Title: PROspective VAlidation of Biomarkers in Ewing Sarcoma for personalised translational medicine.
Uta DIRKSEN (Germany) University Hospital Muenster, Paediatric Haematology and Oncology, Münster
Stefan BURDACH (Germany) Kinderklinik, Klinikums rechts der Isar der Technischen Universität München, Labor f. Funktionelle Genomik & Transplantations Biologie im Forschungszentrum für krebskranke Kinder, München
Enrique DE ALAVA (Spain) University Hospital of Salamanca, Department of Pathology, Salamanca
Olivier DELATTRE (France) Institut Curie, INSERM U 830, Paris
Heinrich KOVAR (Austria) St. Anna Kinderkrebsforschung e.V, Children´s Cancer Research Institute, Vienna
Piero PICCI (Italy) Istituto Ortopedico Rizzoli, Istituto Ortopedico Rizzoli, Bologna
Sue Ann BURCHILL (United Kingdom) St James's University Hospital, Children’s Cancer Research Group, Leeds Institute of Molecular Medicine, Leeds
This is a joint proposal of the three leading investigator-driven European Ewing sarcoma study groups, EURO-EWING, Italian Sarcoma Group (ISG) and the Spanish Sarcoma Group (GEIS). These groups have formed a consortium for collaborating with the leading experts on molecular, cellular and translational Ewing sarcoma (ES) research. Each of these scientists will contribute his and her unique expertise to the validation of prognostically relevant biomarkers of solid tumours. The majority of European ES patients are treated within clinical trials under the auspices of the clinical trial groups cooperating in this consortium. Owing to multimodal treatment concepts, 2/3 of the patients with localized disease achieve sustained remission; still, approximately 30 % relapse. While clinical prognostic markers such as primary dissemination, tumour site, tumour size, patient`s age and histological response to chemotherapy are established and used for therapeutic stratification, little is known about biological factors that determine the risk of relapse or progression and thus might help to differentiate patients at risk from those eligible for less intense treatment. Prospectively validated biomarkers are thus needed to provide personalised risk-adapted therapeutic approaches. ES was the first solid malignancy defined by the presence of tumour- specific EWS-ETS gene fusions, mainly EWSR1-FLI1 translocations. In a recent prospective evaluation, in the largest number of patients studied to date members of the planned consortium demonstrated that the EWS-FLI1 fusion type had no impact on prognosis. This is in contrast to earlier retrospective studies, which suggested a possible advantage in relapse-free survival for EWSR1-FLI1 type 1 patients, and thus highlights the importance of a careful prospective validation of biological markers and demonstrates feasibility for the proposed collaborative studies. Secondary genetic alterations have emerged as candidates to account for the most aggressive forms of ES, and might serve as predictive biomarkers. Our group has recently published a number of promising biomarkers. It is expected that not one single biomarker but a combination of markers will provide the most informative prognostic algorithm for patients with ES. We therefore aim to validate selected biomarkers prospectively; chromosome (chr) 1q,
gain and alteration of chr 16, expression of has-miR34a, LGALS3BP, MGST1 and STEAP1. These prognostic studies will complement on-going circulating biomarkers studies and proposed exploratory studies on activity of promising candidates. To achieve this goal, PROVABES will:
- study a homogenous group of patients with localised disease (60% of all diagnosed patients)
- provide prospective validation of biomarkers where there is existing educated guess for prognostic value from previous retrospective studies
- develop assays fit for use in clinical practice on biomaterial available in clinical practice
- perform exploratory studies on selected additional markers. Where appropriate, assess the potential of analysing proposed biomarker activity in surrogate blood based assays, to inform the development of minimally invasive biomarker assays.
(Project funded under JTC 2011)