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

IF 5 2区医学 Q2 Medicine Translational Oncology Pub Date : 2024-08-31 DOI:10.1016/j.tranon.2024.102109

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 , John P. Neoptolemos

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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.

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Metavert 在人 PDAC 有机体中与标准细胞毒性药物协同作用，并与治疗反应的转录组特征相关联

背景尽管最近取得了一些进展，但胰腺导管腺癌（PDAC）仍然是一个日益严峻的肿瘤挑战。能够靶向一种以上致癌途径的新药可能是改善患者预后的一种方法。方法36个通过RNASeq和全外显子组测序鉴定的患者衍生器官（hPDOs）单独或与标准细胞毒性药物联合使用Metavert进行治疗。在 47 份患者样本中评估了转录组特征（TS），这些特征代表了对单独使用美达韦的敏感性或对美达韦+伊立替康（IR）的敏感性，其中 26 份样本为化疗前样本，21 份样本为化疗后样本（吉西他滨=5；FOLFIRINOX=14，两者均=2），并提供了配套的多重免疫荧光和 RNASeq 数据。结果美托维特与吉西他滨、伊立替康、5FU、奥沙利铂和紫杉醇联合使用，对hPDOs具有协同作用。在 PDAC 组织中评估的 hPDO 衍生 TS 表明，Metavert-TSHi 样本富含 mRNA 剪接和 DNA 修复过程；它们与 Basal-like 组织相关，但也与 GATA6+ve-chemo-naïve 样本相关，而且在吉西他滨治疗后更高，但 FOLFIRINOX 治疗后不高。与此相反，Metavert+IR-TSHI样本富含TP53通路；它们与经典样预处理样本有关，与GATA6+ve/KRT17+ve混合细胞类型有关，在FOLFIRINOX治疗后有关，但与吉西他滨治疗无关，与转录亚型无关。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.