| dc.description.abstract | Antiangiogenic strategies have not provided the cancer control effects predicted from pre-clinical experiments. Obstacles include increasing hypoxia, reducing chemotherapy delivery and acquired resistance. Novel strategies to overcome these obstacles are thus warranted. In particular, exploiting endothelial cell-derived paracrine signalling (angiocrine signalling), manipulating blood vessel numbers and function whilst pursuing options of enhancing blood flow, chemo-delivery and reducing hypoxia become attractive possibilities. My PhD explores two such strategies:
Targeting angiocrine signalling to enhance chemosensitivity
Our laboratory's previously published work demonstrated that deletion of endothelial cell focal adhesion kinase (FAK) in mice with established subcutaneous tumour sensitised tumour cells to doxorubicin (Tavora, Reynolds, et al. 2014). This was through the alteration of endothelial cell signalling, known as angiocrine signalling. My experiments use pdgfb-iCreert;FAKfl/fl;R26K454R/K454R mice, where kinase-dead endothelial cell FAK is expressed in tumour blood vessels in vivo. My results demonstrate that loss of EC-FAK kinase activity had no impact on the tumour growth of PBS treated, established subcutaneous B16F0 melanomas but was sufficient to reduce tumour growth in doxorubicin treated animals. This change in tumour growth occurs with no apparent effect on blood vessel density or doxorubicin delivery but reduced perivascular tumour cell proliferation and increased DNA damage and apoptotic area relative to blood vessel number in vivo. Additionally, loss of EC-FAK kinase activity and pharmacological FAK inhibition were both sufficient to affect doxorubicin-induced cytokine production in vitro. The results suggest that EC-FAK kinase activity is involved in altering cytokine production and in modulating chemosensitisation of tumour cells.
Testing the effect of a low dose of orally available vascular promotion agent 29P in enhancing chemosensitisation in pancreatic ductal adenocarcinoma.
Our laboratory previously published that increasing blood vessel density by treating mice with intraperitoneal injections of low doses of the cyclic Arg-Gly-Asp (RGD)-mimetic, Cilengitide, was sufficient to increase gemcitabine delivery and decrease hypoxia, thus reducing tumour growth in mouse models of pancreatic ductal adenocarcinoma (Wong et al. 2015). Here I tested the utility of a similar RGD-peptide 29P that has been designed to be administered orally. I have carried out pilot in vivo experiments in various models
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of PDAC, but due to technical difficulties, many of these data remain inconclusive. As part of dealing with these technical difficulties, I have also established a protocol for mouse pancreatic ductal adenocarcinoma | en_US |
