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 (Table1). 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.

Gold nanoparticles attenuate metastasis by tumor vasculature normalization and epithelial–mesenchymal transition inhibition

“…However, a few clinical studies have demonstrated that such a monotherapy fails to provoke significant response rates or improve overall survival (OS), even in colon cancer (average 6-8 weeks) due to resistance. 4,5 A randomized trial of anti-VEGF plus irinotecan and 5-fluorouracil showed no difference either in median OS (22.0 vs 25.0 months, P=0.1391) or in the response rate (36.8% vs 35.2%) in patients with advanced colorectal cancer. 6 Similarly, there was no difference in the median OS: 25.4 (95% CI: 22.2-28.9) months in the anti-VEGF continuation arm versus 23.8 (95% CI: 21-26.8) months in the no continuation arm (hazard ratio [HR] 0.83; 95% CI: 0.63-1.1; P=0.…”

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

“…Developing new strategies to target the hypoxic microenvironment is critical for improving patient outcome. Furthermore, antiangiogenic therapy induces tumor hypoxia in approximately half of cases (where the remainder of the tumors exhibit no vascular response or vascular normalization for a period at the start of therapy), and combination strategies that induce apoptosis in the hypoxic microenvironment would be effective in this context (3). Hypoxia results in stabilization of the transcription factors hypoxia inducible factors (HIF) 1a and 2a, via reduced hydroxylation of HIF proteins, preventing ubiquitination pVHL (protein Von Hippel-Lindau), which precedes HIF proteasomal degradation (4).…”

“…Hypoxia results in stabilization of the transcription factors hypoxia inducible factors (HIF) 1a and 2a, via reduced hydroxylation of HIF proteins, preventing ubiquitination pVHL (protein Von Hippel-Lindau), which precedes HIF proteasomal degradation (4). Many HIFregulated genes trigger more aggressive tumor growth, invasion, metabolic adaptation, and survival (3).…”

Manipulating Angiogenesis by Targeting Endothelial Metabolism: Hitting the Engine Rather than the Drivers—A New Perspective?

“…Multiple angiogenic signals, including members of the VEGF, angiopoietin, FGF2, and other families fuel excessive angiogenesis in tumors (see previous reviews, Carmeliet and Jain, 2000;Carmeliet, 2003;Jain, 2014). Activation of HIF-1a by low oxygen conditions in tumors induces the expression of several of these proangiogenic factors (Krock et al, 2011;McIntyre and Harris, 2015).…”

“…Also, upon arrest of anti-VEGF treatment, cancer cells can switch from a glycolytic phenotype to a more lipogenic phenotype, thereby fueling a more aggressive and metastatic tumor growth, which could be reverted by blocking FA synthase with the drug orlistat (Sounni et al, 2014). The metabolic evolution of tumors treated with anti-VEGF substances needs further investigation to better understand its etiology and might open future translational possibilities for tumor (angiogenesis) inhibition (McIntyre and Harris, 2015).…”