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Angiogenesis modulation in cancer research: novel clinical approaches

Nature Reviews Drug Discovery volume 1, pages 415–426 (2002)Cite this article

Key Points

  • For a tumour to grow beyond a certain size, it must develop a network of blood vessels to supply nutrients and oxygen and to remove waste products.

  • Advances in the understanding of this process of tumour angiogenesis have led to the development of many drugs that target the different steps that are involved, more than 30 of which have entered clinical trials. However, so far, none has been approved, and there have been several prominent failures, which might be because clinical approaches that were established for traditional cytotoxic agents are inappropriate for angiogenic modulators.

  • The usual clinical development of a cytotoxic agent is based on the following concepts: first, that the agent is associated with dose-dependent toxicity; second, that there is an upper limit for dose escalation, which is defined as the dose-limiting toxicity (DLT); third, that the maximum-tolerated dose (MTD) has a higher probability of shrinking tumours (defined as objective remission) and improving palliation of symptoms; and finally, that the agent or combination regimens that are associated with tumour shrinkage might prolong survival.

  • By contrast, in early Phase I/II trials, angiogenic modulators have shown modest toxic effects and are mainly cytostatic, slowing or stopping the tumour growth and the development of metastases without producing an objective remission.

  • It seems clear that the end points for dose-defining trials (Phase I) and efficacy trials (Phase II) should be reconsidered. We strongly recommend the extensive use of correlative studies in the early phases of drug development to establish surrogate biomarkers for use in efficacy trials. Novel Phase II trial designs should be considered to address issues such as the low probability of an objective measurable response with angiogenic modulators.

  • Imaging studies could have a key role in assessing the efficacy of treatments. Various imaging modalities, such as magnetic resonance imaging, ultrasonography, positron emission tomography and computed tomography, can be selected for this purpose; the choice of imaging studies should be based on an accurate evaluation of the novel agents in preclinical models.

  • Finally, careful selection of the clinical setting for the investigation (for example, tumour type and stage of disease) must be carried out before expensive, definitive Phase III clinical trials are initiated.

Abstract

Angiogenesis — the formation of new blood vessels — is essential for tumour progression and metastasis. Consequently, the modulation of tumour angiogenesis using novel agents has become a highly active area of investigation in cancer research, from the bench to the clinic. However, the great therapeutic potential of these agents has yet to be realized, which could, in part, be because the traditional strategies that are used in clinical trials for anticancer therapies are not appropriate for assessing the efficacy of agents that modulate angiogenesis. Here, we discuss methods for monitoring the biological activity of angiogenic modulators, and innovative approaches to trial design that might facilitate the integration of these agents into anticancer therapy.

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Figure 1: Simplified overview of some key steps in tumour angiogenesis.
Figure 2: Representation of the clinical drug development process.
Figure 3: Imaging studies to monitor tumour angiogenesis.

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Authors and Affiliations

  1. Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Massimo Cristofanilli & Gabriel N. Hortobagyi

  2. Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Chusilp Charnsangavej

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  1. Massimo Cristofanilli
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  2. Chusilp Charnsangavej
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Correspondence to Massimo Cristofanilli.

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DATABASES

Cancer.gov

AIDS-related Kaposi's sarcoma

brain tumour

breast cancer

cervical cancer

colon cancer

Kaposi's sarcoma

liver cancer

melanoma

multiple myeloma

non-Hodgkin's lymphoma

non-small-cell lung cancer

ovarian cancer

prostate cancer

renal-cell carcinoma

small-cell lung cancer

LocusLink

bFGF

collagen XVIII

COX-2

EGFR

FLK1

HER2

αv-integrin

β3-integrin

interferon-γ

IP-10

MMP2

MMP9

NF-κB

NHE3

p53

PDGF

phospholipase A2

phospholipase Cγ

PI3K

plasminogen

prostate-specific antigen

TNF-α

urokinase

VEGF

VEGFR2

Medscape DrugInfo

Gleevec

interferon-α

thalidomide

trastuzumab

FURTHER INFORMATION

European Organisation for Research and Treatment of Cancer

National Cancer Institute

Southwest Oncology Group

The Cancer and Leukemia Group B

The University of Texas M. D. Anderson Cancer Center

World Health Organization

Glossary

ANGIOPOIETINS

Angiopoietins are a novel family of proteins that specifically recognize and bind to the endothelial-cell-specific Tie2- receptor tyrosine kinase, and have been shown to be crucially involved in establishing the mature vascular network.

MICROVASCULATURE

A network of vessels that have diameters of less than 100 μm, which are beyond the resolution of conventional angiography.

MAGNETIC RESONANCE IMAGING

The use of radio waves in the presence of a magnetic field to extract information from certain atomic nuclei (most commonly hydrogen; for example, in water). Tissues can be differentiated by differences in their water densities. Tumours can be traced, as tumour tissue has a different water density from surrounding healthy tissue.

CONTRAST AGENTS

Contrast agents enhance the differences between normal and abnormal tissue in imaging studies.

ULTRASONOGRAPHY

The use of sound waves above the audible frequency to detect and characterize tumours. Echoes that are reflected off normal and abnormal tissues are captured by a computer to create two-dimensional images.

SINGLE-PHOTON-EMISSION COMPUTED TOMOGRAPHY

The detection and quantification of γ-emitting radionuclides, such as 99mTc, 111In, 123I or 125I.

POSITRON-EMISSION TOMOGRAPHY

An imaging technique that is used to detect decaying nuclides, such as 15O, 13N, 11C, 18F, 124I and 94mTc.

COMPUTED TOMOGRAPHY

A technique that exploits the differences in absorption of X-rays by different tissues to give high-contrast images of anatomical structures. Computed tomography has relatively poor soft-tissue contrast, so iodinated contrast agents, which perfuse different tissue types at different rates, are commonly used to delineate tumours.

GRADE III OR IV TOXICITIES

For each adverse event (AE) that is associated with a specific treatment, grades are assigned and defined using a scale from 0 to V. Grade III, severe and undesirable AE; grade IV, life threatening or disabling AE.

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Cristofanilli, M., Charnsangavej, C. & Hortobagyi, G. Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discov 1, 415–426 (2002). https://doi.org/10.1038/nrd819

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