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Modes of resistance to anti-angiogenic therapy

Key Points

  • Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF)-mediated pro-angiogenic signalling pathways are producing demonstrable clinical benefit for an increasing number of cancer types. However, in some cases (both in humans and in mouse models of cancer) anti-angiogenic therapies produce initial responses followed almost inevitably by progression, thereby affording appreciable but limited survival advantage. In other cases there is no objective benefit. Increasing evidence supports the proposition that progression and mortality following a period of benefit reflects an adaptive response by tumours, manifesting 'evasive resistance' to angiogenesis inhibitors. By contrast, patients for whom there is no tangible benefit indicate that an intrinsic resistance to angiogenesis inhibitors exists.

  • Evasive resistance to VEGF pathway inhibitors (and arguably other angiogenesis inhibitors) involves a number of distinct and interrelated mechanisms that may be variably important. The emergent mechanisms of evasive resistance include revascularization consequent to upregulation of alternative pro-angiogenic signals; protection of the tumour vasculature either by recruiting pro-angiogenic inflammatory cells or by increasing protective pericyte coverage; accentuated invasiveness of tumour cells into local tissue to co-opt normal vasculature; and increased metastatic seeding and tumour cell growth in lymph nodes and distant organs.

  • Intrinsic resistance is likely to involve similar molecular and cellular mechanisms to those that mediate evasive resistance. Whereas rapid adaptive responses (fast evasion) may underlie some cases of apparent intrinsic resistance, there is evidence to suggest that certain tumours, owing to their stage of progression, treatment history, genomic constitution and/or host genotype, may have a pre-existing tumour microenvironment that conveys such indifference.

  • If the postulate of evasive and intrinsic resistance to angiogenesis inhibitors is further validated in preclinical and clinical investigations, we foresee a future of cancer therapeutics in which combinatorial strategies involving angiogenesis inhibition are integrated with drugs targeting resistance mechanisms to afford enduring efficacy.

Abstract

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.

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Figure 1: Two modes of resistance in response to anti-angiogenic therapy imply adaptive evasion and intrinsic non-responsiveness of tumours.
Figure 2: Induced pro-angiogenic factor substitution re-establishes tumour neovascularization.
Figure 3: Recruitment of bone marrow-derived cells can endorse restored neovascularization.
Figure 4: Increased pericyte coverage protects tumour blood vessels.
Figure 5: Increased tumour cell invasiveness to escape oxygen and nutrient deprivation.

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Acknowledgements

We thank R. Kerbel, M. Aghi, H. Rugo and O. Casanovas for insightful discussions. Research in the authors' laboratories was supported by grants from the US National Cancer Institute (to G.B. and D.H.), and by an award to D.H. from the William F. Bowes Charitable Foundation. D.H. is an American Cancer Society Research Professor and G.B. holds the Neill H. and Linda S. Brownstein Chair in Brain Tumour Research.

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DATABASES

National Cancer Institute

breast cancer

colon cancer

glioblastoma

lung cancer

non-small-cell lung cancer

renal cancer

National Cancer Institute Drug Dictionary

bevacizumab

gemcitabine

paclitaxel

semaxanib

sorafenib

sunitinib

FURTHER INFORMATION

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Angiogenesis Inhibitors Therapy

Clinical trials in patients with brain cancer

Clinical trials in patients with breast cancer

Clinical trials in patients with gastrointestinal stromal tumours

Clinical trials in patients with kidney cancer

Clinical trials in patients with liver cancer

Clinical trials in patients with lymphoma

Clinical trials in patients with lung cancer

Clinical trials in patients with pancreatic cancer

FDA approval of bevacizumab

New approval for bevacizumab (Avastin)

Glossary

Hypertension

A medical condition in which the blood pressure is chronically increased.

Doppler ultrasound

A test that uses reflected sound waves to evaluate blood flow.

Hemangiocytes

CXCR4+ VEGFR1+ haematopoietic progenitors.

Intravasation

Part of the metastasis process in which cancer cells invade through the basal membrane into blood vessels.

Co-option

Blood vessel co-option: tumour cells grow around existing blood vessels in the tissue.

Leptomeninges

The two innermost layers, comprised of the arachnoid mater and pia mater, that envelop the brain and spinal cord.

Metronomic chemotherapy

Administration of chemotherapeutic drugs at comparatively low doses on a frequent or continuous schedule, with no extended interruptions.

Oedema

An observable swelling due to an increase of interstitial fluid in any organ.

Desmoplastic stroma

Abnormal and excessive growth of stromal cells that is often associated with invasive cancers.

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Bergers, G., Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8, 592–603 (2008). https://doi.org/10.1038/nrc2442

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