Imaging Angiogenesis: Applications and Potential for Drug Development

Department of Radiology, Massachusetts General Hospital, 100 Charles River Plaza, Boston, MA 02114, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 03/2005; 97(3):172-87. DOI: 10.1093/jnci/dji023
Source: PubMed


Recognition of the importance of angiogenesis to tumor growth and metastasis has led to efforts to develop new drugs that are targeted to angiogenic vasculature. Clinical trials of these agents are challenging, both because there is no agreed upon method of establishing the correct dosage for drugs whose mechanism of action is not primarily cytotoxic and because of the long time it takes to determine whether such drugs have a clinical effect. Therefore, there is a need for rapid and effective biomarkers to establish drug dosage and monitor clinical response. This review addresses the potential of imaging as a way to accurately and reliably assess changes in angiogenic vasculature in response to therapy. We describe the advantages and disadvantages of several imaging modalities, including positron emission tomography, x-ray computed tomography, magnetic resonance imaging, ultrasound, and optical imaging, for imaging angiogenic vasculature. We also discuss the analytic methods used to derive blood flow, blood volume, empirical semiquantitative hemodynamic parameters, and quantitative hemodynamic parameters from pharmacokinetic modeling. We examine the validity of these methods, citing studies that test correlations between data derived from imaging and data derived from other established methods, their reproducibility, and correlations between imaging-derived hemodynamic parameters and other pathologic indicators, such as microvessel density, pathology score, and disease outcome. Finally, we discuss which imaging methods are most likely to have the sensitivity and reliability required for monitoring responses to cancer therapy and describe ways in which imaging has been used in clinical trials to date.


Available from: Homer Pien, Aug 02, 2014
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    • "However, the use of CT for repeated scanning was limited by the high concentrations of CT contrast agent and the relatively high doses of radiation. PET is highly sensitive to very low concentrations of contrast agents and is well suited to molecular imaging, however, it suffers from poor spatial resolution [27]. Ultrasound is an easy available technique for monitoring therapeutic effects and has been frequently used in clinical practice. "
    [Show abstract] [Hide abstract] ABSTRACT: Exactly assessing tumor response to different dose of chemotherapy would help to tailor therapy for individual patients. This study was to determine the feasibility of dynamic contrast-enhanced ultrasound (CEUS) in the evaluation of tumor vascular response to different dose cisplatin. MCF-7 breast cancer bearing mice were treated with different dose of cisplatin in group B (1 mg/kg) and group C (3 mg/kg). A control group A was given with saline. Sequential CEUS was performed on days 0, 3 and 7 of the treatment, in which time-signal intensity curves were obtained from the intratumoral and depth-matched liver parenchyma. Peak enhancement (PE), area under the curve of wash-in (WiAUC), wash-in rate (WiR) and wash-in perfusion index (WiPI) were calculated from perfusion time-intensity curves and normalized with respect to the adjacent liver parenchyma. Histopathological analysis was conducted to evaluate tumor cell density and microvascular density (MVD). Significant decreases in tumor normalized perfusion parameters were observed on day 3 in the high dose group and on day 7 in the low dose group. On day 7, nPE, nWiAUC, and nWiPI significantly decreased in group C and group B as compared with group A (P < 0.05), and further decreased in group C as compared with group B (P < 0.05). Significant decreases of tumor cell density and MVD were seen in treated group (group B and C) compared to control group (P < 0.05) and further decrease in group C compared to group B (P < 0.05). Dynamic CEUS for quantification of tumor perfusion could be used to evaluate tumor vascular response to different dose of chemotherapy.
    Full-text · Article · Dec 2015 · BMC Cancer
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    • "Clinical grading of the microvascular parameters includes the number of mucosal blood vessels and the average microvessel diameter were semiquantitavely assessed independently by two oral medicine specialist and given a scale of 1–3 under the 545 nm light, with 3 given to the most intense vascularity observed, considering both the number and architecture of blood vessels in the oral lesions, and 1 having the least number of microvasculature.21,22,23 Upon completion of the optical measurements, tissue biopsies were obtained from the lesions by using either scalpel or punch technique under local anesthesia and samples were submitted for histopathological assessment. "
    [Show abstract] [Hide abstract] ABSTRACT: Optical spectroscopy devices are being developed and tested for the screening and diagnosis of oral precancer and cancer lesions. This study reports a device that uses white light for detection of suspicious lesions and green-amber light at 545 nm that detect tissue vascularity on patients with several suspicious oral lesions. The clinical grading of vascularity was compared to the histological grading of the biopsied lesions using specific biomarkers. Such a device, in the hands of dentists and other health professionals, could greatly increase the number of oral cancerous lesions detected in early phase. The purpose of this study is to correlate the clinical grading of tissue vascularity in several oral suspicious lesions using the Identafi(®) system with the histological grading of the biopsied lesions using specific vascular markers. Twenty-one patients with various oral lesions were enrolled in the study. The lesions were visualized using Identafi(®) device with white light illumination, followed by visualization of tissue autofluorescence and tissue reflectance. Tissue biopsied was obtained from the all lesions and both histopathological and immunohistochemical studies using a vascular endothelial biomarker (CD34) were performed on these tissue samples. The clinical vascular grading using the green-amber light at 545 nm and the expression pattern and intensity of staining for CD34 in the different biopsies varied depending on lesions, grading ranged from 1 to 3. The increase in vascularity was observed in abnormal tissues when compared to normal mucosa, but this increase was not limited to carcinoma only as hyperkeratosis and other oral diseases, such as lichen planus, also showed increase in vascularity. Optical spectroscopy is a promising technology for the detection of oral mucosal abnormalities; however, further investigations with a larger population group is required to evaluate the usefulness of these devices in differentiating benign lesions from potentially malignant lesions.International Journal of Oral Science advance online publication, 25 July 2014; doi:10.1038/ijos.2014.39.
    Full-text · Article · Jul 2014 · International Journal of Oral Science
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    • "Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) performed at high temporal resolution following the administration of a gadolinium (Gd)-chelated contrast medium is a noninvasive imaging technology that can be used to measure properties of tissue microvasculature. DCE-MRI is sensitive to changes in blood volume and vascular permeability that can be associated with tumor angiogenesis, and consequently DCE-MRI is a promising biomarker for characterizing tumor response to anti-angiogenic treatment46474849. In our study, preliminary assessment of K trans on serial DCE-MRI demonstrated a trend of dose-dependent decrease of K trans at 3 weeks, suggesting that greater inhibition of angiogenic activity was achieved with higher doses of the study medications. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose We hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination. Experimental Design Patients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression. Results Ninety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m2. Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥6 months (Total SD≥6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in Ktrans although analysis was limited by small sample size (N=12). Conclusion Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved.
    Full-text · Article · Jul 2014 · Oncotarget
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