The main aim of our proposal is to offset the vascular complications associated with VEGFi with novel strategies to promote and specifically target the development of therapeutic approaches. We hypothesize that VEGF inhibition increases protein O-GlcNAcylation in vascular cells via redox-sensitive processes, contributing to changes in VSMCs and ECs phenotype, ultimately contributing to hypertension and other cardiovascular complications in cancer patients. By elucidating the mechanistic links between VEGF inhibition, oxidative stress, O-GlcNAc and cardiovascular toxicity, this research could pave the way for the development of novel therapeutic strategies. Targeting aberrant O-GlcNAcylation or its regulatory enzymes (OGT/OGA) may potentially mitigate the adverse cardiovascular effects of anti-angiogenic cancer therapies, improving patient outcomes and quality of life.

Aims

• to investigate at the molecular and cellular levels whether VEGFi increases protein O-GlcNAcylation in vascular cells. In vitro studies will characterise protein O-GlcNAc in VSMCs and ECs
• employing proteomics platforms, we aim to characterize protein expression changes in vascular cells exposed to VEGFi, which will provide deeper insights into the molecular mechanisms underpinning the cardiovascular effects of these anti-cancer drugs and potentially identifying novel biomarkers and therapeutic targets
• to translate our molecular findings to the clinic, we will evaluate OGT and OGA expression, and global protein O-GlcNAcylation in plasma samples from cancer patients treated with VEGFi

Work Package 1

In vitro studies in vascular cells treated with VEGFi.

The milestones are to clarify O-GlcNAc levels in VSMCs and ECs under VEGFi treatment, which it is believed to change vascular cell phenotype. O-GlcNAc acts as an intracellular stress sensor that modifies cell phenotype in response to VEGFi.

Work Package 2 - proteomics analysis

O-GlcNAc modified proteins will be enriched from equal amounts of protein isolated from cells using the G5-lectibody column and proteomics platforms. This will be measured by liquid Chromatography Tandem Mass Spectrometry.

The milestones are to identify novel molecular mechanisms underpinning the cardiovascular effects of VEGFi and potentially identifying novel biomarkers and therapeutic targets.

Work Package 3 – clinical samples

To evaluate OGT and OGA expression and global protein O-GlcNAcylation in plasma samples from cancer patients before and after being treated with VEGFi.

The milestones are to define the role of protein O-GlcNAc glycosylation in VEGFi-treated patients using clinical samples and validate molecular findings from our in vitro study in VEGFi-patient samples

Further information

The start date for this opportunity is 1 October 2025.