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

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-2250mono) and Gemcitabine (Gemmono), 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, Gemmono and GP-2250mono 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-2250mono and Gemmono 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.

The effect of GP-2250 on cultured virus-negative Merkel cell carcinoma cells: preliminary results

“…Cell viability, proliferation, and migration decreased with increasing GP-2250 doses. In this regard, the present data give support to previous studies on the use of GP-2250 in other malignancies (Buchholz et al 2017 , 2022 ; Braumann et al 2020 ; Baron et al 2022 ). Flow cytometry revealed a dose response to GP-2250 in all three MCC cell lines which was comparable to the dosages used for the MTT assay.…”

“…Moreover, GAPDH inhibitors are capable to influence mTOR and AKT mediated responses via changes in TORC1 activity (Guo et al 2013 ). Previous data of our study group, however, indicate that cell death induction through enhanced release both of ROS and mitochondrial alterations may play a major role (Buchholz et al 2017 , 2022 ; Braumann et al 2020 ; Baron et al 2022 ). In animal models, GP-2250 showed a decrease of growth of cancer cells both in xenografts of pancreatic cancer and xenograft models of pancreatic adenocarcinoma while being only infrequently associated with adverse events.…”

“…In nude mice, there were no body weight alterations or organ dysfunctions at applied concentrations (Braumann et al 2020 ). Furthermore, GP-2250 has also been tested combined with chemotherapeutic substances, including gemcitabine, cisplatin and mitomycin C. Several experiments in malignant peritoneal mesothelioma, pancreatic adenocarcinoma, and neuroendocrine pancreatic carcinoma suggest synergistic effects between the substance GP-2250 and gemcitabine or cisplatin and mitomycin C respectively (Braumann et al 2020 ; Baron et al 2022 ; Buchholz et al 2022 ). In neuroendocrine carcinomas of the pancreas, the first-choice treatments are platin-based agents combined with etoposide which are characterized by poor very tolerability (Buchholz et al 2022 ).…”

“…In nude mice, GP-2250 was safe, resulting in acute (2000 mg/kg BW) or chronic (1000 mg/kg BW) toxicity only at extremely high concentrations (Buchholz et al 2017 ). The same research group published further data on anti-neoplastic effects of GP-2250 on different malignancies (Braumann et al 2020 ; Baron et al 2022 ; Buchholz et al 2022 ). In a clinical phase I/II trial on patients with advanced pancreatic carcinoma, GP-2250 is currently investigated in combination with gemcitabine (clinicaltrials.gov: NCT03854110) (Geistlich Pharma 2020 ).…”

GP‐2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP‐Kinase and impairs the NF‐kB pathway in pancreatic cancer cells

“…GP‐2250 inhibited tumour cell proliferation and induced apoptotic cytotoxicity. In vivo, the growth of patient‐derived pancreatic tumour tissue was strongly inhibited in xenograft mouse models 1,2 . GP‐2250 is presently in a clinical trial for the treatment of pancreatic cancer (NCT 03854110) 3 .…”