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Maintenance Therapy for Pancreatic Cancer, a New Approach Based on the Synergy between the Novel Agent GP-2250 (Misetionamide) and Gemcitabine
by
, , , ,
Marie Buchholz
1,*,†,
Britta Majchrzak-Stiller
1,†,
Ilka Peters
1,
Stephan Hahn
2,
Lea Skrzypczyk
1,
Lena Beule
1,
Waldemar Uhl
1,
Chris Braumann
1,3,
Johanna Strotmann
1,‡ and
Philipp Höhn
1,‡ 1
Department of General and Visceral Surgery, Division of Molecular and Clinical Research, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
2
Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, 44780 Bochum, Germany
3
Department of General, Visceral and Vascular Surgery, Evangelische Kliniken Gelsenkirchen, Akademisches Lehrkrankenhaus der Universität Duisburg-Essen, 45878 Gelsenkirchen, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors contributed equally to this work.
Cancers 2024, 16(14), 2612; https://doi.org/10.3390/cancers16142612 (registering DOI)
Submission received: 10 July 2024
/
Accepted: 18 July 2024
/
Published: 22 July 2024
(This article belongs to the Section Cancer Drug Development)
Simple Summary
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer type with rising incidences worldwide and poor survival. GP-2250 is an emerging agent showing a high antineoplastic capacity. Currently, GP‑2250 is under phase I clinical trial for PDAC. This study was the first to evaluate the antineoplastic effects of GP-2250 on pancreatic adenocarcinoma in combination with Gemcitabine in a PDAC patient-derived mouse xenograft (PDX) setting. This combination showed highly synergistic effects in a primary cell culture model, as well as in a first-line and a maintenance setting using PDX. Changes in the CD133 content of treated spheroid cultures provide first indicators for this synergism. These findings demonstrate the vast potential of this highly promising combination in the maintenance therapy of PDAC patients.
Abstract
The novel Oxathiazinane derivative GP-2250 (Misetionamide) displays antineoplastic activity in vitro and in vivo, as previously shown in pancreatic cancer cells and in patient-derived mouse xenografts (PDX). Currently, GP 2250 is under phase I clinical trial in pancreatic ductal adenocarcinoma (PDAC). GP-2250 in combination with Gemcitabine displays a high synergistic capacity in various primary and established pancreatic cancer cell lines. Additionally, in the eight PDX models tested, the drug combination was superior in reducing tumor volume with an aggregate tumor regression (ATR) of 74% compared to Gemcitabine alone (ATR: 10%). Similarly, in a PDX maintenance setting following two weeks of treatment with nab-Paclitaxel plus Gemcitabine, the combination of GP-2250 plus Gemcitabine resulted in outstanding tumor control (ATR: 79%) compared to treatment with Gemcitabine alone (ATR: 60%). Furthermore, GP-2250 reduced the ratio of tumor-initiating CD133+ markers on the surface of PDAC cells in spheroid cultures, indicating a possible mechanism for the synergistic effect of both substances. Considering the high tolerability of GP 2250, these results may open up a new approach to maintenance therapy with GP-2250/Gemcitabine combination following nab-Paclitaxel plus Gemcitabine as first-line treatment.
Keywords:
maintenance; GP-2250; misetionamide; chemotherapy; pancreatic cancer; CD133
