these tumors.
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http://dx.doi.org/10.1126/sciadv.aba3058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608835PMC
October 2020

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials.

Front Genet 2020 11;11:578011. Epub 2020 Sep 11.

Institute of Biomedicine of Seville, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla/CIBERONC, Seville, Spain.

Chemotherapy is one of the most established and effective treatments for almost all types of cancer. However, the elevated toxicity due to the non-tumor-associated effects, development of secondary malignancies, infertility, radiation-induced fibrosis and resistance to treatment limit the effectiveness and safety of treatment. In addition, these multiple factors significantly impact quality of life. Over the last decades, our increased understanding of cancer epigenetics has led to new therapeutic approaches and the promise of improved patient outcomes. Epigenetic alterations are commonly found in cancer, especially the increased expression and activity of histone deacetylases (HDACs). Dysregulation of HDACs are critical to the development and progression of the majority of tumors. Hence, HDACs inhibitors (HDACis) were developed and now represent a very promising treatment strategy. The use of HDACis as monotherapy has shown very positive pre-clinical results, but clinical trials have had only limited success. However, combinatorial regimens with other cancer drugs have shown synergistic effects both in pre-clinical and clinical studies. At the same time, these combinations have enhanced the efficacy, reduced the toxicity and tumor resistance to therapy. In this review, we will examine examples of HDACis used in combination with other cancer drugs and highlight the synergistic effects observed in recent preclinical and clinical studies.
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http://dx.doi.org/10.3389/fgene.2020.578011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516260PMC
September 2020

[Liquid biopsy in oncology: A consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology].

Rev Esp Patol 2020 Oct - Dec;53(4):234-245. Epub 2020 Mar 2.

Departamento de Oncología Médica, Centro Integral Oncológico Clara Campal Barcelona (CIOCCB), HM Delfos, Barcelona, España.

The proportion of cancer patients with tumours that harbour a potentially targetable genomic alteration is increasing considerably. The diagnosis of these genomic alterations can lead to tailoring of treatment, at the onset of disease or during progression, as well as providing additional, predictive information on the efficacy of immunotherapy. However, in up to 25% of cases, the initial tissue biopsy is inadequate for precision oncology and, in many cases, tumour genomic profiling at progression is not possible due to technical limitations of obtaining new tumour tissue specimens. Efficient diagnostic alternatives are therefore required for molecular stratification, such as liquid biopsy. This technique enables the evaluation of the tumour genomic profile dynamically and as well as capturing intra-patient genomic heterogeneity. To date, there are several diagnostic techniques available for use in liquid biopsy, each with different precision and performance levels. The objective of this consensus statement of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) is to evaluate the viability and effectiveness of the different methodological approaches of liquid biopsy in cancer patients, and the potential application of this method to current clinical practice. The experts contributing to this consensus statement agree that, according to current evidence, liquid biopsy is an acceptable alternative to tumour tissue biopsy for the study of biomarkers in various clinical settings. It is therefore important to standardise pre-analytical and analytical procedures to ensure reproducibility and to generate structured and accessible clinical reports. It is essential to appoint multidisciplinary tumour molecular committees to oversee these processes and to enable the most suitable therapeutic decisions for each patient according to the genomic profile.
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http://dx.doi.org/10.1016/j.patol.2019.12.001DOI Listing
October 2021

Sarcoma European and Latin American Network (SELNET) Recommendations on Prioritization in Sarcoma Care During the COVID-19 Pandemic.

Oncologist 2020 10 23;25(10):e1562-e1573. Epub 2020 Sep 23.

Group of Advanced Therapies and Biomarkers in Sarcoma, Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.

Background: The COVID-19 outbreak has resulted in collision between patients infected with SARS-CoV-2 and those with cancer on different fronts. Patients with cancer have been impacted by deferral, modification, and even cessation of therapy. Adaptive measures to minimize hospital exposure, following the precautionary principle, have been proposed for cancer care during COVID-19 era. We present here a consensus on prioritizing recommendations across the continuum of sarcoma patient care.

