Project description
Understanding drug metabolism in pancreatic cancer
Small molecule anti-cancer therapies typically have precise mechanisms of action but often suffer from poor efficacy and high treatment resistance, particularly in pancreatic cancer. A potential cause of this resistance is the inactivation of drugs by components of the tumour microenvironment (TME), including the tumour-associated microbiome. The ERC-funded CITE project aims to develop innovative analytical technologies to study drug metabolism within the TME, both in situ and separately from systemic metabolism, with a focus on understanding the TME’s role in drug resistance. The project will employ a spatial pharmaco-metabolomic approach using Laser Desorption Rapid-Evaporative Ionisation Mass Spectrometry (LD-REIMS). Additionally, it will create a three-dimensional organotypic culture model of pancreatic cancer to explore intratumoural drug metabolism.
Objective
Small molecule anti-cancerSmall molecule anti-cancer therapies generally have a well understood mechanism of action. Still, they are frequently plagued by poor efficacy and high rates of treatment resistance, especially in the context of pancreatic cancer. One promising newly recognised route of therapy resistance is intratumoral drug inactivation through members of the tumour microenvironment (TME) such as the tumour-associated microbiome.
With the CITE project, I aim to develop novel analytical technologies that enable us to study drug metabolism by the TME in situ and in isolation from systemic drug metabolism and provide a novel platform for selectively studying the contribution of the TME to drug resistance mechanisms. . I will deploy a spatial pharmacometabolomics approach using Laser Desorption Rapid Evaporative Ionisation Mass Spectrometry (LD-REIMS). First, a novel and sensitive source setup including laser optics and high efficiency aerosol transfer will be developed, followed by instrumental setups for imaging applications at (sub)cellular resolution, high throughput acquisition of cell lines and thick tissue section imaging. Subsequently, a spectral database of abundant (tumour, endothelial cells, fibroblasts etc) and rare cell types (immune cells, microbiome) in the TME will be created to enable cell-type specific assignment of drug delivery and drug metabolism in mass spectrometry imaging datasets and validated using imaging mass cytometry.
I will develop a organotypic culture (3D-OTC) model of pancreatic cancer to study isolated, intratumoral drug metabolism in a controlled environment while still using relevant clinical material. We will use pancreatic cancer from a genetically engineered mouse as model system to develop our novel analytical technologies and to assess intratumoral metabolism of small molecule cytotoxics and targeted chemotherapies used to treat pancreatic cancer. Lastly, these findings will be translated to tissues of human origin.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Keywords
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-STG
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80333 Muenchen
Germany
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