Prostate Cancer Research Group

• 
  
  Professor Christopher Hovens

  chovens@unimelb.edu.au

Research Overview

The Prostate research group is focused on the area of determining cancer aggressiveness and metastatic potential as well as deciphering the molecular drivers of treatment resistance.

Our work over the past five years has placed our group in a pivotal position to decipher the genomic codes that drive metastasis and lethal disease in prostate cancer. We have established and lead a team of researchers with unique expertise in tracking, sampling and interrogating, with deep genomic analyses, lethal prostate cancer specimens in living patients. These analyses have revealed for the first time, the precise patterns and direction of lethal metastatic spread, as well as determined the tumour complexity at primary and metastatic sites.

Our ongoing work aims to directly assess the prognostic potential of the metastatic signatures by linking genomic signatures to clinical outcomes, potentially having a transformative effect on clinical prognosis in prostate cancer.

Within our research program we leverage our extensive discovery program in localised prostate cancer and treatment resistance to develop and validate new tests that will better inform patients and clinicians when selecting treatment options, as well as implement new treatment intensification strategies for high-risk disease. Specific areas of interest in this area of research include:

Developing tissue and blood tests that will predict future risk of progression in men at the time of diagnosis. Cancer is a disease of DNA, in that changes to DNA lead to the uncontrolled growth and spread associated with the disease (metastasis). Through our involvement in a number of large international DNA analyses, we have described the landscape of changes that occur across the spectrum of localised cancer. We are now linking these changes with important clinical events (e.g. metastasis), to develop a tissue and blood test that will better inform the risk of disease progression. This will help with identifying patients at risk of progression early, and improve patient selection for potentially morbid treatments;

Developing new ‘curative’ treatments in patients with high risk disease.  Although individual patient responses to systemic treatment (hormone treatments, chemotherapy) are often very good, they are rarely curative. Using patient samples from clinical trials and model systems, we have been studying how tumours adapt and develop resistance in early disease, and have identified a number of different approaches to improving patient responses. Based on this information we have designed two clinical studies using novel agents to investigate if treatment effects can be improved;

Developing new tests that will predict how patients will respond to treatment. Tumours quickly stop responding to standard treatments. Our investigations into how tumours become resistant to hormone therapy has led us to identify a number of DNA markers that predict how tumours will response. We will develop these markers into a clinical test that will help individualise patient treatment according to their specific tumour.

Our group is one of the founding members of the Pan Prostate Cancer Group, PPCG, an international consortium which has created the largest tumour specific genome database yet assembled. The PPCG is collecting and interrogating Whole Genome DNA Sequence and exome data generated around the world from over 2000 men with prostate cancer, including men from different clinical categories, and ethnicities. To date over 1800 whole genomes have already been assembled and alignment and initial processing using common analysis pipelines has already completed. This now represents the largest tumour specific data set ever assembled. Most importantly and unlike any other large international tumour sequencing project, the PPCG will have long term and ongoing clinical followup of all patients enrolled in the project. Hence, for the first time, tumour specific genetic variations will be able to be matched with meaningful clinical outcomes and endpoints, and the scale of the project will ensure it has the power to uncover clinically meaningful tumour signatures. The Prostate Group is one of the co-founders of the Consortium and was also chosen to lead the task group focusing on advanced and metastatic disease within the consortium.

Our laboratory has also had a longstanding basic discovery science program which has spanned interests of tumour biology and neuroscience. This has led to the discovery and patenting of a small molecule that targets one of the potential underlying causes of neurodegeneration in the brain. We have successfully translated this molecule, sodium selenate, into firstly the commercial and then the clinical spheres in multiple clinical trials, lead by our brilliant collaborators Professors Terry O’Brien and Dennis Velakoulis, which are now yielding highly encouraging signals of targeted efficacy in early Phase II neurodegenerative disease trials.

Staff

Professor Christopher Hovens, Principal Research Fellow

Dr Niall Corcoran, Research Fellow

Anne Nguyen, Research Officer

Bethany Campbell, Research Assistant

Marree Pechlivanis, Honours Student

Endymion Eistis, Honours Student

Yangyi Wang, Honours student

Ken Chow, PhD student

Anis Hamid, PhD student

Daniel Costello, Masters student

Collaborators

Tony Papenfuss (WEHI)

Bernie Pope and Dan Park (Melbourne Bioinformatics)

Andrew Ryan (TissuPath)

Vanessa Hayes (Garvan Institute of Medical Research)

Ben Tran (Peter MacCallum Cancer Centre)

