Investigating the link between phenotype change and treatment resistance in prostate cancer

Summary The development of resistance to androgen (male sex hormone) deprivation therapy (ADT), the primary treatment for aggressive prostate cancer, is not clearly understood.

Project Details

Our phylogenetic analyses of resistant tumours demonstrate no significant tumour evolution or clonal/subclonal selection with therapy, supporting the concept that resistant tumours are “hardwired” to survive in the castrate environment. We have previously found no mutation or structural variant consistently shared between resistant tumours at any of the gene/pathway/ontology levels, and no evidence of previously characterised genomic drivers of resistance.  We have performed whole genome and RNA sequencing on paired pre- and post-treatment tumour samples obtained from high-risk patients undergoing profound androgen suppression for 6 months before prostatectomy, in whom clinical responses ranged from complete involution to no effect.  Transcriptional profiling indicated that resistant cells undergo a phenotypic reprogramming in response to therapy that may be important for cellular survival, and suggests that these changes are regulated by alterations in post-translational histone modifications. This raises the possibility that hardwired resistance is epigenetically, and not genomically mediated. Our data from patient-derived tumours grown in androgen-deprived conditions support the concept that cancer cells adapt to castration though histone mediated transcriptional reprogramming and development of a stem cell–like phenotype. This project will involve establishing an organoid model of prostate cancer and investigating the effect of perturbing key nodes in this adaptive process.

Skills & Techniques may involve:  tissue culture, organoid growth / 3D printing, western blotting, immunohistochemistry, RNA/DNA extraction, qPCR, RNA/DNA sequencing, functional validation (overexpression/knockdown experiments), work on animal models, drug screening, and datamining.

Benefits to student: Molecular and clinical research, multi-collaborative project encompassing basic research and clinical interaction. Working with clinical samples from prostate cancer patients.

Research students will work within a team of experienced scientists and have access to scientific expertise and equipment through our department, associated institutions and existing collaborations with leading urologists.

Reference

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Collaborators

Walter and Eliza Hall of Institute, AU

Royal Melbourne Hospital, AU

Peter MacCallum, AU

University of California, LA

The Institute of Cancer Research. UK

Funding

NHMRC project grants

Movember