VEGF inhibitors (VEGFi) have significantly improved cancer patient survival but frequently cause hypertension, a major risk factor for cardiovascular disease, leading to treatment interruptions. The exact pathophysiology mechanisms remain unclear but linked to rapid blood pressure increases upon treatment commencement. Some of my previous studies suggest that PARP is protective against VEGFi-induced vascular injury and hypertension. Notably, PARP inhibitors (PARPi) show promise in mitigating VEGFi-associated adverse effects in clinical trials.

The exact pathophysiology of VEGFi-induced hypertension in cancer patients remains unclear. Therefore, our aim is to unravel molecular and vascular mechanisms whereby VEGFi induce hypertension, focusing on PARP-dependent signalling pathways including SIRT1. Our hypothesis here is that PARP inhibition regulates blood pressure during VEGFi treatment via mechanisms involving SIRT1 signalling. This could represent a crucial therapeutic combination in cancer treatment, that would protect against unwanted cardiovascular effects of VEGFi.  

Aims

• to investigate at the molecular and cellular levels whether SIRT1 activation contributes to the protective effects of PARP inhibition during VEGFi-induced vascular dysfunction. In vitro studies will characterise VEGFi-PARPi-SIRT1 axis in VSMCs and ECs
•  In vivo studies in mice to determine the role of PARP-regulating signalling (including SIRT1) in VEGFi-induced hypertension and vascular dysfunction
• to translate our molecular and in vivo findings to the clinic, we will evaluate biomarkers of vascular injury and oxidative stress in plasma samples from cancer patients treated with VEGFi and PARPi, and correlate these with BP and endothelial function

Work Package 1 - In vitro studies

PARP and SIRT1 signalling will be characterized in commercially available human vascular smooth muscle cells (hVSMC) and endothelial cells (hECs) in response to monotherapy and combination.

The milestones are the characterisation of SIRT1 signalling in vascular cells exposed to VEGFi and PARPi, alone or in combination. Understanding the role of SIRT1 in the vascular effects of VEGFi and PARPi.

Work Package 2 - In vivo studies

Mice will be treated with monotherapy and combination and cardiovascular parameters (for example, blood pressure, cardiac and vascular function) will be assessed.

The milestones are the identification of cardiovascular effects of VEGF and PARP inhibition when administered alone or in combination in an in vivo setting, focusing on SIRT1 and vascular injury biomarkers. 

Work Package 3 – Proteomic analysis

Quantitation and identification of proteins that might be contributing to cardiovascular toxicities induced by VEGFi and that are potentially ameliorated by PARPi.

The milestones are the quantitation and identification of new targets and biomarkers associated with cardiovascular injury in cancer patients treated with VEGFi. Validate the molecular findings from our in vitro and in vivo models in cancer patients.

Further information

The start date for this opportunity is 1 October 2025.