Belinda Parker (PMCI)

Pan Prostate Cancer Group

Melbourne Bioinformatics, University of Melbourne
Melbourne Bioinformatics provides computational resources and analytics expertise for the Australian component of the Pan Prostate project, working in close collaboration with Prof Chris Hovens.
Principal Investigator:  Dr Bernie Pope

Canadian Prostate Cancer Genome Network (CPC-GENE), University of Toronto, Canada
Principal Investigators:  Dr. Paul Boutros and Dr. Rob Bristow

CRUK-ICGC Prostate Cancer Group, University College London, University of Oxford, University of East Anglia, University of Manchester, UK
Consists of a multidisciplinary team of histopathologists, urologists, molecular biologists, geneticists and experts in genome technology and bioinformatics.
Joint Lead of Project: Colin S. Cooper and Ros A. Eeles
Principal Investigators: G. Steven Bova, Daniel S. Brewer, Peter Campbell, Christopher S. Foster, Andy G. Lynch, Charlie Massie, David C. Wedge

Funding

Movember Foundation: Prostate Cancer Research Alliance Award 2019-2022 $5m
PRECEPT (PRostatE CancEr Prognosis and Treatment)
Principal Investigator: Corcoran NM. Co Investigator Hovens CM,

Current NHMRC Grant Support 

APP1162514        CIA Hovens CM                   2019: 3yrs - $600,000
The genomic drivers of high risk prostate cancer

APP1104010          CIA Hovens CM                 2016: 4yrs - $1,022,600
Tracking the origins and drivers of metastasis in prostate cancer

Research Outcomes

1. Hong MKH, Macintyre G, Wedge DC, Van Loo P, Patel K, Lunke S, Alexandrov LB, Sloggett C, Cmero M, Marass F, Tsui D, Mangiola S, Lonie A, Naeem H, Sapre N, Phal PM, Kurganovs N, Chin X, Kerger M, Warren A , Neal D, Gnanapragasam V, Rosenfeld N, Pedersen JS, Ryan A, Haviv I, Costello AJ, Corcoran NM, Hovens CM.
   ‘Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer.’ Nature Communications 2015 Apr 1;6:6605. doi: 10.1038/ncomms7605. The first paper to track the origins and longitudinal development of metastases in living prostate cancer patients by cataloguing the set of tumour subclones present in primary tumours and monitoring the expansion and spread of subclones with metastatic potential throughout the disease course.
2. Cancer Genome Atlas Research Network…Abeshouse A..Corcoran NM..Costello AJ..Hovens CM..Zmuda E.
   ‘The Molecular Taxonomy of Primary Prostate Cancer.’Cell. 2015 Nov 5;163(4):1011-25. As part of The Cancer Genome Atlas (TCGA), this paper presents the most comprehensive molecular analysis of 333 primary prostate carcinomas yet published. These results reveal a new molecular taxonomy for prostate cancer in which 74% of these tumours fell into one of seven subtypes defined by specific gene fusions. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signalling pathways, and DNA repair genes were inactivated in 19%. This analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.
3. Fankhauser M, Tan Y, Macintyre G, Haviv I, Hong MK, Nguyen A, Pedersen JS, Costello AJ, Hovens CM, Corcoran NM.
   ‘Canonical androstenedione reduction is the predominant source of signalling androgens in hormone-refractory prostate cancer.’Clinical Cancer Research 2014 20(21):5547-57. The first paper to measure and compare the actual production of androgenic steroids by fresh human prostate tumour tissue harvested from hormone refractory patients.
4. Naeem H, Wong N, Chatterton Z, Hong MK, Pedersen JS, Corcoran NM, Hovens CM, Macintyre G.
   ‘Reducing the risk of false discovery enabling identification of biologically significant genomewide methylation status using the HumanMethylation450 array.’ BMC Genomics. 2014 Jan 22;15(1):51. Development of a specific methylation array algorithm enabling integration of biologically relevant cancer genome data.
5. Hong MK, Sapre N, Phal PM, Macintyre G, Chin X, Pedersen JS, Ryan A, Kerger M, Costello AJ, Corcoran NM, Hovens CM.
   ‘Percutaneous image-guided biopsy of prostate cancer metastases yields samples suitable for genomics and personalised oncology.’ Clin Exp  Metastasis. 2014 Feb;31(2):159-67. The most advanced report on the methodology involved in procuring osseous metastatic specimens from advanced cancer patients, permitting serial sampling of metastatic tissue with of isolation of sufficient quality and quantity genomic material for next-gen sequencing