Treatment for breast cancer is improving but new therapies are often only successful in a proportion of patients and some patients develop resistance. A key problem is that tumours change the functions of our immune system, so instead of killing cancer cells, signals from the changed immune system helps them grow. Macrophages are the most abundant immune cells within breast tumour stroma, representing up to 50% of infiltrating cells. Tumour associated macrophages (TAM), through their highly immunosuppressive, neoangiogenic, carcinogenic and tissue remodelling characteristics, are fundamental to growth and spread of malignant cells. TAMs are associated with the aggressiveness of the disease, with strong clinical correlation between macrophage density and poor prognosis. A high infiltration of TAM correlates with immune checkpoint inhibitor therapy and chemotherapy resistance. Therefore, defining pharmacological strategies that effectively switch TAM function from an immunosuppressive pro-tumour phenotype to an immune active state to promote tumour cell killing is a promising target for intervention.
The aim of this studentship is to test the hypothesis that PTP1B-inhibitors that have already reached phase 1 clinical trials for breast cancer due to their anti-proliferative effects on cancer cells, is a powerful strategy to functionally alter the ability of macrophages to destroy tumours. The rationale stems from our published and pilot research in other clinical disorders including infection and metabolic disease, where PTP1B inhibition significantly reprogrammes macrophage functions and favourably alters immune responses to change disease outcome.
You will use human primary macrophage and 2D and 3D human mammosphere-preclinical models and state-of-the-art technologies in molecular and cellular biology/biochemistry/immunology will define effects of PTP1B inhibitor conditioned macrophages on tumour growth, immunosuppression, angiogenesis, invasion and signalling pathways in tumours to deliver fundamental information on how to effectively skew macrophage function for increased efficacy of future therapies, using PTP1B inhibition as the switch.
You will work in a multidisciplinary team and will receive training in cutting edge techniques and use of materials derived from a national breast cancer biorepository (www.breastcancertissuebank.org). The project will provide important information to inform future clinical trials whether PTP1B-inhibitor therapy, if synergised with immunotherapeutic strategies, would provide cumulative, more powerful tumour-retarding effects for breast cancer treatment or improve therapy for other cancers where macrophages are predominant in the microenvironment and immunotherapy has low efficacy.
APPLICATION PROCEDURE:
Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.
NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.
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