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Metabolic and hypoxic adaptation to anti‐angiogenic therapy: a target for induced essentiality
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Journal Article
Metabolic and hypoxic adaptation to anti‐angiogenic therapy: a target for induced essentiality
2015
Overview
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.
Graphical Abstract
Improving progression‐free survival in cancer: the importance of combining anti‐angiogenic therapy with inhibitors of hypoxic and metabolic adaptation to target induced essentiality and overcome tumour adaption.
Publisher
Nature Publishing Group UK,EMBO Press,BlackWell Publishing Ltd,Springer Nature
Subject
/ Angiogenesis Inhibitors - therapeutic use
/ Animals
/ Basic Helix-Loop-Helix Transcription Factors - genetics
/ Basic Helix-Loop-Helix Transcription Factors - metabolism
/ EMBO03
/ EMBO21
/ EMBO46
/ Gene Expression Regulation, Neoplastic - drug effects
/ Humans
/ Hypoxia
/ Neovascularization, Pathologic - drug therapy
/ Neovascularization, Pathologic - genetics
/ Neovascularization, Pathologic - metabolism
/ Neovascularization, Pathologic - pathology
/ Patients
/ Proteins
/ Review
/ Survival
/ Tumors