Material And Methods: A total of 125 recommendations were proposed in soft-tissue, bone, and visceral sarcoma care. Recommendations were assigned as higher or lower priority if they cannot or can be postponed at least 2-3 months, respectively. The consensus level for each recommendation was classified as "strongly recommended" (SR) if more than 90% of experts agreed, "recommended" (R) if 75%-90% of experts agreed and "no consensus" (NC) if fewer than 75% agreed. Sarcoma experts from 11 countries within the Sarcoma European-Latin American Network (SELNET) consortium participated, including countries in the Americas and Europe. The European Society for Medical Oncology-Magnitude of clinical benefit scale was applied to systemic-treatment recommendations to support prioritization.

Results: There were 80 SRs, 35 Rs, and 10 NCs among the 125 recommendations issued and completed by 31 multidisciplinary sarcoma experts. The consensus was higher among the 75 higher-priority recommendations (85%, 12%, and 3% for SR, R, and NC, respectively) than in the 50 lower-priority recommendations (32%, 52%, and 16% for SR, R, and NC, respectively).

Conclusion: The consensus on 115 of 125 recommendations indicates a high-level of convergence among experts. The SELNET consensus provides a tool for sarcoma multidisciplinary treatment committees during the COVID-19 outbreak.

Implications For Practice: The Sarcoma European-Latin American Network (SELNET) consensus on sarcoma prioritization care during the COVID-19 era issued 125 pragmatical recommendations distributed as higher or lower priority to protect critical decisions on sarcoma care during the COVID-19 pandemic. A multidisciplinary team from 11 countries reached consensus on 115 recommendations. The consensus was lower among lower-priority recommendations, which shows reticence to postpone actions even in indolent tumors. The European Society for Medical Oncology-Magnitude of Clinical Benefit scale was applied as support for prioritizing systemic treatment. Consensus on 115 of 125 recommendations indicates a high level of convergence among experts. The SELNET consensus provides a practice tool for guidance in the decisions of sarcoma multidisciplinary treatment committees during the COVID-19 outbreak.
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http://dx.doi.org/10.1634/theoncologist.2020-0516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543334PMC
October 2020

An inducible ectopic expression system of EWSR1-FLI1 as a tool for understanding Ewing sarcoma oncogenesis.

PLoS One 2020 5;15(6):e0234243. Epub 2020 Jun 5.

Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla/CIBERONC, Seville, Spain.

The presence of the chimeric EWSR1-FLI1 oncoprotein is the main and initiating event defining Ewing sarcoma (ES). The dysregulation of epigenomic and proteomic homeostasis induced by the oncoprotein contributes to a wide variety of events involved in oncogenesis and tumor progression. Attempts at studying the effects of EWSR1-FLI1 in non-tumor cells to understand the mechanisms underlying sarcomagenesis have been unsuccessful to date, as ectopic expression of EWSR1-FLI1 blocks cell cycle progression and induces apoptosis in the tested cell lines. Therefore, it is essential to find a permissive cell type for EWSR1-FLI1 expression that allows its endogenous molecular functions to be studied. Here we have demonstrated that HeLa cell lines are permissive to EWSR1-FLI1 ectopic expression, and that our model substantially recapitulates the endogenous activity of the EWSR1-FLI1 fusion protein. This model could contribute to better understanding ES sarcomagenesis by helping to understand the molecular mechanisms induced by the EWSR1-FLI1 oncoprotein.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234243PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274397PMC
August 2020

Treatment-driven selection of chemoresistant Ewing sarcoma tumors with limited drug distribution.

J Control Release 2020 08 1;324:440-449. Epub 2020 Jun 1.

