Figure 5.

Assays and treatment for hypoxia mediated aggression: (a) Clinical outcome studies following surgery or radiotherapy for localised prostate cancer have shown that the patients whose prostate cancers acquire both high PGA and increased hypoxia have adverse outcomes when compared to patients who have only one or none of these two biological states.^27,96 (b) Intraprostatic hypoxia subregions can be visualised in-situ using intrinsic (e.g. staining for HIF-1, GLUT-1) or extrinsic (e.g. pimonidazole binding) biomarkers, or metabolic imaging techniques such as OE-MRI and CSI-MRI.⁹⁷ To date, imaging with PET hypoxic tracers (e.g. PET-FAZA or PET-MISO) has been less successful. Ascertainment of genetic instability or DNA repair deficiencies can be accomplished using genome sequencing techniques for CNAs or single nucleotide mutations. In-situ staining showing reduced DNA repair protein expression (e.g. reduced RAD51) relative to hypoxic staining may be a biomarker of hypoxia-mediated DNA repair deficiencies⁷². Treatments to target hypoxia-mediated aggressive biology and improve cure in localised prostate cancer with surgery or radiotherapy includes the use of direct hypoxic cell toxins (e.g. evofosfamide and OCT1002) or radiosensitisation during radiotherapy using radiosensitisers (e.g. nimorazole, an oxygen mimetic) or increasing tumour oxygen content (e.g. carbogen and nicotinamide). DNA repair-deficient or cell cycle checkpoint-deficient hypoxic tumours can be targeted with PARP or ATR inhibition^98,99. Additionally, androgen deprivation has been shown to increase oxygen content and decrease DNA repair in prostate cancer.^100,101 (c) These treatments can be used in neoadjuvant or concurrent settings to clear resistant and genetically unstable hypoxic cells within the primary tumour in combination with radiotherapy or surgery.⁹⁴ Adjuvant treatments can improve outcomes by targeting occult metastatic disease and therefore prevent the outgrowth of lethal CRPC and NEPC metastases²². Note concurrent use of DNA repair inhibitors with radiotherapy is generally too toxic to normal tissues and therefore neoadjuvant or adjuvant use of these agents may be preferred. CNA, copy number alteration; CRPC, castrate-resistant prostate cancer; CS-MRI, chemical shift MRI; NEPC, neuroendocrine prostate cancer; OE-MRI, oxygen-enhanced MRI; PET, positron emmision tomography; PGA, percent genome alteration.