Kliniken & Institute ... Kliniken Chirurgische Klinik... Allgemein-, Viszeral-... Forschung Pankreasforschung Sektion... AG Integrative...

AG Integrative Oncology Group

Research Laboratory of the European Pancreas Centre (EPZ)


Dr. med. Nathalia Giese
Im Neuenheimer Feld 116
69120 Heidelberg
Gebäude 6116

06221 56-6440

I. Pancosys: System Biology. Immunogenetic targets and microenvironment

Project leaders: Miriam Schenk

The PancoBank serves as resources platform for our studies committed to developing personalized treatment options for patients with pancreatic cancer. We use this infrastructure to search for potential therapeutic targets and biomarkers, focusing on immunogenic antigens and on editing impact of tumor’s microenvironment. Most promising candidates undergo comprehensive characterization in vitro and in vivo. Bioinformatics as well as mathematical modeling and in silico approaches (e.g., CTRNN-based approaches and reverse engineering) are then used to reconstruct specifics of tumor-stroma interactions in pancreatic cancer. This project is supported by the grants provided by the BMBF’ NGFN and E:med-PancStrat, EU-BioPac, Dietmar-Hopp-Stiftung and Heidelberger Stiftung Chirurgie.

Cooperation partners:

Mathematical modeling: Dr. Matt Rogon  and  Prof. Roland Eils, Division of Theoretical Bioinformatics, DKFZ Heidelberg

Seromics and immunogenic targets: Dr. Inka Zörnig and Prof. Dr. Dirk Jäger, Medical Oncology, NCT, Heidelberg; Dr. Sacha Gnjatic, Mount Sinai Hospital, New York, USA.

Animal models: HI-STEM (The Heidelberg Institute for Stem Cell Technology and Experimental Medicine; Cancer Stem Cells and Metastasis group of Dr. Martin Sprick, Prof. Dr. Andreas Trumpp)

Molecular diagnostics and  immunophenotyping: PD Dr. Thomas Giese, Institute of Immunology, University Hospital Heidelberg

Selected PancoSys Publications:

Keleg, S. et al. Chondroitin sulfate proteoglycan CSPG4 as a novel hypoxia-sensitive marker in pancreatic tumors. PLoS One 9, e100178 (2014)

Welsch, T. et al. Prognostic significance of erythropoietin in pancreatic adenocarcinoma. PLoS One 6, e23151 (2011)

Gnjatic, S. et al. Seromic profiling of ovarian and pancreatic cancer. Proc Natl Acad Sci U S A 107, 5088-5093 (2010)

Heller, A. et al. Immunogenicity of SEREX-identified antigens and disease outcome in pancreatic cancer. Cancer Immunol Immunother 59, 1389-1400 (2010)

Bartel, M. et al. Abnormal crosstalk between pancreatic acini and macrophages during the clearance of apoptotic cells in chronic pancreatitis. Journal of Pathology 215, 195-203 (2008)

Sperveslage, J. et al. Lack of CCR7 expression is rate limiting for lymphatic spread of pancreatic ductal adenocarcinoma. Int J Cancer 131, E371-381 (2012)

Loos, M. et al. Clinical significance and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Letters 268, 98-109 (2008)

Erkan, M. et al. Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity. Gastroenterology 132, 1447-1464 (2007)

Erkan, M. et al. The Activated Stroma Index Is a Novel and Independent Prognostic Marker in Pancreatic Ductal Adenocarcinoma. Clinical Gastroenterology and Hepatology 6, 1155-1161 (2008)

Koninger, J. et al. Overexpressed decorin in pancreatic cancer: Potential tumor growth inhibition and attenuation of chemotherapeutic action. Clinical Cancer Research 10, 4776-4783 (2004)

Koninger, J. et al. Pancreatic tumor cells influence the composition of the extracellular matrix. Biochemical and Biophysical Research Communications 322, 943-949 (2004)

II. Pancovir: Chemovirotherapy of pancreatic cancer

Project leaders: Dr. Svitlana Grekova

Efficient treatment of pancreatic cancer, an extremely aggressive therapy-resistant malignancy, requires innovative therapeutic strategies. Recent studies indicated that induction of immunogenic cell death is required for long-term anticancer protection. Oncolytic viruses are known for their ability to target and kill transformed cells. We discovered that oncolytic autonomous parvovirus, H1-PV, in synergy with gemcitabine, significantly prolongs the survival of immune-competent rats bearing orthotopic pancreatic tumors. Using different models, we then established that in addition to the well-known direct oncotoxicity, immune-related processes and a predilection for secondary lymphoid organs are required for maximal parvoviral anticancer action.

In order to elucidate modus operandi of chemo-virotherapy, we are now studying i) whether H1-PV is inducing release of damage-associated molecular patterns (DAMPs), thus granting an immunogenic status to the tumor cell death, and ii) which therapeutic consequences this context-dependent adjuvant activity might have. Simultaneous quantification of viral permissiveness, cell death and release of danger-associated molecules in pancreatic tumor cells, together with measurements of gemcitabine/H1-PV-induced activation of immune cells in vitro and in vivo (xenografts in humanized NOD/scid mice; rat model; viral, autologous and allogenic vaccination), should provide information necessary  for designing novel vaccination protocols which, in addition to the temporary cytoreduction by oncolysis, might trigger a long-lasting immune defense. This project is supported by the DFG-grant.

Cooperation partners:

Prof. Dr. Jean Rommelaere and Dr. Jürg Nüsch, Tumor Virology, DKFZ, Heidelberg

Selected PancoVir Publications:

Angelova, A. L. et al. Complementary Induction of Immunogenic Cell Death by Oncolytic Parvovirus H-1PV and Gemcitabine in Pancreatic Cancer. Journal of Virology 88, 5263-5276 (2014).

Raykov, Z. et al. TLR-9 contributes to the antiviral innate immune sensing of rodent parvoviruses MVMp and H-1PV by normal human immune cells. PLoS One 8, e55086 (2013)

Grekova, S. P. et al. Interferon gamma improves the vaccination potential of oncolytic parvovirus H-1PV for the treatment of peritoneal carcinomatosis in pancreatic cancer. Cancer Biol Ther 12, 888-895 (2011)

Grekova, S. et al. Immune cells participate in the oncosuppressive activity of parvovirus H-1PV and are activated as a result of their abortive infection with this agent. Cancer Biol Ther 10, 1280-1289 (2011)

Angelova, A. L. et al. Improvement of Gemcitabine-Based Therapy of Pancreatic Carcinoma by Means of Oncolytic Parvovirus H-1PV. Clinical Cancer Research 15, 511-519 (2009)

Raykov, Z. et al. B1 lymphocytes and myeloid dendritic cells in lymphoid organs are preferential extratumoral sites of parvovirus minute virus of mice prototype strain expression. Journal of virology 79, 3517-3524 (2005)

Giese, N. A. et al. Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice. Cancer Gene Therapy 9, 432-442 (2002)

Financial support: