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Impact of the immune landscape on androgen ablation therapy and progression to therapy-resistant disease


Project Description

Prostate cancer is the most commonly diagnosed cancer in men and is a leading cause of cancer related death. The androgen receptor is important for the development and function of the prostate gland and is a driver of prostate cancer progression and metastasis. Gene amplification and overexpression of the receptor are associated with hormone-resistance and poor patient prognosis. Normal prostate tissue and cancer is made up of different cell types, which are imbedded in a protein matrix. Cancer arises in the glandular epithelial cells, but it is known that other cells, including stromal fibroblasts, can influence tumour growth and migration.

In addition, there is growing recognition that the immune landscape can have effects on prostate cancer progression and the effectiveness of different therapeutic options. There is also growing evidence for the role of androgens and androgen receptor in different cells of the innate immune system. Of particular interest is the involvement of the androgen receptor in signalling between macrophages and cancer cells. However, the impact of androgens and androgen ablation therapy on the innate immune landscape has largely been unexplored. In this project we will investigate the expression and function of the androgen receptor in tumour-associated macrophages (TAMs) and the development of castrate resistant prostate cancer.

In this project we aim to investigate the regulation of the expression and activity of the androgen receptor in different cellular compartments and the impact on the immune landscape. We hypothesise that a feedforward loop exists whereby activation of the androgen receptor, in the stromal and/or epithelial cells, influences the extracellular environment and tumour associated macrophages, which in turn, modulates receptor expression and signalling. The combination of these effects is promotion of cancer cell growth, invasion and metastasis.

Research aims/questions:
1. How is the regulation of the AR gene and protein expression in TAMs altered in response to androgens and soluble factors in the tumour microenvironment?
2. Can we identify of gene signatures associated with macrophage phenotypes/ function in response to hormone and/or androgen ablation treatment?
3. Does this change influence the responsiveness of new therapies for prostate cancer?

It has been suggested that signalling through the androgen receptor in macrophages changes their phenotype to a more immunosuppressive cell. However, how castration or androgen ablation treatment alters the phenotype of macrophages and whether this changes their function from a tumor promoting to a tumor destroying cell in human patients is unknown. We will test this question using state of the art methodology and define if a change in macrophenotype within tumours can improve the efficacy of new immunotherapies for prostate cancer. We will also validate our findings from cell-based studies in patient tissue which we have access to through the Grampian Biorepository. The outcome of these studies will be a better understanding of the role of stromal factors and other steroid receptors on the androgen receptor axis and the development of therapy-resistance and cancer progression.

This will be critical in identifying novel intervention strategies and improving treatment options for men with metastatic and CRPC.

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.

Further information on Cancer research at Aberdeen can be found here: https://www.abdn.ac.uk/smmsn/research/cancerabdn-1022.php

Funding Notes

This project is part of a competition funded by the School of Medicine, Medical Sciences and Nutrition for a 4 year PhD programme. Full funding is available to UK/EU candidates only. Overseas candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £15,680 per annum).

Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Merit/Commendation/Distinction at Masters level.

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