About the Project
Cancer patients who develop venous thromboembolism (VTE) have a 3-fold lower cancer survival than those remaining VTE-free, irrespective of cancer stage. In breast cancer, hypercoagulability correlates with presence of circulating tumour cells (CTCs) and reduced survival, highlighting the role of coagulation in facilitating dissemination and survival of CTCs.
Tumour stroma resembles a non-healing wound. The primary phase of wound healing is leakage of extrinsic clotting factors and blood components to instigate clot formation. This procoagulant environment creates a permissive milieu for extravasation, extracellular remodelling, cell differentiation and angiogenesis. Tissue factor (TF, initiator of extrinsic clotting cascade) induces apoptosis resistance, tumour cell migration and invasion. Downstream of TF, thrombin induces angiogenesis, proliferation, invasion and induction of cancer associated fibroblasts (CAFs), which promote tumour growth and angiogenesis. In breast cancer, TF, thrombin and their receptors PAR2 and 1, have increased expression in CAFs compared to normal breast fibroblasts, with further increased expression in poor prognosis breast cancer phenotypes (ER-/Her2+/high Ki67).
Rivaroxaban is a rapidly-acting, targeted (anti-Factor Xa) oral anticoagulant prescribed for thromboprophylaxis and for stroke prevention in atrial fibrillation. In vitro, the stimulatory effect of exogenous procoagulants and procoagulant CAFs on breast cancer growth is abrogated by Rivaroxaban. The effects of Rivaroxaban on early breast cancer are currently being investigated in a short-term pre-operative randomised clinical trial (TIP, ISRCTN14785273).
This PhD investigates the effects of the extrinsic clotting system and Rivaroxaban on breast cancer in a comprehensive bench-to-bedside workflow. In vitro studies will determine the effects of procoagulant CAFs on cancer cell proliferation, migration and invasion. In vivo studies will use cell lines and patient derived samples (PDX) in mouse models to investigate tumour growth and identify novel biomarkers of tumour response, in a procoagulant and anticoagulant (Rivaroxaban) setting. These biomarkers will be validated in archived clinical specimens from the TIP trial.
This Clinical Research Training Fellowship will be funded by the CRUK Manchester Centre, and are usually three years in length, with the option to extend to four years under certain circumstances.
Please formally apply via the University of Manchester online system, and select PhD Cancer Sciences. Include your CV, two reference letters (or names of referees) with a covering letter (500 - 750 words max) indicating your first choice project and explaining why you want to apply. Please also comment on your suitability for the post, giving an overview of your relevant experience and training.
More information about the CRUK Manchester Centre PhD Training Scheme, including the application process, can be found on our website: http://crukcentre.manchester.ac.uk/Training/PhD-Training-Scheme.
Funding Notes
The Fellowship will cover an annual stipend (currently at £19,000 per annum), running expenses and PhD tuition fees at UK/EU rates. Where international student fees are payable, please provide evidence with your application of how the shortfall will be covered (approximately £16,000 per annum).
All applicants must:
• hold a minimum upper second class (or equivalent) undergraduate degree in relevant subject
• be post-registration clinicians and ideally have a specialist training post
• have been resident and worked within the EEA (European Economic Area) for at least three years prior to application
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