Selected research projects:
> Identification of novel therapeutic targets through functional characterization of oncogenic pathways in synovial sarcoma (SySa)
Synovial sarcomas (SySa) account for 5-10% of all soft tissue sarcomas. In the majority, SySa arise mainly in adolescents and young adults with predominance in male gender. They are molecularly characterized by a reciprocal t(X;18) translocation which juxtaposes the SS18 gene on chromosome 18 to either the SSX1, the SSX2, or rarely to the SSX4 gene on the X chromosome. The SS18-SSX chimeric proteins act as transcriptional co-activators, leading to deregulation of oncogenic pathways. Current treatment protocols for synovial sarcoma are based on radical surgery and standardized chemo- and radiotherapy; however, prognosis is still poor in advanced disease. Targeted therapeutic approaches, which have significantly improved the clinical course of patients with e.g. GIST or dermato- fibrosarcoma protuberans, are still lacking for SySa. Several receptor tyrosine kinases have been shown to be expressed in SySa, including the EGF receptor, and the IGF-IR, leading to an activation of the PI3K/AKT signaling pathway. Beyond kinase signals, we have shown an essential role of WNT/ß-catenin signals in SySa.
Our current studies analyze the functional relevance of diverse oncogenic signaling pathways in synovial sarcoma, aiming at a better understanding of tumor biology as a basis for the definition of innovative therapeutic approaches.
> Functional characterization of transcription factors in the context of activated PI3K/AKT signaling in myxoid liposarcomas (MLS)
Accounting for ~5-10% of all soft tissue sarcomas, myxoid liposarcoma (MLS) represent ~20% of all malignant adipocytic tumors. In the majority of cases, MLS arise in younger adults, defining the most frequent LS subtype in patients <20 years of age. Clinically, MLS are characterized by a high rate of local recurrences and development of metastases affecting in total ~40% of patients. Morphologically, MLS comprise a large spectrum ranging from paucicellular myxoid tumors to hypercellular round cell sarcomas associated with a more aggressive clinical course. Genetically, the vast majority of MLS is characterized by a chromosomal t(12;16)(q13;p11) translocation, juxtaposing the FUS and DDIT3 genes. About 5% of all MLS display an alternative chromosomal t(12;22) rearrangement leading to an EWSR1-DDIT3 gene fusion. The resulting FUS‑DDIT3 and EWSR1-DDIT3 fusion proteins are thought to play an essential role in MLS pathogenesis, acting as transcriptional (dys-)regulators; however, the functional details and the specific impact of the chimeric fusion protein on oncogenic signaling pathways known to be activated in MLS is incompletely understood. It has been shown recently that MLS are characterized by EGFR, PDGFRB, RET, and MET as well as VEGFR1 activation sustained by autocrine/paracrine loops and receptor tyrosine kinase (RTK) cross-talk, resulting in activation of the downstream PI3K/AKT signaling pathway. PI3K/AKT signaling is a central hub in the transduction of different RTK inputs involving diverse growth-controlling effectors such as GSK-3ß and the cell cycle regulator Cyclin D1. Current therapeutic approaches in high-grade MLS complement radical surgery with radiotherapy and/or conventional chemotherapy based on anthracyclines and ifosfamide. However, though MLS display higher chemosensitivity than other LS, the high rate of recurrences and metastases in MLS underlines the urgent need of novel therapeutic options.
Our current studies analyze the functional relevance of diverse oncogenic signaling pathways in myxoid liposarcoma, aiming at a better understanding of tumor biology as a basis for the definition of innovative therapeutic approaches.
> Identification and characterization of molecular targets in sarcoma cell lines as a basis of innovative therapeutic strategies
Synovial sarcoma (SySa) and dedifferentiated liposarcoma (DDLS) represent major cytogenetically well-defined soft tissue sarcoma (STS) subgroups, both being associated with limited effects of conventional cytotoxic drugs and a poor prognosis in advanced disease. Though the molecular understanding of these tumors has improved significantly in the recent years, standardized individualized therapeutic concepts have not entered clinical routine yet. Starting from the growing insight that mono-directed therapeutic approaches are of limited effect and sustainability, we aim at the delineation of tumor-driving protein kinase activation patterns, including the detailed analysis of signaling pathway inter-dependencies and the systematic preclinical evaluation of innovative therapeutic concepts in SySa and DDLS, based on a comprehensive library of well-characterized sarcoma cell lines. The project is based on a phosphor kinome screen of primary tumor tissues, cell lines and in vitro cell model systems of SySa and DDLS. For analysis, results are integrated with available data from the comprehensive genomic screens in STS by the competence network sarcoma (KoSar). Recurrent kinase activation profiles detected in the primary tumor tissues are functionally characterized by RNA interference and pharmacological inhibition in SySa and DDLS cell lines, primary tumor cell cultures and in vitro cell model systems. Particular emphasis is put on potential synergistic effects of different kinase signals and kinase/non-kinase pathway interactions.
The results of the project are expected to improve our biological understanding of cytogentically well-defined STS, to identify novel therapeutic concepts for patients with SySa and DDLS and to provide convincing evidence for future clinical trials.
Ewing sarcoma is an aggressive small round blue cell tumor occurring from birth to late adulthood with a peak incidence in adolescents and an overall incidence of 1 case per 1 million. Ewing sarcoma mainly arises in the bones of the pelvis, chest wall and the extremities. While primary disease most frequently is local, in a subset of patients metastases develop in lung, bone, and bone marrow. For patients with disseminated disease at multiple sites at primary diagnosis (25% of the patients) prognosis is particularly dismal with a 5-year overall survival between 10% and 30%. Genetically, classic Ewing sarcoma is defined by specific balanced chromosomal TET-ETS translocations that give rise to oncogenic chimeric proteins, the most common being EWS-FLI1 as a consequence of the t(11;22)(q24;q12) translocation. TET-ETS chimeric proteins promote cell transformation through abnormal regulation of specific target genes involved in the control of a variety of cellular processes. However, many details of the molecular pathogenesis of Ewing sarcoma remain enigmatic. Recently, novel non-TET-ETS gene fusions involving the CIC and BCOR genes have been identified in "atypical" Ewing tumors, but their downstream pathogenic mechanisms have not been understood.
Our current studies analyze the functional impact of the oncogenic fusion proteins in Ewing sarcomas on oncogenic processes in Ewing sarcomas, aiming at a better understanding of tumor biology as a basis for the definition of innovative therapeutic approaches.
GDI - CANCER RESEARCH LAB
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+49 (0)251/83-55444 or -58461
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48149 Münster, Germany