New Therapy Options for Neuroendocrine Carcinoma of the Pancreas-The Emergent Substance GP-2250 and Gemcitabine Prove to Be Highly Effective without the Development of Secondary Resistances In Vitro and In Vivo

Marie Buchholz; Johanna Strotmann; Britta Majchrzak-Stiller; Stephan Hahn; Ilka Peters; Julian Horn; Thomas Müller; Philipp Höhn; Waldemar Uhl; Chris Braumann

doi:10.3390/cancers14112685

New Therapy Options for Neuroendocrine Carcinoma of the Pancreas-The Emergent Substance GP-2250 and Gemcitabine Prove to Be Highly Effective without the Development of Secondary Resistances In Vitro and In Vivo

Cancers (Basel). 2022 May 29;14(11):2685. doi: 10.3390/cancers14112685.

Authors

Affiliations

¹ Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
² Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, 44780 Bochum, Germany.
³ Geistlich Pharma AG, 6110 Wolhusen, Switzerland.
⁴ Department of General, Visceral and Vascular Surgery, Evangelische Kliniken Gelsenkirchen, Akademisches Lehrkrankenhaus der Universität Duisburg-Essen, 45879 Gelsenkirchen, Germany.

Abstract

Neuroendocrine carcinoma of the pancreas (pNEC) is an aggressive form of neuroendocrine tumor characterized by a rising incidence without an increase in survival rates. GP-2250 is an oxathiazinane derivate possessing antineoplastic effects, especially in combination with Gemcitabine on the pancreatic adenocarcinoma. The cytotoxic effects of the monotherapy of GP-2250 (GP-2250_mono) and Gemcitabine (Gem_mono), as well as the combination therapy of both, were studied in vitro using an MTT-assay on the QGP-1 and BON-1 cell lines, along with in vivo studies on a murine xenograft model of QGP-1 and a patient-derived xenograft model (PDX) of Bo99. In vitro, Gem_mono and GP-2250_mono showed a dose-dependent cytotoxicity. The combination of GP-2250 and Gemcitabine exhibited highly synergistic effects. In vivo, the combination therapy obtained a partial response in QGP-1, while GP-2250_mono and Gem_mono showed progressive disease or stable disease, respectively. In Bo99 PDX, the combination therapy led to a partial response, while the monotherapy resulted in progressive disease. No development of secondary resistances was observed, as opposed to monotherapy. This study was the first to evaluate the effects of the emerging substance GP-2250 on pNEC. The substance showed synergism in combination with Gemcitabine. The combination therapy proved to be effective in vitro and in vivo, without the development of secondary resistances.

Keywords: chemotherapy; neuroendocrine carcinoma; pancreas; secondary resistance; xenograft.

Grants and funding

The consumables used in this work were partially funded by Geistlich Pharma AG, Wolhusen, Switzerland. Geistlich Pharma AG played no role in the design of the study or in the collection, analysis or interpretation of the data.