Project Details
Projekt
SP4: Exploring resistance mechanisms and therapeutic vulnerabilities in GSK3β;NFATc1high subtype tumors
Applicant
Professor Dr. Volker Ellenrieder
Subject Area
Gastroenterology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426671079
In the first funding period, we identified a GSK3β;NFATc1high subtype that accounts for ~15% of all pancreatic cancer (PDAC) patients and correlates with a poorly differentiated phenotype. The pathway is induced by and predicts resistance to FOLFIRINOX chemotherapy, specifically to platinum derivates (e.g. cisplatin). In close collaboration with CP1/CP2, Lena Conradi (SP5) and Holger Bastians (SP6), we utilized patient-derived xenografts (PDX), CDX cells and organoids (PDOs) to show that activation of the nuclear GSK3β-NFATc1 signaling pathway promotes DNA repair and resistance through activation of the Homologous Recombination Repair (HRR) system. Targeted disruption of the GSK3β-NFATc1 pathway in GSK3β;NFATc1high subtype tumors (i) disables sufficient DNA damage repair through repression of HRR genes, e.g. BRCA1, BRCA2 and RAD51 (termed “inducible BRCAness”) and (ii) overcomes resistance to cisplatin. Based on these encouraging findings and in collaboration with Actuate Therapeutics (Fort Worth, TX, USA) we are currently designing a GSK3β;NFATc1high stratification-based multicenter trial concept for combinatorial treatment with platin-based chemotherapy +/- GSK3β-inhibitor in advanced PDAC. Importantly, work from the first funding period provided strong evidence that GSK3β;NFATc1high subtype resistance also requires the transcriptional control of and tight cooperation with glutamine metabolism. GSK3β;NFATc1high subtype tumors tightly control the transcription of genes with key functions in metabolic reprogramming, nucleotide biosynthesis and mitochondrial fitness. Importantly, GSK3β;NFATc1high subtype cells are particularly vulnerable to glutamine deficiency. In collaboration with Researchers from the subprojects SP1, SP2, SP5 and SP6, we will assess in detail the molecular mechanisms, metabolic consequences and subtype-specific vs subtype-overlapping therapeutic relevance of this novel transcription-metabolism crosstalk in PDAC. With Günter Schneider (SP8 and CP1), we will investigate whether targeting glutamine metabolism enhances the efficacy of combined GSK3β inhibition and cisplatin therapy and has potential to profoundly shape the strategy of tailored treatment in GSK3β;NFATc1high subtype tumors.
DFG Programme
Clinical Research Units
