Mechanistic Evaluation of the Androgen Receptor Inhibition Driven Hypoxic Prostate Microenvironment

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Research context: The studentship will focus on understanding the role of the androgen receptor under concentrations of low oxygen that can be found within the prostate during various disease or treatment conditions. The androgen receptor is a key protein that under normal physiological conditions bind to testosterone to regulate the development and maintenance of the male phenotype. During different prostate diseases, including cancer, or treatment conditions such as radiation or androgen-deprivation therapy, a resulting change in oxygenation results and changes the biological response of the prostate cells and surrounding and supporting cells within the prostate.Research from our group and others have demonstrated that the androgen receptor signalling regulates the microenvironment of the prostate gland, whereby inhibition, either castration or therapeutically, results in rapid vascular atrophy and reduced microvessel density as a result of vascular endothelial cell death. This result, in part, from induction of signalling molecules within the prostate cells that are activated follow a change in oxygenation to increase cell proliferation, survival, angiogenesis, metabolism and invasion. Importantly, the genetic background of the prostate cells significantly contributes to the response to inhibitors of androgen receptor. Our lab focuses on PTEN, where its deficiency has been shown to be a major molecular hallmark for aggressive prostate cancer. Our research has shown that prostate cancer cells with PTEN-loss have increased abundance of angiogenic promoting factors that contribute to reduced efficacy of currently used treatments pf prostate cancer including radiotherapy and androgen receptor inhibitors. This context of PTEN-loss and increased angiogenic promoting factors is a focus of this study and may define a mechanism of resistance to androgen-signaling inhibitors, where we need further mechanistic understanding of contribution and role of PTEN-depleted tumour foci and the surrounding microenvironment on development and treatment resistance.Aims and objectives: The proposed body of work will characterize the influence of PTEN-loss on the remodelling of the prostate microenvironment and alterations in the immune cell component following androgen receptor inhibition alone and in combination with inactivation of angiogenesis promoting factors. Mechanistically the study will investigate various angiogenesis promoting factors and their redundancy within the prostate and importance of dual inhibition on the microenvironment and therapeutic response. Application and benefit: As part of this project, the student will develop several novel models of PTEN-deficient prostate cells that will be a resource to the research community and importantly model relevant biology and the microenvironment of the prostate. The research will provide insight into the mechanisms of redundancy that exist between angiogenesis promoting factors leading to insights into normal development, wound healing, inflammation and cancer biology.