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Clinical trials for Ewing sarcoma

P Dutton, S B Love, L Billingham, A B Hassan
Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic...
September 1, 2016: Statistical Methods in Medical Research
Vadim S Koshkin, Vanessa Bolejack, Lawrence H Schwartz, Richard L Wahl, Rashmi Chugh, Denise K Reinke, Binsheng Zhao, Joo H O, Shreyaskumar R Patel, Scott M Schuetze, Laurence H Baker
PURPOSE: Despite the rapidly increasing use of [(18)F]fluorodeoxyglucose (FDG) -positron emission tomography (PET), the comparison of anatomic and functional imaging in the assessment of clinical outcomes has been lacking. In addition, there has not been a rigorous evaluation of how common radiologic criteria or the location of the radiology reader (local v central) compare in the ability to predict benefit. In this study, we aimed to compare the effectiveness of various radiologic response assessments for the prediction of overall survival (OS) within the same data set of patients with sarcoma...
August 29, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
J Andrew Livingston, Kenneth R Hess, Aung Naing, David S Hong, Shreyaskumar Patel, Robert S Benjamin, Joseph A Ludwig, Anthony Conley, Cynthia E Herzog, Pete Anderson, Funda Meric-Bernstam, Razelle Kurzrock, Vivek Subbiah
BACKGROUND: We sought to validate the Royal Marsden Hospital (RMH) and MD Anderson Cancer Center (MDACC) prognostic scoring systems for the selection of bone sarcoma patients for phase I clinical trials and to identify additional risk factors related to survival. PATIENTS AND METHODS: We retrospectively reviewed the baseline characteristics and outcomes of 92 bone sarcoma patients who were referred to MDACC's Phase I Clinical Trials Program. RESULTS: Ninety-two patients with Ewing sarcoma (N = 47), osteosarcoma (N = 22), chondrosarcoma (N = 16), and other tumors (N = 7) were evaluated; 78 were enrolled in at least 1 of 43 different phase I trials...
September 27, 2016: Oncotarget
Marilena Cesari, Alberto Righi, Luca Cevolani, Emanuela Palmerini, Daniel Vanel, Davide M Donati, Silvia Cammelli, Marco Gambarotti, Cristina Ferrari, Anna Paioli, Alessandra Longhi, Massimo E Abate, Piero Picci, Stefano Ferrari
PURPOSE: Patients with Ewing sarcoma who are 40 years old or older are usually excluded from clinical trials. For this reason, information on this subset of patients is limited. METHODS: Clinical characteristics and treatment-related variables of patients aged 40 years or more, with a diagnosis of Ewing sarcoma, treated at the authors' institution had been prospectively collected since 1999. RESULTS: Thirty-one patients were identified, with ages ranging from 40 to 70 years (median 45 years)...
October 13, 2016: Tumori
Neerav Shukla, Romel Somwar, Roger S Smith, Sri Ambati, Stanley Munoz, Melinda Merchant, Padraig D'Arcy, Xin Wang, Rachel Kobos, Christophe Antczak, Bhavneet Bhinder, David Shum, Constantin Radu, Guangbin Yang, Barry S Taylor, Charlotte K Y Ng, Britta Weigelt, Inna Khodos, Elisa de Stanchina, Jorge S Reis-Filho, Ouathek Ouerfelli, Stig Linder, Hakim Djaballah, Marc Ladanyi
Ewing sarcoma is a primitive round cell sarcoma with a peak incidence in adolescence that is driven by a chimeric oncogene created from the fusion of the EWSR1 gene with a member of the ETS family of genes. Patients with metastatic and recurrent disease have dismal outcomes and need better therapeutic options. We screened a library of 309,989 chemical compounds for growth inhibition of Ewing sarcoma cells to provide the basis for the development of novel therapies and to discover vulnerable pathways that might broaden our understanding of the pathobiology of this aggressive sarcoma...
