Escape from therapy, are neuropilins the key?

Background- Angiogenesis is the formation of new blood vessels from the pre-existing vasculature and is crucial for the development and progression of solid tumours. Vascular Endothelial Growth Factor (VEGF) is the most potent angiogenic factor identified to date and mediates its mitogenic and angiogenic activity on endothelial cells via tyrosine kinase receptors VEGF-R1 and VEGF-R2. Bevacizumab (Bz) is a humanised antibody to VEGF and prevents VEGF binding to VEGF-R1 and VEGF-R2 thereby inhibiting angiogenesis, and has been shown to increase progression free survival in breast cancer. However, tumours treated with Bz eventually acquire resistance and subsequently escape treatment control. Aim- The aim of the study was to assess if combining Bz with a neuropilin 1 targeted peptide would enhance the inhibitory effects observed with Bz on breast cancer growth. Methods-Three cell types were utilised the in vitro studies; human dermal microvascular endothelial cells (HuDMECs) and two breast cancer cell (MDA-MB-231 and MDA-MB-436). A number of in vitro functional assays were carried out to assess if any of the neuropilin1 peptides demonstrated biological activity. Based on the in vitro data a primary sub-cutaneous tumour model was set up to assess the effects of Bz in combination with the neuropilin1 peptides in a more relevant and dynamic setting. Results- Overall the Np1 peptides failed to demonstrate additive effects on inhibiting breast cancer growth and activity. The ‘true’ inhibitory effects of Bz were observed in the bone metastasis ex vivo analysis, whereby the health of the bone in a animal with bone metastases was significantly healthier in the Bz treated animals compared with the control vehicle. Conclusion- To conclude the effects of the neuropilin 1 peptides in enhancing inhibitory effects on breast cancer growth when combined with Bz remains inconclusive due to a number of reasons discussed in this thesis. In addition, the thesis highlighted that going forward differentiating the actions of Bz from those observed with the vehicle control is crucial and needs to be bought to light. Finally, expanding on the bone metastasis model is key, as preliminary data with Bz looks promising.