Modes of resistance to anti-angiogenic therapy

By G. Bergers, D. Hanahan. Nature Reviews. Cancer, 2008

2,895 citations recorded by the source corpus.

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e06bf527eed8916d623509fb19543466623d9cf5

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In Molecular Biology

1. D. Hanahan
2. J. Joyce
3. Rakesh K. Jain
4. N. Ferrara
5. R. Weinberg
6. Peter Carmeliet
7. J. Pollard
8. R. Kerbel

Citations in the corpus

• Microenvironmental regulation of metastasis (2009, background): “The translational promise of this first targeted therapy against the tumour microenvironment, however, is somewhat tempered by emerging instances of resistance to anti-angiogenic therap”
• PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. (2009, background): “Other studies investigating tumor resistance/refractoriness to antiangiogenic therapies with VEGF blockers have identified additional potential mechanisms, including expression of alternative angiogenic factors (Bergers and Hanahan, 2008; Fischer et al., 2007), selection of hypoxia-resistant tumor c”
• Molecular mechanisms and clinical applications of angiogenesis (2011, background): “Aberrant FGF signalling promotes tumour angiogenesis and mediates the escape of tumour vascularization from VEGF- or epidermal growth factor receptor (EGFR)-inhibitor treatmen”
• Signal transduction by vascular endothelial growth factor receptors. (2012, background): “Finally, the recent challenges in the application of VEGF-targeted therapies with resistance, rescue (Bergers and Hanahan 2008), and, at least in mouse models, increased invasion and metastasis (Ebos et al. 2009; Paez-Ribes et al. 2009) have shown that we need to learn more about how blood vessels…”
• Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. (2009, background): “Notably, like most systemic therapies, these drugs have not produced enduring efficacy in terms of either tumor shrinkage or dormancy (stable disease) or long-term survival; rather, the common result is delayed time to progression following a period of clinical benefit, which is suggestive of an eme”
• Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. (2013, background): “Other evasive pathways emerging from preclinical and clinical studies include Ang2 and cMET.(16,89,90,97,171-173) These biomarkers and pathways need to be tested prospectively.”
• Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization (2009, positive): “Nonetheless, current antiangiogenic agents induce tumor hypoxia by pruning vessels or forming hypoperfused vessels, which can stimulate angiogenesis and limit their success (Bergers and Hanahan, 2008).”
• Hypoxia-induced angiogenesis: good and evil. (2011, background): “Tumors often evade single-agent antiangiogenic therapies through the selective activation of alternate pro-angiogenic pathways.(95) Consequently, simultaneous blockade of multiple pro-angiogenic pathways is more effective than single-agent anti-angiogenics.”
• Basic and therapeutic aspects of angiogenesis. (2011, neutral): “…adoption of a quiescent endothelial phalanx phenotype, basement membrane deposition, pericyte coverage, and branch regression. patients show benefit as tumors evolve mechanisms of resistance or are refractory towardVEGF (receptor) inhibitors (Bergers and Hanahan, 2008; Crawford and Ferrara, 2009a).”
• Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. (2011, background): “However, antiangiogenic treatments targeting the VEGF pathway rarely induce durable tumor responses, both in mice and patients with cancer (Bergers and Hanahan, 2008), and may also favor metastasis in selected tumor models (Ebos et al., 2009; Paez-Ribes et al., 2009).”
• Antiangiogenic therapy: impact on invasion, disease progression, and metastasis (2011, background): “Numerous mechanisms of resistance to antiangiogenic therapy have been propose”
• Hallmarks of cancer: the next generation. (2011, positive): “…where potent angiogenesis inhibitors succeed in suppressing this hallmark capability, tumors adapt and shift from a dependence upon continuing angiogenesis to heightening the activity of another instead—invasiveness and metastasis (Azam et al., 2010: Ebos et al., 2009; Bergers and Hanahan, 2008).”