HYpoxia-driven PROstate cancer GENomics (HYPROGEN)
Research type
Research Study
Full title
Illuminating the genomic landscape of hypoxia-driven early metastatic prostate cancer
IRAS ID
262789
Contact name
Robert Bristow
Contact email
Sponsor organisation
The Christie NHS Foundation Trust
Clinicaltrials.gov Identifier
CFTSp155, Sponsor Ref Number; 18_DOG04_201, Christie Ref Number
Duration of Study in the UK
0 years, 11 months, 30 days
Research summary
Summary of Research
Due to the rapid growth, tumour demand for oxygen often is higher than what can be delivered by the newly forming blood vessels. Tumour adaption to this imbalanced oxygen supply and demand (hypoxia) is associated with poor prognosis and genetic changes (genomic instability) that allow it to become more resistant to chemo- and radiotherapy. Patients with hypoxic tumours therefore die earlier. Limited information is available on hypoxia in newly diagnosed prostate cancer, especially to what degree hypoxia in the prostate tumour is associated with the presence of metastases to bones. This study will therefore aim to determine the association between hypoxia in the primary tumour with the presence of skeletal metastases. Secondly this study will aim to determine if hypoxia is also present in the metastatic sites themselves. Hypoxia presence will be determined by using a hypoxia identifying stain (by giving a patient a tablet of the stain to take orally) and by identifying genomic alterations that are associated with hypoxia. After taking the tablet of the hypoxia marker (Pimonidazol) patients will receive both a biopsy of the prostate and of one of the bone metastasis. Patients who already have undergone a diagnostic biopsy of the prostate may opt to not undergo a second biopsy solely for research purposes, in which case existing archival samples from the diagnostic biopsies willl be assessed to address the research questions. This will, however, limit the information contant to be retrieved from the study assessments. The presence or not as well as the degree of hypoxia in both sites will be assessed.
Summary of Results
The HYPROGEN trial was a biomarker development trial (treatment-naive patients enrolled in Arm A for M1 metastatic disease or Arm B for M0 localised disease) designed to interrogate low oxygen sub-regions in prostate cancer tissues (primary tumours and metastatic) as to their aggression and genetics, both within and between patients.
The diagnostic used was oral pimonidazole (PIMO) taken which binds to low oxygen tissues and DNA/RNA/Protein species and can be detected using immunohistochemistry on formalin-fixed tissues.
Arm A tested whether PIMO was detected in both the prostate gland and paired bone metastases - planned accrual was 30 patients and 7 patients were accused to this arm, which biopsied the prostate gland and bony metastases at the Christie NHS Trust followed by a whole-body MRI scan. All prostate tumours showed sub-regions of PIMO positivity. We found that only 1 patient's bone metastasis was PIMO positive, the other 6 accrued patients did not show PIMO positivity. We are currently completing spatial biology s and whole genome of the prostate gland to understand intraprostatic heterogeneity and associated genomics.
ARM B accrued 23 patients out of a planned 30 and used radical prostatectomy specimens to interrogate PIMO and hypoxia. We were able to quantitate the hypoxia in the prostate gland sub-regions and found significant correlations to alterer cancer driver gene expression: increased MYC expression, increased gains and deletions along chromosomes, and decreased PTEN expression. This suggests that hypoxic tumour cells can outgrow growth arrest in harsh low oxygen conditions and proliferate to acquire increased genomic alterations. A sub-study showed that MRI scans done in parallel with PIMO staining can be used to characterise the amount of tumour hypoxia.
REC name
North West - Greater Manchester East Research Ethics Committee
REC reference
19/NW/0569
Date of REC Opinion
24 Sep 2019
REC opinion
Favourable Opinion