Targeting a novel adaptive neovascular response of the tumour microenvironment to treat advanced prostate cancer

Overview

Prostate cancer (PCa) is a significant healthcare burden in Australia. Androgen signalling inhibition using androgen receptor (AR) antagonists is the principal systemic therapy for advanced PCa. Androgen receptors (AR) are an attractive therapeutic target due to their elevated expression in tumour epithelial cells and the retention of androgen signalling throughout the disease continuum.

However, patients eventually develop resistance to treatment, and PCa cells metastasise to distant bone and visceral organs, representing an incurable stage of the disease. Understanding mechanisms that contribute to resistance is therefore of major clinical significance.

In addition to expression of AR in tumour epithelial cells, there is an AR-positive population detected within other cell lineages present within the prostate tumour microenvironment, including stromal fibroblasts. Recent reports also demonstrate that androgen signalling has distinct and differential (opposing) effects in prostate epithelial cells and stromal fibroblasts, which may have relevance to the acquisition of treatment resistance in prostate cancer.

We have detected AR expression in the vascular endothelium of human PCa tissue. We have also observed that the administration of AR-targeted therapeutics induces growth arrest in human microvascular cells in vitro, consistent with our observation of vascular collapse and the development of local hypoxia within growing prostate tumours in vivo.

Understanding the molecular and cellular changes that result from the administration of AR-targeted therapeutics to vascular endothelial cells remains largely uncharacterised. Moreover, the combined effects of hypoxia and inhibition of AR-signalling are unknown. Further research is warranted to understand how these concurrent events alter the molecular footprint and phenotypic response of vascular endothelial cells.

Hypothesis

Hypoxia alters AR functionality within epithelial and vascular endothelial cells.

Aims

• Characterise the molecular and phenotypic effect of AR signalling inhibitors on vascular endothelial cells, using 3D culture technology.
• Determine how induction of hypoxia affects the molecular and phenotypic effect of AR signalling inhibitors on vascular endothelial cells.
• Understand how hypoxia may induce spatial and temporal changes in AR-directed gene expression in tumour explant models.

Research activities

This project is highly interdisciplinary and designed to expose you to a wide array of experimental techniques. It will facilitate the development of skills and experimental proficiency in the areas of cancer research, 3D cell culture, cell biology, and biomaterials.

You will develop expertise and technical skills in:

• traditional and 3D cell culture
• patient-derived organoid culture/tumour explants
• gene and protein expression analysis (multiplex qRT-PCR, western blot, ELISA)
• bioassays (cell viability, metabolic activity, proliferation)
• immunofluorescence staining and histology
• data analysis and presentation.

Outcomes

This research will contribute to our understanding of novel treatment resistance mechanisms in prostate cancer. You will develop new insights into the functionality of the AR in vascular endothelial cells, and how this is altered under hypoxia that develops within tumours undergoing treatment with AR-targeted therapy.

It will contribute to an overall program of work focused on the development of informed targeted-therapeutics that may prevent endothelial-cell dependent angiogenesis and outgrowth of treatment-resistant prostate cancer.

Skills and experience

You should have a keen interest in cancer research and demonstrate a high level of organisation, attention to detail and ability to work in a team environment. Basic skills in cell culture and general PC2 laboratory techniques are desired.

Keywords

• prostate cancer
• tumour microenvironment
• 3D cancer models
• in vitro drug testing
• therapy resistance

Contact

Contact the supervisor for more information.