Translational GI oncology, Lab Dr. med. Ralph Fritsch

​Our laboratory aims to

  1. Study RAS and PI3 Kinase signalling in order to develop better strategies to target these key oncogenic pathways in patients
  2. Optimize and exploit co-clinical ex vivo organoid modelling for Precision Oncology
  3. Establish novel biomarkers for therapeutic stratification and response monitoring in difficult-to-treat GI cancers

Part of our group is still located at the University of Freiburg (Germany) Hospital Center.

My mission as Head of Medical GI Oncology at USZ is to implement Precision Oncology in all aspects of the clinical management of gastrointestinal and hepato-pancreatico-biliary (HPB) tumors.

Members
Projects

1. Oncogenic RAS and PI3 Kinase (PI3K) Signalling

Our laboratory employs in vitro and in vivo models to study the interplay between small RAS GTPases und PI3K isoforms both on the molecular and translational level. RAS and PI3K lie at the heart of oncogenic signalling and therapeutic targeting of these pathways has remained extremely challenging.

A focus of our laboratory is to integrate next generation patient-derived models into signalling research in order to foster bi-directional translation for Precision Oncology.

Collaboration:
Julian Downward, The Crick Institute, London
Chantal Pauli, Institute of Pathology and Molecular Pathology, USZ

2. Modeling of GI Cancers with Patient-derived Organoids (PDOs)

Comprehensive molecular profiling fails to identify effective personalized treatment strategies in a large proportion of GI tumors highlighting the need for improved pre- and co-clinical modeling.

Patient-derived cancer organoids (PDOs) uniquely preserve genotype and phenotype of individual tumors and can be studied ex vivo in a co-clinical setting. In an interdisciplinary effort, we have established a large collection of tumor organoids derived from patients undergoing resection or surgical biopsy of pancreatic adenocarcinoma. We study several aspect of tumor biology ex vivo including invasiveness and metastatic behavior and explore individual therapeutic vulnerabilities through combinatorial drug screening.

Key future objectives are to

  • Improve co-clinical organoid modeling (efficiency, representation, complexity, time frame)
  • Expand our efforts to other difficult-to-treat GI tumor entities (BTC, CRC, GEJ/gastric)
  • Validate ex vivo drug testing results in co-clinical organoid trials

Collaboration:
Chantal Pauli, Institute of Pathology and Molecular Pathology, USZ
Uwe Wittel, Department of Surgery, Freiburg University Hospital
Melanie Boerries, Institute of Medical Bioinformatics and Systems Medicine, Freiburg University Hospital
Michael Scharl, Department of Gastroenterology and Hepatology, USZ

3. Novel biomarkers for therapeutic stratification and response monitoring

Innovative biomarkers and molecular monitoring hold great potential to personalize multi-modality treatment of GI cancers and better guide systemic therapy. Detection and quantification of tumor-derived cell-free DNA (cfDNA) and the integration of novel protein biomarkers can help better stratify patients and monitor treatment efficacy.

The goal of our laboratory is to establish and integrate innovative liquid biomarkers into the clinical management of GI cancer patients. We employ personalized single- and multi-target digital droplet PCR assays as well as NGS panels and conduct prospective biomarker trials exploring the potential of longitudinal liquid biomarker analysis for personalizing systemic cancer therapy.

Collaboration:
Stefan Balabanov, Department of Medical Oncology and Hematology (MOH), USZ
Thorsten Zenz, Department of Medical Oncology and Hematology (MOH), USZ
Uwe Wittel, Department of Surgery, Freiburg University Hospital
Melanie Boerries, Institute of Medical Bioinformatics and Systems Medicine, Freiburg University Hospital
Michael Scharl, Department of Gastroenterology and Hepatology, USZ

Publications

Selected Publications:

Lionarons, D.A., Hancock, D.C., Rana, S., East, P., Moore, C., Murillo, M.M., Carvalho, J., Spencer-Dene, B., Herbert, E., Stamp, G., Damry, D., Calado, D. P., Rosewell, I., Fritsch, R., Neubig, R. R., Molina-Arcas, M., and Downward, J. (2019). RAC1(P29S) Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance. Cancer cell 36, 68-83 e69.

Fritsch, R., and Hoeppner, J. (2019). Oxaliplatin in perioperative chemotherapy for gastric and gastroesophageal junction (GEJ) adenocarcinoma. Expert review of gastroenterology & hepatology 13, 285-291.

Le Tourneau, C., Claus, R., Ricci, F., Hackanson, B., Rummelt, C., Fietz, O., Arnhold, T., Roy, D., Oum'Hamed, Z., and Fritsch, R. (2018). First-in-human phase I trial of BI 836880, a vascular endothelial growth factor (VEGF)/angiopoietin-2 (Ang-2)-blocking nanobody, given every 3 weeks (q3w) in patients (pts) with advanced/metastatic solid tumors. Paper presented at: Journal of Clinical Oncology (ASCO Poster Presentation)

Klett, H., Fuellgraf, H., Levit-Zerdoun, E., Hussung, S., Kowar, S., Kusters, S., Bronsert, P., Werner, M., Wittel, U., Fritsch, R., et al. (2018). Identification and Validation of a Diagnostic and Prognostic Multi-Gene Biomarker Panel for Pancreatic Ductal Adenocarcinoma. Frontiers in genetics 9, 108.

Hoefflin, R., Geißler, A.-L., Fritsch, R., Claus, R., Wehrle, J., Metzger, P., Reiser, M., Mehmed, L., Fauth, L., and Heiland, D.H. (2018). Personalized clinical decision making through implementation of a molecular tumor board: a German single-center experience. JCO Precision Oncology 2, 1-16.

Kulemann, B., Rosch, S., Seifert, S., Timme, S., Bronsert, P., Seifert, G., Martini, V., Kuvendjiska, J., Glatz, T., Hussung, S., Fritsch, R., Becker, H., Pitman, M. B. and Hoeppner, J. (2017). Pancreatic cancer: Circulating Tumor Cells and Primary Tumors show Heterogeneous KRAS Mutations. Scientific reports 7, 4510.

Geissler, A.L., Geissler, M., Kottmann, D., Lutz, L., Fichter, C.D., Fritsch, R., Weddeling, B., Makowiec, F., Werner, M., and Lassmann, S. (2017). ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer. Oncotarget 8, 17164-17190.

Kovaleva, V., Geissler, A.L., Lutz, L., Fritsch, R., Makowiec, F., Wiesemann, S., Hopt, U.T., Passlick, B., Werner, M., and Lassmann, S. (2016). Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing. Molecular cancer 15, 63.

Houslay, D.M., Anderson, K.E., Chessa, T., Kulkarni, S., Fritsch, R., Downward, J., Backer, J.M., Stephens, L.R., and Hawkins, P.T. (2016). Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells. Sci Signal 9, ra82-ra82.

Fritsch, R., and Downward, J. (2013). SnapShot: class I PI3K isoform signaling. Cell 154, 940-940. e941.

Fritsch, R., de Krijger, I., Fritsch, K., George, R., Reason, B., Kumar, M.S., Diefenbacher, M., Stamp, G., and Downward, J. (2013). RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms. Cell 153, 1050-1063.


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