Metabolism-based GP-2250 in combination with gemcitabine as a novel approach to pancreatic cancer: A mouse xenograft study.

Abstract

e16750 Background: GP-2250, a novel oxathiazine derivative, displayed apoptotic cytotoxicity against various tumor cell lines but not normal cells. It was therefore tested whether its antineoplastic potential - alone or in combination – could be leveraged specifically against pancreatic cancer. Methods: GP-2250 is a cancer metabolism-based therapeutic. It depleted metabolic energy through inhibition of the enzyme GAPDH (glyceraldehyde-3-phosphate dehydrogenase) which is rate limiting for aerobic glycolysis. ATP was decreased in a time- and dose-dependent manner in pancreatic tumor cell lines and ROS was increased. Mitochondrial dysfunction was triggered by an increased expression of Bax and decreased expression of Bcl2, leading to apoptosis. Cytotoxicity of GP-2250 was ROS-dependent. It was blocked by N-acetylcysteine. Results: GP-2250 substantially increased the sensitivity of pancreatic tumor cells to various chemotherapeutics in particular to gemcitabine (Gem). At doses which were inactive or barely active per se, the combination of GP-2250 and Gem caused striking cytotoxicity in patient-derived primary tumor cells in vitro, pointing to a strong synergy between the two agents. This finding was substantiated in vivo by patient-derived xenograft (PDX) studies in nude mice. While GP-2250 and Gem, given as monotherapy (500 mg/kg and 50 mg/kg respectively, 2x/week), showed only a limited antineoplastic response, the combination treatment resulted in a significantly higher anti-tumor activity as shown in further PDX. Tumor regression was found in 5 out of 9 PDX based on RECIST criteria. Stable disease was reached in 3 of the remaining grafts. In 1 xenograft, which was unresponsive to Gem, the combination treatment nevertheless achieved a reduction in tumor growth which significantly exceeded that of GP-2250 monotherapy. Conclusions: GP-2250 is a novel cancer metabolism-based therapeutic. GP-2250, in combination with Gem, strongly reduces tumor growth in patient-derived xenografts exceeding by far the response to monotherapy. GP-2250 is being evaluated in a Phase I clinical trial in patients diagnosed with advanced pancreatic cancer (Clinical Trial NCT03854110).

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

“…The clinical course of our PDX model Bo99 indicates a necessary second-line therapy with moderate side effects. The first experiments in pancreatic adenocarcinoma suggest a synergistic effect of the novel agents GP-2250 and Gemcitabine [ 21 ].…”

“…It has a six-ring structure with oxygen, sulfurdioxide and nitrogen atoms on the positions 1, 4 and 5, respectively. The exact mechanism of action is yet to be fully explored; the findings of our research group suggest the induction of cell death via the increased release of reactive oxygen species as well as mitochondrial dysfunction [ 20 , 21 , 22 ]. In vivo, GP-2250 shows the reduction of tumor growth in the xenografts of established pancreatic cancer cell lines, as well as in patient-derived xenograft (PDX) models of pancreatic adenocarcinoma, accompanied by rarely occurring side effects [ 20 ].…”

Antineoplastic activity of GP-2250 in-vitro and in mouse xenograft models

“…Previous studies have shown that GP-2250 has a synergistic antineoplastic effect when administered in combination with anticancer agents in patient-derived xenograft models [2,3]. GP-2250 shows promise as an effective adjuvant to conventional chemotherapeutics in human cancers and is currently being evaluated in a phase 1 dose-escalation study in patients with advanced pancreatic cancer (NCT03854110).…”

“…In addition, data from an in-vitro cell line assessment and a patient-derived xenograft model showed that GP-2250, when used in combination with other anticancer drugs, synergistically stabilized or regressed tumor growth [ 2 , 3 ]. The synergistic effect of GP-2250 with multiple anticancer agents provides strong proof of concept for GP-2250 as a promising new chemotherapeutic.…”

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

“…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 ).…”