Institut de Recerca Sant Joan de Deu, Barcelona 08950, Spain; Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona 08950, Spain. Electronic address:

Ewing sarcoma is a bone and soft tissue tumor predominantly affecting adolescents and young adults. To characterize changes in anticancer drug activity and intratumor drug distribution during the evolution of Ewing sarcomas, we used immunodeficient mice to establish pairs of patient-derived xenografts (PDX) at early (initial diagnosis) and late (relapse or refractory progression) stages of the disease from three patients. Analysis of copy number alterations (CNA) in early passage PDX tissues showed that two tumor pairs established from patients which responded initially to therapy and relapsed more than one year later displayed similar CNAs at early and late stages. For these two patients, PDX established from late tumors were more resistant to chemotherapy (irinotecan) than early counterparts. In contrast, the tumor pair established at refractory progression showed highly dissimilar CNA profiles, and the pattern of response to chemotherapy was discordant with those of relapsed cases. In mice receiving irinotecan infusions, the level of SN-38 (active metabolite of irinotecan) in the intracellular tumor compartment was reduced in tumors at later stages compared to earlier tumors for those pairs bearing similar CNAs, suggesting that distribution of anticancer drug shifted toward the extracellular compartment during clonal tumor evolution. Overexpression of the drug transporter P-glycoprotein in late tumor was likely responsible for this shift in drug distribution in one of the cases.
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http://dx.doi.org/10.1016/j.jconrel.2020.05.032DOI Listing
August 2020

Clinical performance evaluation of the Idylla™ EGFR Mutation Test on formalin-fixed paraffin-embedded tissue of non-small cell lung cancer.

BMC Cancer 2020 Apr 3;20(1):275. Epub 2020 Apr 3.

Department of Pathology, Molecular Pathology Laboratory, Hospital Universitario Virgen del Rocío-IBIS, Av. Manuel Siurot, S/n, 41013, Sevilla, Spain.

Background: Detection of epidermal growth factor receptor (EGFR) mutations in exons 18-21 is recommended in all patients with advanced Non-small-cell lung carcinoma due to the demonstrated efficiency of the standard therapy with tyrosine kinase inhibitors in EGFR-mutated patients. Therefore, choosing a suitable technique to test EGFR mutational status is crucial to warrant a valid result in a short turnaround time using the lowest possible amount of tissue material. The Idylla™ EGFR Mutation Test is a simple, fast and reliable method designed for the detection of EGFR mutations from formalin-fixed paraffin-embedded samples. The aim of this study was the Clinical Performace Evaluation of the Idylla™ EGFR Mutation Test on the Idylla™ System.

Methods: EGFR mutational status was determined on 132 archived formalin-fixed paraffin-embedded tissue sections with Idylla™ technology. Results were compared with the results previously obtained by routine method in the reference lab (Therascreen® EGFR RGQ PCR v2, Qiagen in Molecular Pathology lab, Hospital Universitario Virgen del Rocío de Sevilla).

Results: The overall agreement between results obtained with the Idylla™ EGFR Mutation Test and the Comparator test method was 95.38% (with 1-sided 95% lower limit of 91.7%) showing Positive Diagnostic Agreement of 93.22% and Negative Diagnostic Agreement of 97.18%, with a Limit Of Detection ≤5%.

Conclusions: The Idylla™ EGFR Mutation Test passed its clinical validity performance characteristics for accuracy.
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http://dx.doi.org/10.1186/s12885-020-6697-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126408PMC
April 2020

Breakthrough Technologies Reshape the Ewing Sarcoma Molecular Landscape.

Cells 2020 03 26;9(4). Epub 2020 Mar 26.

Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, 41013 Seville, Spain.

Ewing sarcoma is a highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. At the molecular level, it is characterized by the presence of recurrent chromosomal translocations. In the last years, next-generation technologies have contributed to a more accurate diagnosis and a refined classification. Moreover, the application of these novel technologies has highlighted the relevance of intertumoral and intratumoral molecular heterogeneity and secondary genetic alterations. Furthermore, they have shown evidence that genomic features can change as the tumor disseminates and are influenced by treatment as well. Similarly, next-generation technologies applied to liquid biopsies will significantly impact patient management by allowing the early detection of relapse and monitoring response to treatment. Finally, the use of these novel technologies has provided data of great value in order to discover new druggable pathways. Thus, this review provides concise updates on the latest progress of these breakthrough technologies, underscoring their importance in the generation of key knowledge, prognosis, and potential treatment of Ewing Sarcoma.
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http://dx.doi.org/10.3390/cells9040804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226764PMC
March 2020

Pazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.

