Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality

Abstract

Anti-angiogenic therapy has increased the progression-free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6-8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table 1). Many mechanisms of resistance to anti-VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti-angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia-inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre-clinical studies combining anti-angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti-angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre-clinical and clinical studies that have potential for producing synthetic lethality in combination with anti-angiogenic therapy as a future therapeutic strategy.

Keywords: angiogenesis; anti‐VEGF therapy; combination therapy; hypoxia; metabolism.

Figure 1. Angiogenesis into the hypoxic tumour microenvironment

This figure highlights the role of hypoxia-regulated proteins in the angiogenic process.

Figure 2. Metabolic reprogramming in the hypoxic microenvironment

This figure shows the metabolic processes that are upregulated in response to hypoxia and the therapeutic drugs that target these processes, which are in clinical trials (highlighted in white boxes). Proteins in red have increased expression or activity in hypoxia. Arrows in red denote increased flux in hypoxia. ALDOA, aldolase A; CA, carbonic anhydrase; CD36, fatty acid translocase; DCA, dichloroacetate; ENO1, enolase 1; FABP, fatty acid binding protein; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GLUT, glucose transporter; GYS1, glycogen synthase; HK, hexokinase; HIF, hypoxia-inducible factor; IDH2, isocitrate dehydrogenase 2; LDHA, lactate dehydrogenase A; MCT, monocarboxylate transporter; NHE1, sodium hydrogen antiporter 1; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PFK, phosphofructokinase; PFKFBP, phosphofructokinase bisphosphatase; PGK1, phosphoglycerate kinase 1; PGM, phosphoglycerate mutase; PKM2, pyruvate kinase M2; PYGL, liver glycogen phosphorylase.