Capturing tumoral drug metabolism by Cells In the Tissue Environment using spatial pharmacometabolomics

Introduction

Small 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 recognized route of therapy resistance is intratumoral drug inactivation through members of the tumour microenvironment (TME) such as the tumour-associated microbiome.

Project Goals

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. This will provide a novel platform for selectively studying the contribution of the TME to drug resistance mechanisms.

Methodology

I will deploy a spatial pharmacometabolomics approach using Laser Desorption Rapid Evaporative Ionisation Mass Spectrometry (LD-REIMS).

1. Development of Source Setup:

   • A novel and sensitive source setup including laser optics and high-efficiency aerosol transfer will be developed.

2. Instrumental Setups:

   • Instrumental setups for imaging applications at (sub)cellular resolution.
   • High throughput acquisition of cell lines.
   • Thick tissue section imaging.

3. Creation of Spectral Database:

   • A spectral database of abundant (tumour, endothelial cells, fibroblasts, etc.) and rare cell types (immune cells, microbiome) in the TME will be created.
   • This will enable cell-type specific assignment of drug delivery and drug metabolism in mass spectrometry imaging datasets and will be validated using imaging mass cytometry.

Organotypic Culture Model

I will develop an 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 a model system to:
  • Develop our novel analytical technologies.
  • Assess intratumoral metabolism of small molecule cytotoxics and targeted chemotherapies used to treat pancreatic cancer.

Translation to Human Tissues

Lastly, these findings will be translated to tissues of human origin.