Lancet Oncol 2020 03 14;21(3):456-466. Epub 2020 Feb 14.

Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale Tumori, Milan, Italy.

Background: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.

Methods: In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.

Findings: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]).

Interpretation: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.

Funding: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(19)30826-5DOI Listing
March 2020

LOXL2 promotes oncogenic progression in alveolar rhabdomyosarcoma independently of its catalytic activity.

Cancer Lett 2020 04 3;474:1-14. Epub 2020 Jan 3.

Sarcoma Research Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; CIBERONC, Carlos III Institute of Health (ISCIII), Madrid, Spain; Institut Català D'Oncologia (ICO), L'Hospitalet de Llobregat, Barcelona, Spain. Electronic address:

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. Patients with the most aggressive histological variant have an unfavorable prognosis due to a high metastasis incidence. Lysyl oxidase-like 2 (LOXL2) is a lysyl oxidase, member of a family of extracellular matrix (ECM) crosslinking enzymes that recently have emerged as important regulators of tumor progression and metastasis. We report that LOXL2 is overexpressed in RMS, suggesting a potential role for LOXL2 in RMS oncogenic progression. Consistently, transient and stable LOXL2 knockdown decreased cell migratory and invasive capabilities in two ARMS cell lines. Furthermore, introduction of LOXL2 in RMS non-expressing cells using wild type or mutated (catalytically inactive) constructs resulted in increased cell migration, cell invasion and number and incidence of spontaneous lung metastasis in vivo, independently of its catalytic activity. To further study the molecular mechanism associated with LOXL2 expression, a pull-down assay on LOXL2-transfected cells was performed and analyzed by mass spectrometry. The intermediated filament protein vimentin was validated as a LOXL2-interactor. Thus, our results suggest an oncogenic role of LOXL2 in RMS by regulating cytoskeleton dynamics and cell motility capabilities.
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http://dx.doi.org/10.1016/j.canlet.2019.12.040DOI Listing
April 2020

Hippo pathway effectors YAP1/TAZ induce an EWS-FLI1-opposing gene signature and associate with disease progression in Ewing sarcoma.

J Pathol 2020 04 4;250(4):374-386. Epub 2020 Feb 4.

Department of Pathology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, CSIC-Universidad de Sevilla, Seville, Spain.

YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving the gene EWSR1 and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis, but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of the RASSF1 locus (a regulator of the Hippo pathway) was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the pro-tumorigenic isoform RASSF1C, which promotes YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be explained partly by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5379DOI Listing
April 2020

[Clinical challenges and implications of intratumor heterogeneity].

Rev Esp Patol 2019 Oct - Dec;52(4):234-241. Epub 2019 Jun 6.

Servicio de Anatomía Patológica, Hospital Universitario Cruces, Instituto Biocruces-Bizkaia, Universidad del País Vasco (UPV/EHU), Barakaldo, Vizcaya, España; Servicio de Anatomía Patológica, Hospital Universitario Cruces, Instituto Biocruces-Bizkaia, Universidad del País Vasco (UPV/EHU), Barakaldo, Vizcaya, España. Electronic address:

Tumors display a high, albeit variable, grade of intratumor heterogeneity, both from a clinical and a morphological viewpoint. Furthermore, recent methods of large-scale molecular analysis demonstrate to what extent tumors can also be heterogeneous from a molecular perspective. This is of paramount importance for patients as it has a great impact on the success of so-called precision therapies and explains the reason for a significant number of therapeutic failures in modern oncology. We present an up-to-date review of the latest findings in a group of tumors with a high social impact, commonly seen in the daily routine of the pathology laboratory.
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http://dx.doi.org/10.1016/j.patol.2019.04.004DOI Listing
June 2020

Pazopanib for treatment of advanced extraskeletal myxoid chondrosarcoma: a multicentre, single-arm, phase 2 trial.

Lancet Oncol 2019 09 19;20(9):1252-1262. Epub 2019 Jul 19.