August 1, 2016: Cancer Research
Michael J Wagner, J Andrew Livingston, Shreyaskumar R Patel, Robert S Benjamin
The largest studies of chemotherapy for bone sarcomas are in the pediatric population. Although increasing age is often found to be an adverse prognostic factor in these clinical trials, few studies are aimed at assessing regimens specifically in the adult population. Osteosarcoma and Ewing sarcoma have peak incidences in the pediatric and young adult population but also occur in adults. Chondrosarcoma and giant cell tumor of bone are generally found in adults. In this review, we describe the current status of our knowledge about treating adults with cancers of bone origin...
March 2016: Journal of Oncology Practice
Dominik Sturm, Brent A Orr, Umut H Toprak, Volker Hovestadt, David T W Jones, David Capper, Martin Sill, Ivo Buchhalter, Paul A Northcott, Irina Leis, Marina Ryzhova, Christian Koelsche, Elke Pfaff, Sariah J Allen, Gnanaprakash Balasubramanian, Barbara C Worst, Kristian W Pajtler, Sebastian Brabetz, Pascal D Johann, Felix Sahm, Jüri Reimand, Alan Mackay, Diana M Carvalho, Marc Remke, Joanna J Phillips, Arie Perry, Cynthia Cowdrey, Rachid Drissi, Maryam Fouladi, Felice Giangaspero, Maria Łastowska, Wiesława Grajkowska, Wolfram Scheurlen, Torsten Pietsch, Christian Hagel, Johannes Gojo, Daniela Lötsch, Walter Berger, Irene Slavc, Christine Haberler, Anne Jouvet, Stefan Holm, Silvia Hofer, Marco Prinz, Catherine Keohane, Iris Fried, Christian Mawrin, David Scheie, Bret C Mobley, Matthew J Schniederjan, Mariarita Santi, Anna M Buccoliero, Sonika Dahiya, Christof M Kramm, André O von Bueren, Katja von Hoff, Stefan Rutkowski, Christel Herold-Mende, Michael C Frühwald, Till Milde, Martin Hasselblatt, Pieter Wesseling, Jochen Rößler, Ulrich Schüller, Martin Ebinger, Jens Schittenhelm, Stephan Frank, Rainer Grobholz, Istvan Vajtai, Volkmar Hans, Reinhard Schneppenheim, Karel Zitterbart, V Peter Collins, Eleonora Aronica, Pascale Varlet, Stephanie Puget, Christelle Dufour, Jacques Grill, Dominique Figarella-Branger, Marietta Wolter, Martin U Schuhmann, Tarek Shalaby, Michael Grotzer, Timothy van Meter, Camelia-Maria Monoranu, Jörg Felsberg, Guido Reifenberger, Matija Snuderl, Lynn Ann Forrester, Jan Koster, Rogier Versteeg, Richard Volckmann, Peter van Sluis, Stephan Wolf, Tom Mikkelsen, Amar Gajjar, Kenneth Aldape, Andrew S Moore, Michael D Taylor, Chris Jones, Nada Jabado, Matthias A Karajannis, Roland Eils, Matthias Schlesner, Peter Lichter, Andreas von Deimling, Stefan M Pfister, David W Ellison, Andrey Korshunov, Marcel Kool
Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features...
February 25, 2016: Cell
Emily R Theisen, Kathleen I Pishas, Ranajeet S Saund, Stephen L Lessnick
Ewing sarcoma is an aggressive primary pediatric bone tumor, often diagnosed in adolescents and young adults. A pathognomonic reciprocal chromosomal translocation results in a fusion gene coding for a protein which derives its N-terminus from a FUS/EWS/TAF15 (FET) protein family member, commonly EWS, and C-terminus containing the DNA-binding domain of an ETS transcription factor, commonly FLI1. Nearly 85% of cases express the EWS-FLI protein which functions as a transcription factor and drives oncogenesis. As the primary genomic lesion and a protein which is not expressed in normal cells, disrupting EWS-FLI function is an attractive therapeutic strategy for Ewing sarcoma...
