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2025 The John Black Charitable Foundation – PCF Challenge Award

Detecting Molecular and Histopathological Correlates of Whole Genome Duplication in High-Risk Prostate Cancer

Principal Investigators: Ian Mills, PhD (University of Oxford), Srinivasa Rao Rao, PhD, MBBS (University of Oxford)

Co-Investigators: Freddie Hamdy, MD, PhD (University of Oxford), Jens Rittscher, PhD (University of Oxford), Clare Verrill, MD (University of Oxford), Dan Woodcock, PhD (University of Oxford), Roman Fischer, PhD (University of Oxford), Simon Davis, PhD (University of Oxford), Gerhardt Attard, MD, PhD (University College London (UCL) Cancer Institute), Peter Nelson, MD (University of Washington), Claire Edwards, PhD (University of Oxford)

Young Investigator: Mazlina Ismail, PhD (University College London (UCL) Cancer Institute)

Collaborators: Kenneth Pienta, MD (Johns Hopkins University), Willem Bonnaffe PhD (University of Oxford)

Description:

  • There is a pressing need to improve risk stratification for prostate cancer to identify cases with the highest probability of metastasizing and killing patients at the earliest possible interception point, when still confined to the prostate.
  • Dr. Ian Mills and team have identified a prostate cancer subtype that is impaired in its ability to distribute its genetic material (DNA) among its daughter cells. This leads to the accumulation of extra (more than the usual 2) copies of entire genome in tumor cells, called Whole Genome Doubling (WGD). This impairment is associated with increased risk of cancer progression and has mainly been detected in metastatic prostate cancer. 
  • In this project, Dr. Mills and team will employ a novel spatial DNA sequencing method to detect small populations of cells bearing this genomic defect in localized prostate cancer.   They also test whether deep learning-based image analysis of RNA and protein levels or other image-based features on prostate pathology slides can identify WGD. 
  • Pre-clinical models will be used to identify therapeutic vulnerabilities associated with this defect that can be exploited and are linked to the metabolic, segregation and replicative stress hard-wired into these cells. 
  • If successful, this project will result in the development of biomarker test that can detect the earliest molecular or imaging changes that precede WGD, and identify strategies to therapeutically target this metastasis-prone prostate cancer subtype more effectively.

What this means to patients: The ability to better identify patients diagnosed with localized prostate cancer who are most likely to develop metastatic, lethal disease will improve patient treatment and outcomes. The team, working as part of the Pan-Prostate Cancer Genomics Consortium, has found thatWhole Genome Doubling (WGD) is a common feature of metastatic-prone prostate cancer and in this project will develop molecular and pathology-based biomarker tests to identify these cases when tumors are still localized, and will also identify new treatment strategies for this tumor subtype. This will lead to better diagnosis, management, and treatment of patients with potentially lethal disease at a time there is still a potential for cure.