Department of Medical Oncology, University Hospital Virgen del Rocio, Seville, Spain; Institute of Biomedicine of Sevilla, Universidad de Sevilla, Seville, Spain.

Background: Extraskeletal myxoid chondrosarcoma is a rare sarcoma with low sensitivity to cytotoxic chemotherapy. Retrospective evidence suggests that antiangiogenic drugs could be a treatment option. We aimed to investigate the activity of pazopanib, an antiangiogenic drug, in patients with advanced extraskeletal myxoid chondrosarcoma.

Methods: In this single-arm, open-label phase 2 trial, three parallel independent cohorts of different histotypes of advanced sarcomas were recruited (extraskeletal myxoid chondrosarcoma, typical solitary fibrous tumour, and malignant-dedifferentiated solitary fibrous tumour). In each cohort, patients received pazopanib. In this Article, we report the results of the cohort of patients with advanced extraskeletal myxoid chondrosarcoma. Separate reporting of the three cohorts was prespecified in the study protocol. In this cohort, adult patients (aged ≥18 years) with a diagnosis of NR4A3-translocated, metastatic, or unresectable extraskeletal myxoid chondrosarcoma, who had Response Evaluation Criteria in Solid Tumors (RECIST) progression in the previous 6 months, and had an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled at 11 study sites of the Spanish, Italian, and French sarcoma groups. Patients received oral pazopanib (800 mg/day) continuously, until disease progression, unacceptable toxicity, death, non-compliance, patient refusal, or investigator's decision. The primary endpoint was the proportion of patients achieving an objective response according to RECIST 1·1 in the modified intention-to-treat population (patients who provided consent and had a central molecularly confirmed diagnosis of extraskeletal myxoid chondrosarcoma). The safety analysis included all patients who received at least one dose of pazopanib. This study is registered with ClinicalTrials.gov, number NCT02066285.

Findings: Between June 24, 2014, and Jan 17, 2017, 26 patients entered the study and started pazopanib. Of these, 23 met the eligibility criteria for the modified intention-to-treat analysis. Median follow-up was 27 months (IQR 18-30). 22 patients (one patient died before the primary analysis) were evaluable for the primary endpoint: four (18% [95% CI 1-36]) had a RECIST objective response. No deaths or grade 4 adverse events occurred. The most frequent grade 3 adverse events were hypertension (nine [35%] of 26 patients), increased concentration of alanine aminotransferase (six [23%]), and increased aspartate aminotransferase (five [19%]).

Interpretation: Pazopanib had clinically meaningful antitumour activity in patients with progressive and advanced extraskeletal myxoid chondrosarcoma, and could be considered a suitable option after failure to respond to first-line anthracycline-based chemotherapy in these patients.

Funding: Spanish Group for Research on Sarcomas, Italian Sarcoma Group, French Sarcoma Group, GlaxoSmithKline, and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(19)30319-5DOI Listing
September 2019

DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma.

J Cancer Res Clin Oncol 2019 May 20;145(5):1273-1281. Epub 2019 Mar 20.

Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.

Purpose: Recent studies revealed divergent gene expression patterns in Ewing sarcoma (EwS) with canonical EWSR1-ETS gene fusions and undifferentiated round cell sarcomas (URCS) with EWSR1 rearrangements fused to the non-ETS gene NFATc2. Thus, the question arises whether the latter tumors really belong to EwS.

Methods: We collected five cases matching the group of URCS with EWSR1-NFATc2 fusion and performed DNA methylation and copy number profiling. Results were compared to methylation data of 30 EwS with various EWSR1-ETS fusions and one EwS with FUS-ERG fusion, 16 URCS with CIC rearrangement and 10 URCS with BCOR alteration and a total of 81 EWSR1-associated soft tissue sarcomas including 7 angiomatoid fibrous histiocytomas, 7 clear cell sarcomas of the soft tissue, 28 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas and 29 myxoid liposarcomas.

