DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents

O’Connor, James P.B.; Jackson, Alan; Parker, Geoffrey; Jayson, Gordon C

doi:10.1038/sj.bjc.6603515

Cited by 450 publications

(378 citation statements)

References 38 publications

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“…This observation indicates that the tumor vasculature of MDA-MB-435, as seen in real time at multiple time points in individual mice, was highly permeable and leaky. This is consistent with previous reports (2,(18)(19)(20)(21)(22).…”

Section: Resultssupporting

confidence: 83%

“…We used this window of normalization for the design of an effective antiangiogenic and chemotherapy combination that improved the antitumor efficacy of paclitaxel by greatly increasing tumor drug penetration and cancer cell uptake. Our observations support the concept of vascular normalization by antiangiogenesis drugs (1,2), and show that judicious application of antiangiogenic treatment can functionally normalize the tumor vasculature as well as facilitate a more uniform delivery of therapeutic agents to cancer cells. Prolonged treatment with a subclinical dose of anti-VEGF antibody led to functional vessel normalization, which enhanced the antitumor efficacy of paclitaxel.…”

Section: Discussionsupporting

confidence: 68%

“…Tumor vessel normalization has been proposed as the main mechanism of antitumor efficacy of vascular targeting agents (1,2). Vascular normalization in the tumor can allow increased drug delivery to the tumor.…”

Section: Introductionmentioning

confidence: 99%

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Time-Course Imaging of Therapeutic Functional Tumor Vascular Normalization by Antiangiogenic Agents

Zhang

Bindokas

Shen

et al. 2011

Molecular Cancer Therapeutics

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We describe here new technology that enables noninvasive imaging of therapeutic functional normalization of tumor blood vessels by antiangiogenic agents. Noninvasive variable-magnification in vivofluorescence imaging as well as fluorescence tomography was used to visualize functional vessel normalization. Changes in the same vessel before and after drug treatment were imaged with high resolution in real time. Differences in vascular responses to the mTOR inhibitor rapamycin and to an anti-VEGF antibody were functionally imaged. Tumor vessel normalization was shown by significantly reduced leakiness and subsequent improved tumor delivery of Paclitaxel-BODPY as well as by normalized morphology. The tumor vascular pool agent, AngioSense 750 , was retained only in tumors after either anti-VEGF antibody or rapamycin treatment, as visualized by noninvasive fluorescence tomography. The antiangiogenic therapy normalized vessels, which significantly enhanced the antitumor efficacy of paclitaxel because of increased drug penetration throughout the tumor. The optical imaging technology described here is thus a powerful, noninvasive, time-course imaging tool of functional tumor vessel normalization and its therapeutic consequences. Mol Cancer Ther; 10(7); 1173-84. Ó2011 AACR.

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Section: Resultssupporting

confidence: 83%

Section: Discussionsupporting

confidence: 68%

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Time-Course Imaging of Therapeutic Functional Tumor Vascular Normalization by Antiangiogenic Agents

Zhang

Bindokas

Shen

et al. 2011

Molecular Cancer Therapeutics

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“…Low-molecularweight gadolinium-based contrast agents have been used for mapping blood volume in tissue (9) and for MR angiography (10). T 1 -weighted dynamic contrast-enhanced MRI has been used extensively as a measure of various parameters associated with angiogenesis that can be calculated using compartmental modeling (11,12), including vascular permeability, vascular and extravascular volumes, and blood flow (13). Ultrasmall paramagnetic iron oxide (USPIO) contrast agents, which remain intravascular with a half-life of several hours, have also proven useful for MR angiography (14) and blood volume measurements (15).…”

mentioning

confidence: 99%

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Ungersma

Pacheco²,

et al. 2010

Magnetic Resonance in Med

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Imaging of tumor microvasculature has become an important tool for studying angiogenesis and monitoring antiangiogenic therapies. Ultrasmall paramagnetic iron oxide contrast agents for indirect imaging of vasculature offer a method for quantitative measurements of vascular biomarkers such as vessel size index, blood volume, and vessel density. Here, this technique is validated with direct comparisons to ex vivo micro-CT angiography and histologic vessel measurements, showing significant correlations between in vivo vascular MRI measurements and ex vivo structural vessel measurements. The sensitivity of the MRI vascular parameters is also demonstrated, in combination with a multispectral analysis technique for segmenting tumor tissue to restrict the analysis to viable tumor tissue and exclude regions of necrosis. It is shown that this viable tumor segmentation increases sensitivity for detection of significant effects on blood volume and vessel density by two antiangiogenic therapeutics (anti-VEGF and anti-neuropilin-1) on an HM7 colorectal tumor model. Anti-VEGF reduced blood volume by 36 6 3% (P < 0.0001) and vessel density by 52 6 3% (P < 0.0001) at 48 h posttreatment; the effects of anti-neuropilin-1 were roughly half as strong with a reduction in blood volume of 18 6 6% (P < 0.05) and a reduction in vessel density of 33 6 5% (P < 0.05) at 48 h posttreatment.

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“…VEGF markedly increases vascular permeability; monitoring changes in vascular permeability presents an attractive approach to the imaging of target inhibition by anti-VEGF antibodies or VEGF receptor kinase inhibitors. 39 DCE-MRI was used to determine the effective dose for the pan-VEGF receptor kinase inhibitor PTK 787/ZK 222584 (PTK/ZK). Treatment with this drug resulted in a dose-dependent decrease of K trans , a marker of vascular permeability and perfusion.…”

Section: Measuring Target Inhibitionmentioning

confidence: 99%

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

et al. 2008

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SUMMARYTargeted drugs hold great promise for the treatment of malignant tumors; however, there are several challenges for efficient evaluation of these drugs in preclinical and clinical studies. These challenges include identifying the 'correct', biologically active concentration and dose schedule, selecting the patients likely to benefit from treatment, monitoring inhibition of the target protein or pathway, and assessing the response of the tumor to therapy. Although anatomic imaging will remain important, molecular imaging provides several new opportunities to make the process of drug development more efficient. Various techniques for molecular imaging that enable noninvasive and quantitative imaging are now available in the preclinical and clinical settings, to aid development and evaluation of new drugs for the treatment of cancer. In this Review, we discuss the integration of molecular imaging into the process of drug development and how molecular imaging can address key questions in the preclinical and clinical evaluation of new targeted drugs. Examples include imaging of the expression and inhibition of drug targets, noninvasive tissue pharmacokinetics, and early assessment of the tumor response.

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DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents

Cited by 450 publications

References 38 publications

Time-Course Imaging of Therapeutic Functional Tumor Vascular Normalization by Antiangiogenic Agents

Time-Course Imaging of Therapeutic Functional Tumor Vascular Normalization by Antiangiogenic Agents

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

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