April 5, 2016: Oncotarget
Joo Hyun O, Brandon S Luber, Jeffrey P Leal, Hao Wang, Vanessa Bolejack, Scott M Schuetze, Lawrence H Schwartz, Lee J Helman, Denise Reinke, Laurence H Baker, Richard L Wahl
UNLABELLED: The aim of this study was to assess the prognostic and predictive value of early quantitative (18)F-FDG PET to monitor therapy with an antibody to the insulinlike growth factor 1 receptor (IGF-1R antibody) in patients with Ewing sarcoma family of tumors (ESFT). METHODS: (18)F-FDG PET images at baseline and approximately 9 d after initiation of IGF-1R antibody therapy in 115 patients with refractory or relapsed ESFT were prospectively obtained as part of the Sarcoma Alliance for Research through Collaboration trial...
May 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Annemiek M van Maldegem, Judith V M G Bovée, Elleke F P Peterse, Pancras C W Hogendoorn, Hans Gelderblom
BACKGROUND: In the last three decades the outcome for patients with localised Ewing sarcoma (ES) has improved significantly since the introduction of multimodality primary treatment. However, for patients with (extra-) pulmonary metastatic and/or non-resectable relapsed disease the outcome remains poor and new treatment options are urgently needed. Currently the insulin-like growth factor 1 receptor (IGF-1R) pathway and the poly-ADP(adenosinediphosphate)-ribose-polymerase (PARP) pathway are being investigated for potential targeted therapies...
January 2016: European Journal of Cancer
Anthony J Hesketh, Caroline Maloney, Christopher A Behr, Morris C Edelman, Richard D Glick, Yousef Al-Abed, Marc Symons, Samuel Z Soffer, Bettie M Steinberg
Metastatic Ewing Sarcoma carries a poor prognosis, and novel therapeutics to prevent and treat metastatic disease are greatly needed. Recent evidence demonstrates that tumor-associated macrophages in Ewing Sarcoma are associated with more advanced disease. While some macrophage phenotypes (M1) exhibit anti-tumor activity, distinct phenotypes (M2) may contribute to malignant progression and metastasis. In this study, we show that M2 macrophages promote Ewing Sarcoma invasion and extravasation, pointing to a potential target of anti-metastatic therapy...
2015: PloS One
Sonja J Gill, Jon Travers, Irina Pshenichnaya, Fiona A Kogera, Syd Barthorpe, Tatiana Mironenko, Laura Richardson, Cyril H Benes, Michael R Stratton, Ultan McDermott, Stephen P Jackson, Mathew J Garnett
Ewing's sarcoma is a malignant pediatric bone tumor with a poor prognosis for patients with metastatic or recurrent disease. Ewing's sarcoma cells are acutely hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition and this is being evaluated in clinical trials, although the mechanism of hypersensitivity has not been directly addressed. PARP inhibitors have efficacy in tumors with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair by homologous recombination (HR). This drives dependence on PARP1/2 due to their function in DNA single-strand break (SSB) repair...
2015: PloS One
B A Wilky, C Kim, G McCarty, E A Montgomery, K Kammers, L R DeVine, R N Cole, V Raman, D M Loeb
RNA helicase DDX3 has oncogenic activity in breast and lung cancers and is required for translation of complex mRNA transcripts, including those encoding key cell-cycle regulatory proteins. We sought to determine the expression and function of DDX3 in sarcoma cells, and to investigate the antitumor activity of a novel small molecule DDX3 inhibitor, RK-33. Utilizing various sarcoma cell lines, xenografts and human tissue microarrays, we measured DDX3 expression at the mRNA and protein levels, and evaluated cytotoxicity of RK-33 in sarcoma cell lines...
May 19, 2016: Oncogene
Lilly Magdalena Weiß, Manuela Hugle, Sarah Romero, Simone Fulda
Since polo-like kinase 1 (PLK1) is highly expressed in Ewing sarcoma (ES), we evaluated the therapeutic potential of the PLK1 inhibitor BI 6727. Here, we identify a synergistic induction of apoptosis by BI 6727 and several microtubule-interfering drugs in ES cells, including vincristine (VCR), vinblastine (VBL), vinorelbine (VNR) and eribulin. Synergistic drug interaction is confirmed by calculation of combination index (CI). Also, BI 6727 and VCR act in concert to reduce long-term clonogenic survival. Mechanistically, BI 6727/VCR co-treatment cooperates to trigger mitotic arrest, phosphorylation of BCL-2 and BCL-XL and downregulation of MCL-1...