Results: Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis of DNA methylation data revealed a homogeneous methylation cluster for URCS with EWSR1-NFATc2 fusion, which clearly segregated from EwS and the other subtypes. Copy number profiles of EWSR1-NFATc2 cases showed recurrent losses on chromosome 9q and segmental gains on 20q13 and 22q12 involving the EWSR1 and NFATc2 loci, respectively.

Conclusion: In summary, URCS with EWSR1-NFATc2 fusion share a distinct DNA methylation signature and carry characteristic copy number alterations, which emphasizes that these sarcomas should be considered separately from EwS.
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http://dx.doi.org/10.1007/s00432-019-02895-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607515PMC
May 2019

Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.

Lancet Oncol 2019 01 18;20(1):134-144. Epub 2018 Dec 18.

Department of Medical Oncology, University Hospital of Canarias, Tenerife, Spain.

Background: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.

Methods: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.

Findings: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).

Interpretation: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.

Funding: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(18)30676-4DOI Listing
January 2019

What's in a name? Molecular subclassification of sarcomas creates fresh challenges.

J Pathol 2019 Apr 16;247(4):409-412. Epub 2019 Jan 16.

Department of Pathology, Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Seville, Spain.

This commentary addresses the issue of the classification of sarcomas in the article written by Watson and colleagues published recently in this journal. The article delves into the molecular characterization and distinct phenotypes of some recently described entities (e.g. BCOR-rearranged sarcomas, CIC-fused sarcomas) and describes new groups with common characteristics. This commentary focuses on several questions raised in the article, such as what makes a group of sarcomas become a clinical entity, which should be the main driver of sarcoma classification, how the classification of small round cell sarcomas is expected to evolve and how high-throughput techniques could be applied to sarcoma diagnosis in the short term. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5206DOI Listing
April 2019

Preclinical Efficacy of Endoglin-Targeting Antibody-Drug Conjugates for the Treatment of Ewing Sarcoma.

Clin Cancer Res 2019 04 12;25(7):2228-2240. Epub 2018 Nov 12.

Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Seville, Spain.

Purpose: Endoglin (ENG; CD105) is a coreceptor of the TGFβ family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFβ, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease.

Experimental Design: We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody-drug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma.

Results: Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed . Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line-derived xenografts and patient-derived xenografts in a dose-dependent manner.

Conclusions: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445738PMC
April 2019

The combination of epigenetic drugs SAHA and HCI-2509 synergistically inhibits EWS-FLI1 and tumor growth in Ewing sarcoma.

Oncotarget 2018 Jul 31;9(59):31397-31410. Epub 2018 Jul 31.

Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla/CIBERONC, Seville, Spain.

Purpose: Epigenetic regulation is crucial in mammalian development and maintenance of tissue-cell specific functions. Perturbation of epigenetic balance may lead to alterations in gene expression, resulting in cellular transformation and malignancy. Previous studies in Ewing sarcoma (ES) have shown that the Nucleosome Remodeling Deacetylase (NuRD) complex binds directly to EWS-FLI1 oncoprotein and modulates its transcriptional activity. The role of EWS-FLI1 as a driver of proliferation and transformation in ES is widely known, but the effect of epigenetic drugs on fusion activity remains poorly described. The present study evaluated the combination effects of the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and Lysine-specific demethylase1 inhibitor (HCI-2509) on different biological functions in ES and in comparison to monotherapy treatments.

Results: The study of proliferation and cell viability showed a synergistic effect in most ES cell lines analyzed. An enhanced effect was also observed in the induction of apoptosis, together with accumulation of cells in G1 phase and a blockage of the migratory capacity of ES cell lines. Treatment, either in monotherapy or in combination, caused a significant decrease of mRNA and protein levels and this effect is mediated in part by fusion gene promoter regulation. The anti-tumor effect of this combination was confirmed in patient-derived xenograft mouse models, in which only the combination treatment led to a statistically significant decrease in tumor volume.

Conclusions: The combination of SAHA and HCI-2509 is proposed as a novel treatment strategy for ES patients to inhibit the essential driver of this sarcoma and tumor growth.
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http://dx.doi.org/10.18632/oncotarget.25829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101143PMC
July 2018
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