Project Details
Projekt
Exploiting the transcription cycle to tailor rational-based combination therapies for PDAC
Applicant
Professor Dr. Günter Schneider
Subject Area
Gastroenterology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426671079
The high failure rate of a cancer drug from target definition to clinical implementation highlights the need to prioritize context-specific targets. Cancer-dependency scores for pancreatic ductal adenocarcinoma (PDAC) revealed the catalytically active subunit of protein phosphatase 2A (PP2A) as a top-ranked target. PP2A is connected to metabolic, inflammatory, and proliferative pathways and high expression of the phosphatase is assocoiated with a worse prognosis. We used a clinical-grade PP2A inhibitor to understand the functions of the enzyme. Using unbiased genome-wide CRISPR/Cas9 genetic screens, we detected the contribution of transcription cycle components, like cyclin-dependent kinase 9 (CDK9), to the PP2A inhibitor (PP2Ai) response. PP2A inhibition unleashes the RNA polymerase II (RNA Pol II) pause checkpoint, leading to CDK9-mediated transcriptional elongation of a conserved program. The transcription output of this program is higher in mesenchymal PDAC cells and results in the breakdown of cellular homeostatic networks and consequent cell death. To understand the underpinnings of PP2A inhibitor sensitivity in molecular detail, we will employ a multifaceted approach, combining pharmacological inhibition of PP2A with genetic gain- and loss-of-function models. Through these experiments, we aim to establish a causal relationship between the antagonism of CDK9 and PP2A and the observed response to PP2Ai (with SP5). Furthermore, we will follow the hypothesis that glycolysis, active in mesenchymal PDAC, is a major determinant of the increased transcriptional output upon PP2A inhibition (with SP1, SP2, SP4, SP5). In addition, we aim to develop PP2Ai-based combination therapies. This will be guided by our (i) mechanistic insights of the PP2Ai response, (ii) our LB100-connected synthetic lethal genes detected in CRISPR screens, and (iii) unbiased combinatorial drug screening efforts conducted in the context of the in vitro PDAC model platform (with CP1, CP2). Finally, we aim to understand the molecular mode of action of the novel PP2Ai-based combination therapy and will validate the translational relevance by testing biomarker-directed interventions in primary patient-derived PDAC models provided by the CRU5002.
DFG Programme
Clinical Research Units