January 15, 2016: International Journal of Cancer. Journal International du Cancer
Erin E Karski, Elizabeth McIlvaine, Mark R Segal, Mark Krailo, Holcombe E Grier, Linda Granowetter, Richard B Womer, Paul A Meyers, Judy Felgenhauer, Neyssa Marina, Steven G DuBois
BACKGROUND: Although multiple prognostic variables have been proposed for Ewing sarcoma (EWS), little work has been done to further categorize these variables into prognostic groups for risk classification. PROCEDURE: We derived initial prognostic groups from 2,124 patients with EWS in the SEER database. We constructed a multivariable recursive partitioning model of overall survival using the following covariates: age; stage; race/ethnicity; sex; axial primary; pelvic primary; and bone or soft tissue primary...
January 2016: Pediatric Blood & Cancer
Quanchi Chen, Zifei Zhou, Liancheng Shan, Hui Zeng, Yingqi Hua, Zhengdong Cai
Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy...
July 2015: Oncology Letters
P Schlegel, T Feuchtinger, C Nitschke-Gérard, U J Eva Seidel, A-M Lang, C Kyzirakos, H-M Teltschik, M Ebinger, M Schumm, E Koscielniak, R Handgretinger, P Lang
Natural killer (NK) cell activity has been shown to have potential activity against Ewing's sarcoma (EWS) especially in tumors with low HLA I expression and high NKG2D expression. Two patients with metastatic relapsed and primary metastatic stage IV EWS who had received two courses of high dose chemotherapy with autologous stem cell rescue were transplanted from a haploidentical parental stem cell donor. Patients are alive in ongoing CR for 10.2 and 3.4 years now. Post transplant local second and first relapses were treated successfully in both patients...
June 2015: Bone Marrow Transplantation
Rocio K Rivera-Valentin, Limin Zhu, Dennis P M Hughes
The pediatric bone sarcomas osteosarcoma and Ewing sarcoma represent a tremendous challenge for the clinician. Though less common than acute lymphoblastic leukemia or brain tumors, these aggressive cancers account for a disproportionate amount of the cancer morbidity and mortality in children, and have seen few advances in survival in the past decade, despite many large, complicated, and expensive trials of various chemotherapy combinations. To improve the outcomes of children with bone sarcomas, a better understanding of the biology of these cancers is needed, together with informed use of targeted therapies that exploit the unique biology of each disease...
August 2015: Paediatric Drugs
T Bölling, G Braun-Munzinger, S Burdach, G Calaminus, A Craft, O Delattre, M-C L Deley, U Dirksen, B Dockhorn-Dworniczak, J Dunst, S Engel, A Faldum, B Fröhlich, H Gadner, U Göbel, G Gosheger, J Hardes, D S Hawkins, L Hjorth, C Hoffmann, H Kovar, J Kruseova, R Ladenstein, I Leuschner, I J Lewis, O Oberlin, M Paulussen, J Potratz, A Ranft, C Rössig, C Rübe, R Sauer, O Schober, A Schuck, B Timmermann, F Tirode, H van den Berg, F van Valen, V Vieth, N Willich, W Winkelmann, J Whelan, R B Womer
Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival...
May 2015: Klinische Pädiatrie
Salah-Eddine Lamhamedi-Cherradi, Brian A Menegaz, Vandhana Ramamoorthy, Ramani A Aiyer, Rebecca L Maywald, Adrianna S Buford, Dannette K Doolittle, Kirk S Culotta, James E O'Dorisio, Joseph A Ludwig
Ewing sarcoma is a transcription factor-mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity...
July 2015: Molecular Cancer Therapeutics
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