Metavert synergises with standard cytotoxics in human PDAC organoids and is associated with transcriptomic signatures of therapeutic response

Jingyu An; Roma Kurilov; Teresa Peccerella; Frank Bergmann; Mouad Edderkaoui; Adrian Lim; Xu Zhou; Katrin Pfütze; Angela Schulz; Stephan Wolf; Kai Hu; Christoph Springfeld; Sadaf S Mughal; Lenart Zezlina; Franco Fortunato; Georg Beyer; Julia Mayerle; Susanne Roth; Johannes Hulkkonen; Daniela Merz; Shigenori Ei; Arianeb Mehrabi; Martin Loos; Mohammed Al-Saeedi; Christoph W Michalski; Markus W Büchler; Thilo Hackert; Benedikt Brors; Stephen J Pandol; Peter Bailey; John P Neoptolemos

doi:10.1016/j.tranon.2024.102109

Metavert synergises with standard cytotoxics in human PDAC organoids and is associated with transcriptomic signatures of therapeutic response

Transl Oncol. 2024 Nov:49:102109. doi: 10.1016/j.tranon.2024.102109. Epub 2024 Aug 31.

Authors

Jingyu An¹, Roma Kurilov², Teresa Peccerella¹, Frank Bergmann³, Mouad Edderkaoui⁴, Adrian Lim⁴, Xu Zhou¹, Katrin Pfütze⁵, Angela Schulz⁶, Stephan Wolf⁶, Kai Hu¹, Christoph Springfeld⁷, Sadaf S Mughal², Lenart Zezlina², Franco Fortunato¹, Georg Beyer⁸, Julia Mayerle⁸, Susanne Roth¹, Johannes Hulkkonen¹, Daniela Merz¹, Shigenori Ei⁹, Arianeb Mehrabi¹, Martin Loos¹, Mohammed Al-Saeedi¹, Christoph W Michalski¹, Markus W Büchler¹⁰, Thilo Hackert¹¹, Benedikt Brors¹², Stephen J Pandol⁴, Peter Bailey¹³, John P Neoptolemos¹⁴

Affiliations

¹ Heidelberg University Hospital, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, Heidelberg 69120, Germany.
² Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Berliner Str. 41, Heidelberg 69120, Germany.
³ Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Department of Medicine, Cedars-Sinai Medical Center and University of California at Los Angeles, Thalians W204 8700 Beverly Blvd. Los Angeles, California CA 90048, United States.
⁵ Sample Processing Laboratory, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany.
⁶ NGS Core Facility, The German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ Department of Medical Oncology, National Center for Tumor Diseases, University Clinic Heidelberg, Heidelberg 69120, Germany.
⁸ Department of Internal Medicine II, Ludwig-Maximilians-University of Munich, Germany.
⁹ Department of Gastroenterological Surgery, Tokai University School of Medicine, Kanagawa, Japan.
¹⁰ Heidelberg University Hospital, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, Heidelberg 69120, Germany; Botton-Champalimaud Pancreatic Cancer Centre, Lisbon, Portugal.
¹¹ Heidelberg University Hospital, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, Heidelberg 69120, Germany; Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
¹² Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Berliner Str. 41, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, Im Neuenheimer Feld 280, Heidelberg 69120, Germany; Medical Faculty and Faculty of Biosciences, Heidelberg University, Im Neuenheimer Feld 234, Heidelberg 69120, Germany; National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany.
¹³ Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Berliner Str. 41, Heidelberg 69120, Germany; Botton-Champalimaud Pancreatic Cancer Centre, Lisbon, Portugal. Electronic address: [email protected].
¹⁴ Heidelberg University Hospital, Department of General, Visceral and Transplantation Surgery, Im Neuenheimer Feld 420, Heidelberg 69120, Germany; Botton-Champalimaud Pancreatic Cancer Centre, Lisbon, Portugal. Electronic address: [email protected].

Abstract

Background: Despite some recent advances, pancreatic ductal adenocarcinoma (PDAC) remains a growing oncological challenge. New drugs capable of targeting more than one oncogenic pathway may be one way to improve patient outcomes. This study characterizes the effectiveness of Metavert a first-in-class dual inhibitor of GSK3-β and histone deacetylase in treating PDAC as a single agent or in combination with standard cytotoxics.

Methods: Thirty-six Patient-Derived Organoids (hPDOs) characterised by RNASeq and whole exome sequencing were treated with Metavert alone or in combination with standard cytotoxics. Transcriptomic signatures (TS) representing sensitivity to Metavert alone or sensitivity to Metavert + irinotecan (IR) were evaluated in 47 patient samples, chemo-naïve in 26 and post-chemotherapy in 21 (gemcitabine=5; FOLFIRINOX=14, both=2) with companion multiplexed immunofluorescence and RNASeq data.

Results: Metavert combined with gemcitabine, irinotecan, 5FU, oxaliplatin, and paclitaxel was synergistic in the hPDOs. Basal-subtype hPDOs were more sensitive to Metavert alone whereas the Metavert+IR combination exhibited synergy in Classical-subtype hPDOs with increased apoptosis and autophagy. hPDO-derived TS evaluated in PDAC tissues demonstrated that Metavert-TS^Hi samples were enriched for mRNA splicing and DNA repair processes; they were associated with Basal-like tissues but also with GATA6^+ve-chemo-naïve samples and were higher following gemcitabine but not FOLFIRINOX treatment. In contrast, Metavert+IR-TS^HI samples were enriched for TP53 pathways; they were associated with Classical-like pretreatment samples and with GATA6^+ve/KRT17^+ve hybrid cell types following FOLFIRINOX, but not gemcitabine treatment, and were unrelated to transcriptional subtypes.

Conclusions: Metavert as a single agent and in combination with irinotecan offers novel strategies for treating pancreatic cancer.

Keywords: Apoptosis; Autophagy; GSK3-β; Histone deacetylases; Molecular subtypes; Pancreatic cancer.