ICF: Microfluidic investigation of the role of transcapillary resistance and vascular permeability/normalisation on cancer outcomes via vasodilation

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In a landmark study involving 12,456 male patients diagnosed with colorectal cancer, those who took Sildenafil (marketed as Viagra) after diagnosis had over twice the odds of survivng for 10 years than those who did not. Sildenafil is commonly prescribed for erectile dysfunction and pulmonary arterial hypertension and acts by widening blood vessels (vasodilation). We propose that this drug influences colorectal cancer outcomes via two mechanisms: a) increasing the diameter of small vessels which inhibits tumour cell occlusion, a key step in metastasis progression and b) modification of the permeability and architecture of blood vessels, which may assist drug and immune cell delivery to tumours (Fig. 1). We will explore these hypothesis via 3 key aims: 1) development of a microvascular microfluidic platform that incorporates vasodilation induced by precapillary sphincter contraction, 2) investigate how vasodilation-mediated hemodynamic resistance influences tumour cell entrapment, invasion and metastasis formation, 3) explore the influence of endothelial permeability and microvascular normalisation on the tumour penetration and distribution of antibody therapeutics and immune cell infiltration & activity in microfluidic & mice models. Vasodilator drugs have long track records of safe use in humans and an understanding of how this drug influences cancer outcomes via the vasculature may provide a pathway to develop next generation vasodilator adjuvants without unwanted side effects for patients with cancer.