Sabine Taschner-Mandl, PhD
Biology and innovative treatment strategies for high-risk neuroblastoma patients.
Background – neuroblastoma biology and clinical needs
The childhood cancer neuroblastoma is the most frequent extra-cranial tumor in infants and children and originates from the neuronal crest during embryogenesis. Neuroblastoma accounts for 11% of all cancer-related deaths in children. Its heterogeneous tumor biology creates clinical diversity spanning from spontaneous regression/maturation to highly aggressive clinical course. Despite considerable international efforts, long-term survival of high-risk disease remains poor, with <40% overall survival after first-line treatment and <10% after relapse.
Recent research – new therapeutic concepts
Novel therapeutic options for MYCN-amplified high-risk neuroblastoma patients
Poor prognosis and frequent relapses are major challenges for patients with high-risk neuroblastoma, especially when tumors show an amplification of the MYCN oncogene. In contrast to high-dose chemotherapy, low-dose metronomic (LDM) therapy is administered at lower doses continuously or at predefined intervals. Functional consequences involve, among others, inhibition of angiogenesis and induction of senescence. Our lab previously found that in MYCN-amplified neuroblastoma senescence, a permanent proliferative arrest, occurs spontaneously or upon LDM chemotherapy (Ambros et al., EJC, 1997, Taschner-Mandl et al., Oncotarget 2016). We investigated the mechanism of action of LDM topotecan treatment in low-passage MYCN-amplified cell lines in vitro and in mouse xenograft models in vivo.
We have uncovered the mechanism of MYCN inactivation upon LDM topotecan treatment and demonstrated its preclinical efficacy. Further, we established methods to track the amplified MYCN gene in liquid biopsies, a prerequisite for future clinical testing as a maintenance therapy for NB patients with MYCN-amplification.
Exploiting stromal Schwann cell derived factors for targeting aggressive neuroblastoma
While aggressive neuroblastomas are composed of un-/poorly differentiated tumor cells, maturation into benign ganglioneuroma is hallmarked by Schwann cell stroma and tumor cell differentiation. Our lab has previously disproven the neoplastic nature of stromal Schwann cells in ganglioneuroma and demonstrated a tumor – Schwann cell cross-talk (Ambros IM et al., EJC, 1995; Ambros IM et al., NEJM, 1996; Ambros IM et al., MPO, 2001). Based on their reactive nature, Schwann cells can undergo an adaptive response to genetically favorable neuroblastic tumor cells by similar mechanisms as during nerve injury or development.
Our analysis using primary human Schwann cell cultures, fresh nerve tissue and tumor specimen revealed that stromal Schwann cells in ganglioneuroma adopt similar functions as repair-type Schwann cells (Weiss T and Taschner-Mandl S et al, Glia, 2016) e.g. the regulation of neuronal differentiation, and Schwann cell derived factors can be exploited to trigger differentiation also in aggressive neuroblastoma. By analyzing the status of stromal Schwann cells by RNA-sequencing and proteomics analysis (in collaboration with C. Gerner, University of Vienna) and deciphering Schwann cell interactions with NB-cells we identified a new potent secreted neuritogen with anti-tumor activity which could be of therapeutic interest for a subset of aggressive NBs.
Ongoing research projects focus on
- Identification of biomarker (prognostic and MRD-marker and therapeutic targets) and development of tools for personalized medicine (e.g. liquid biopsies, VISIOMICS) and
- Identify druggable vulnerabilities of (ultra) high-risk disease neuroblastomas , i.e. tumors which do not sufficiently respond to current treatment options.
VISIOMICS – Platform supporting an integrated analysis of image and multiOMICs data based on liquid biopsies for tumor diagnostics
Funded by the Austrian Research Agency FFG
- Development of new diagnostic tools to predict aggressive features, e.g. relapse by an integrative approach combining image classification using machine-learning approaches and multiple OMICS datasets
- Studying metastatic tumor cells. i.e. tumor cells disseminated into the bone marrow and the metastatic niche in neuroblastoma
Research Studios Austria FG (RSA), Software Competence Center Hagenberg GmbH (SCCH), Platomics GmbH, CogVis Software and Consulting GmbH, VRVis Zentrum für Virtual Reality und Visualisierungs-GmbH, Universitätsklinikum Erlangen, Germany, Hautklinik
Senior scientist/PI of the group Tumor Biology (November 2018)
NEUROBLASTOMA CELLS UNDERGO TRANSCRIPTOMIC ALTERATIONS UPON DISSEMINATION INTO THE BONE MARROW AND SUBSEQUENT TUMOR PROGRESSION. Rifatbegovic F, Frech C, Abbasi MR, Taschner-Mandl S, Weiss T, Schmidt WM, Schmidt I, Ladenstein R, Ambros IM, Ambros PF. Int J Cancer. 2017 Sep 16. doi: 10.1002/ijc.31053.
EVALUATION OF INFLAMMATION-RELATED SIGNALING EVENTS COVERING PHOSPHORYLATION AND NUCLEAR TRANSLOCATION OF PROTEINS BASED ON MASS SPECTROMETRY DATA. Bileck A, Mayer RL, Kreutz D, Weiss T, Taschner-Mandl S, Meier SM, Slany A, Gerner C. J Proteomics. 2017 Jan 30;152:161-171.
METRONOMIC TOPOTECAN IMPEDES TUMOR GROWTH OF MYCN-AMPLIFIED NEUROBLASTOMA CELLS IN VITRO AND IN VIVO BY THERAPY INDUCED SENESCENCE. Taschner-Mandl S, Schwarz M, Blaha J, Kauer M, Kromp F, Frank N, Rifatbegovic F, Weiss T, Ladenstein R, Hohenegger M, Ambros IM, Ambros PF. Oncotarget. 2016 Jan 19;7(3):3571-86. doi: 10.18632/oncotarget.6527.
PROTEOMICS AND TRANSCRIPTOMICS OF PERIPHERAL NERVE TISSUE AND CELLS UNRAVEL NEW ASPECTS OF THE HUMAN SCHWANN CELL REPAIR PHENOTYPE. Weiss T*, Taschner-Mandl S*, Bileck A, Slany A, Kromp F, Rifatbegovic F, Frech C, Windhager R, Kitzinger H, Tzou CH, Ambros PF, Gerner C, Ambros IM. Glia. 2016 Dec;64(12):2133-2153. doi: 10.1002/glia.23045. *contributed equally
MACHINE LEARNING FRAMEWORK INCORPORATING EXPERT KNOWLEDGE IN TISSUE IMAGE ANNOTATION. Kromp F., Ambros I., Weiss T., Bogen D., Dodig H., Berneder M., Gerber T., Taschner-Mandl S., Ambros P. F., Hanbury A. IEEE International Conference on Pattern Recognition, 2016.
- SIOPEN Best oral presentation (2014 and 2017)
- ÖGMBT Best oral presentation (2010)
- ECI travel award (2006)
- Patent AT Patentschrift Nr. A990/2001 C12N, Co-inventor
- Patent EP 3 054 279 A1, Co-inventor, METHODS FOR CLASSIFICATION AND VISUALIZATION OF CELLULAR POPULATIONS ON A SINGLE CELL LEVEL BASED ON MICROSCOPY IMAGES