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  • 1
    Abstract: PURPOSE: Altered FGFR1 signaling has emerged as therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties and potential as drug target of FGFR1 in STS. EXPERIMENTAL DESIGN: The frequency of FGFR1 amplification and overexpression, as assessed by fluorescence in situ hybridization, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis. RESULTS: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; Cohort 1), 13 of 79 (16.5%; Cohort 2), and 80 of 254 (31.5%; Cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, Cohort 2) and 39 of 254 (15.4%; Cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway. CONCLUSIONS: These data identify FGFR1 as driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to FGFR1 expression and monitoring of MAPK-ERK1/2 signaling, as therapeutic option in this challenging group of diseases.
    Type of Publication: Journal article published
    PubMed ID: 27535980
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  • 2
    Abstract: BACKGROUND: Breast cancer is one of the most common malignancies with increasing incidences every year and a leading cause of death among women. Although early stage breast cancer can be effectively treated, there are limited numbers of treatment options available for patients with advanced and metastatic disease. The novel breast cancer associated antigen NY-BR-1 was identified by SEREX analysis and is expressed in the majority (〉70%) of breast tumors as well as metastases, in normal breast tissue, in testis and occasionally in prostate tissue. The biological function and regulation of NY-BR-1 is up to date unknown. METHODS: We performed an in silico analysis on the genetic variations of the NY-BR-1 gene using data available in public SNP databases and the tools SIFT, Polyphen and Provean to find possible functional SNPs. Additionally, we considered the allele frequency of the found damaging SNPs and also analyzed data from an in-house sequencing project of 55 breast cancer samples for recurring SNPs, recorded in dbSNP. RESULTS: Over 2800 SNPs are recorded in the dbSNP and NHLBI ESP databases for the NY-BR-1 gene. Of these, 65 (2.07%) are synonymous SNPs, 191 (6.09%) are non-synoymous SNPs, and 2430 (77.48%) are noncoding intronic SNPs. As a result, 69 non-synoymous SNPs were predicted to be damaging by at least two, and 16 SNPs were predicted as damaging by all three of the used tools. The SNPs rs200639888, rs367841401 and rs377750885 were categorized as highly damaging by all three tools. Eight damaging SNPs are located in the ankyrin repeat domain (ANK), a domain known for its frequent involvement in protein-protein interactions. No distinctive features could be observed in the allele frequency of the analyzed SNPs. CONCLUSION: Considering these results we expect to gain more insights into the variations of the NY-BR-1 gene and their possible impact on giving rise to splice variants and therefore influence the function of NY-BR-1 in healthy tissue as well as in breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 27863482
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  • 3
    Keywords: cytokines ; IMMUNOTHERAPY ; vaccination ; tumor immunology ; tumor microenvironment ; IHC ; neoantigens ; neo-epitopes
    Abstract: Neuroendocrine tumors (NETs) of the gastrointestinal tract are a rare and heterogeneous group of neoplasms with unique tumor biology and clinical management issues. While surgery is the only curative treatment option in patients with early stage NETs, the optimal management strategy for patients with advanced metastatic NETs is unknown. Based on the tremendous success of immunotherapeutic approaches, we sought to investigate such approaches in a case of metastatic rectal NET. Here, we apply an integrative approach using various computational and experimental methods to explore several aspects of the tumor-host immune interactions for immunotherapeutic options. Sequencing of six different liver metastases revealed a quite homogenous set of mutations, and further analysis of these mutations for immunogenicity revealed few neo-epitopes with pre-existing T cell reactivity, which can be used in therapeutic vaccines. Staining for immunomodulatory proteins and cytokine profiling showed that the immune setting is surprisingly different, when compared to liver metastases of colorectal cancer for instance. Taken together, our results highlight the broad range and complexity of tumor-host immune interaction and underline the value of an integrative approach.
    Type of Publication: Journal article published
    PubMed ID: 27999735
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