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

Research Opportunity
PhD, Masters by Research, Honours
Number of Honour Places Available
1
Number of Master Places Available
1
Department
Surgery
Location
Royal Melbourne Hospital
Primary Supervisor Email Number Webpage
Associate Professor Niall Corcoran niallmcorcoran@gmail.com Personal web page
Co-supervisor Email Number Webpage
Professor Christopher Hovens cbhovens@gmail.com Personal web page

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

  1. Corcoran NM, Clarkson MJ, Stuchbery R, Hovens CM. Molecular Pathways: Targeting DNA Repair Pathway Defects Enriched in Metastasis. Clin Cancer Res. 2016;22(13):3132-7.
  2. Tindall EA, Monare LR, Petersen DC, van Zyl S, Hardie RA, Segone AM, et al. Clinical presentation of prostate cancer in black South Africans. Prostate. 2014;74(8):880- 91.
  3. Australian Institute of Welfare and Health. Cancer incidence projections: Australia, 2011 to 2020. Cancer Series No : 66. 2012.
  4. Cancer Genome Atlas Research N. The Molecular Taxonomy of Primary Prostate Cancer. Cell. 2015;163(4):1011-25.
  5. Fraser M, Sabelnykova VY, Yamaguchi TN, Heisler LE, Livingstone J, Huang V, et al. Genomic hallmarks of localized, non-indolent prostate cancer. Nature. 2017;541(7637):359-64.
  6. Hong MK, Macintyre G, Wedge DC, Van Loo P, Patel K, Lunke S, et al. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat Commun. 2015;6:6605. 7. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.
  7. Conti DV, Wang K, Sheng X, Bensen JT, Hazelett DJ, Cook MB, et al. Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry. J Natl Cancer Inst. 2017;109(8).

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



Faculty Research Themes

Cancer

School Research Themes

Cancer in Medicine



Research Opportunities

PhD, Masters by Research, Honours
Students who are interested in joining this project will need to consider their elegibility as well as other requirements before contacting the supervisor of this research

Graduate Research application

Honours application

Key Contact

For further information about this research, please contact a supervisor.

Department

Surgery

Research Node

Royal Melbourne Hospital

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