Table 1.

Key hypoxia response pathways and relevance to PCa

Hypoxia factor	HIF dependent?	Hypoxic response	PCa clinical relevance	Targeted agents?	Drug development status (used to treat PCa?)
HIF1α	Yes	Multiple	Reduced time to biochemical failure29	Aminoflavone,30,31 EZN-296832	Clinical, both withdrawn (No)
HIF2α	Yes	Multiple	Negative prognostic factor for MFS33	PT2385,34 PT297735	Clinical (No)
VEGF-A	Yes	Angiogenesis36	Reduced time to biochemical failure29	sorafenib, sunitinib, pazopanib, bevacizumab37	All FDA approved (No)
GLUT1	Yes	Aerobic glycolysis20	Reduced time to biochemical failure38	Fasentin,39 BAY-87640	Both pre-clinical (No)
CAIX	Yes	Cytoplasmic alkalisation20,41	Conflicting, further investigation required42–45	SLC-011146	Clinical (No)
PERK/IRE1	No	Unfolded Protein Response47	Poor prognosis and PSA recurrence48	MKC8866 (IRE1 inhibitor)49	Pre-clinical (No)

HIF, hypoxia inducible factor; MFS, metastasis free survival; PCa, prostate cancer; PSA, prostate specific antigen.

Hypoxia acts via HIF dependent and HIF independent signalling pathways to induce molecular responses associated with tumourigenesis. HIF1α, VEGF-A and GLUT1 have been associated with reduced time to biochemical failure, while HIF2α is a negative prognostic factor for MFS. PERK and IRE1 dependent arms of the unfolded protein response have also been associated with poor prognosis and PSA recurrence. Although multiple VEGF-A targeting agents have gained FDA approval, none of these are used to treat PCa, while other molecular targeted approaches have not yet yielded great success in the clinic.