Children’ Cancer Research Center, Technische Universitaet Muenchen, Munich, Germany
AIM OF THE PROJECT
Owing to multimodal treatment concepts, 70% of patients with localised Ewing Sarcoma (ES) achieve sustained remission; still, approximately 30% relapse. While clinical prognostic markers such as primary dissemination, tumour site, tumour size 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. Therefore, and to be able to develop new treatment modalities, the transcriptome of this tumour was compared by us to normal tissue and resulted in the identification of genes such as EZH2 and STEAP1; now known - based on our data - to be significant not only for the pathogenesis but also for prognosis of the disease. Furthermore, potential prognostic biomarkers, such as CXCR4, LGALS3BP and PARP1 were identified by other members within PROVABES. These genes shall be further explored on retrospective patient samples, STEAP1 based on our data, in addition, shall be evaluated as a biomarker in a cooperative prospective study.
Prospective evaluation of the predictive power of high STEAP1 expression. In order to validate the method we will perform two consecutive retrospective studies in independent tissue microarray (TMA) sets from other institutions of PROVABES. We will cross-evaluate the results of the initial and consecutive TMA studies with those obtained from the use of different STEAP1 antibodies.
Generating of TMAs of retrospective / prospective probes obtained from members of PROVABES. Subsequently, we will perform a cooperative prospective evaluation of the predictive power of high STEAP1 expression within the European ES studies in cooperation with the project coordinator. PROVABES will enable us to achieve the number of >300 patients required for solid multivariate analyses.
Establishing of specific IHC for CXCR4, LGALS3BP and PARP1. Subsequently, biomarkers with a presumed general role in ES malignancy such as CXCR4, EZH2, LGALS3BP and PARP1, will be further analysed on ES samples of PROVABES. Explorative analysis will be accomplished in cooperation with WP1.1, WP2 and WP4.
Evaluation of CXCR4, EZH2, PARP1 and LGALS3BP expression on TMAs of PROVABES. Having established specific immune histology (IHC) with validated antibodies, expression of CXCR4, EZH2, LGALS3BP and PARP1 on the afore mentioned TMAs of retrospective patient material of PROVABES will be evaluated. For each antigen to be investigated we expect 150 TMAs derived from 150 ES patients as sufficient.
EXPLOITATION OF THE RESULTS
This work package is a highly cooperative project and based on the number of biomarkers to be investigated but mainly on the amount of needed, statistically valid patient material only possible on a collaborative basis within the European Community. It aims, based on a rare but molecular well characterized pediatric tumor such as Ewing Sarcoma, to evaluate new potential biomarkers for the prognosis of this disease not only on a retrospective basis but also in a prospective study. This shall enable us to improve therapy and to develop new treatment modalities on a personalized basis that can be directly integrated into the leading European Sarcoma studies within PROVABES and is considered as a general procedure for other cancers as well.