VEGF-PET Imaging Is a Noninvasive Biomarker Showing Differential Changes in the Tumor during Sunitinib Treatment

Nagengast, Wouter B.; Hooge, Marjolijn N. Lub-de; Oosting, Sjoukje F.; Dunnen, Wilfred F. A. den; Warnders, Frank-Jan; Brouwers, Adrienne H.; Jong, Johan R. de; Price, Patricia M; Hollema, Harry; Hospers, Geke A.P.; Elsinga, Philip H.; Hesselink, Jan Willem; Gietema, Jourik A.; Vries, Elisabeth G.E. de

doi:10.1158/0008-5472.can-10-1088

Cited by 103 publications

(69 citation statements)

References 35 publications

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“…Tumor 89 Zr-bevacizumab uptake decreased during treatment in lung and brain metastases but increased in normal liver and bone metastases, with reverse pattern after 2 drug-free weeks. The small decrease that we observed in mean tumor 89 Zrbevacizumab uptake after 2 wk of sunitinib and the rebound exceeding baseline after 2 wk off treatment correspond with our preclinical findings (27). Preclinical studies showed increased invasiveness and metastasis after a short sunitinib course (4,5).…”

Section: Discussionsupporting

confidence: 86%

⁸⁹Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

et al. 2014

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No validated predictive biomarkers for antiangiogenic treatment of metastatic renal cell carcinoma (mRCC) exist. Tumor vascular endothelial growth factor A (VEGF-A) level may be useful. We determined tumor uptake of 89 Zr-bevacizumab, a VEGF-A-binding PET tracer, in mRCC patients before and during antiangiogenic treatment in a pilot study. Methods: Patients underwent 89 Zrbevacizumab PET scans at baseline and 2 and 6 wk after initiating either bevacizumab (10 mg/kg every 2 wk) with interferon-α (3-9 million IU 3 times/wk) (n 5 11) or sunitinib (50 mg daily, 4 of every 6 wk) (n 5 11). Standardized uptake values were compared with plasma VEGF-A and time to disease progression. Results: 89 Zrbevacizumab PET scans visualized 125 evaluable tumor lesions in 22 patients, with a median SUV max (maximum standardized uptake value) of 6.9 (range, 2.3-46.9). Bevacizumab/interferon-α induced a mean change in tumor SUV max of −47.0% (range, −84.7 to 120.0%; P , 0.0001) at 2 wk and an additional −9.7% (range, −44.8 to 138.9%; P 5 0.015) at 6 wk. In the sunitinib group, the mean change in tumor SUV max was −14.3% at 2 wk (range, −80.4 to 1269.9; P 5 0.006), but at 6 wk the mean change in tumor SUV max was 172.6% (range, −46.4 to 1236%; P , 0.0001) above baseline. SUV max was not related to plasma VEGF-A at all scan moments. A baseline mean tumor SUV max greater than 10.0 in the 3 most intense lesions corresponded with longer time to disease progression (89.7 vs. 23.0 wk; hazard ratio, 0.22; 95% confidence interval, 0.05-1.00). Conclusion: Tumor uptake of 89 Zr-bevacizumab is high in mRCC, with remarkable interpatient and intrapatient heterogeneity. Bevacizumab/interferon-α strongly decreases tumor uptake whereas sunitinib results in a modest reduction with an overshoot after 2 drugfree weeks. High baseline tumor SUV max was associated with longer time to progression.

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Section: Discussionsupporting

confidence: 86%

⁸⁹Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

et al. 2014

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“…Although several of these tracers have been tested in a preclinical and clinical setting in which they successfully visualized several types of tumors and their metastases (15,16), none of these are routinely used in the clinic and few have been used to detect antiangiogenic therapy response. In 2 studies, response to antiangiogenic therapy was successfully detected using 99m Tc-hydrazinonicotinamide-VEGF and 89 Zr-ranibizumab (17,18). However, because of the long biologic half-life of VEGF, labeling of VEGF or VEGF-targeting molecules with long-lived iso- topes such as 89 Zr or 111 In is needed (18,19), resulting in high radiation exposures.…”

Section: Discussionmentioning

confidence: 99%

“…In 2 studies, response to antiangiogenic therapy was successfully detected using 99m Tc-hydrazinonicotinamide-VEGF and 89 Zr-ranibizumab (17,18). However, because of the long biologic half-life of VEGF, labeling of VEGF or VEGF-targeting molecules with long-lived iso- topes such as 89 Zr or 111 In is needed (18,19), resulting in high radiation exposures. Using RGD (asparagine-glycineaspartic acid) peptide-based tracers, several studies also successfully evaluated treatment response to antiangiogenic therapy (20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

^99mTc-Labeled Tricarbonyl His-CNA35 as an Imaging Agent for the Detection of Tumor Vasculature

et al. 2012

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Given the importance of angiogenesis for a tumor's survival and growth, several therapeutic strategies rely on the selective inhibition of angiogenesis and the destruction of existing tumor vasculature. These strategies raise the need for a noninvasive tool to evaluate tumor vasculature. We describe the radiosynthesis and evaluation of an imaging tracer that specifically binds tumor subendothelial collagen and thereby images tumor vasculature. Methods: 99m Tc-tricarbonyl was prepared and labeled with His-collagen-binding adhesion protein 35 (CNA35). After in vitro specificity testing, in vivo biodistribution and dosimetric studies were performed in healthy nude mice via planar imaging. 99m Tc-(CO) 3 His-CNA35 was evaluated for in vivo imaging of tumor vasculature in a HT29 colorectal carcinoma xenograft. Results: The labeling procedure yielded a compound with 95%-99% radiochemical purity and good in vitro stability. An in vitro binding test confirmed specificity and functionality. 99m Tc-(CO) 3 His-CNA35 rapidly cleared from the blood and predominantly accumulated in the kidneys and liver. The effective dose for a proposed single injection of 500 MBq of 99m Tc-(CO) 3 His-CNA35 is 3.70 mSv per organ or 2.01 mSv/g of tissue.Tumors were successfully visualized, and uptake correlated with ex vivo immunohistochemical staining of tumor vasculature. Conclusion: 99m Tc-(CO) 3 His-CNA35 may be a useful radioligand for the in vivo detection of tumor vasculature through subendothelial collagen binding. A noninvasive method of imaging tumor vasculature that could provide a reliable assessment of tumor vasculature would allow evaluation of the effectiveness of commonly used antiangiogenic therapies and determination of their optimal dosing and scheduling. As a tumor mass grows beyond the support capacity of the vasculature it relies on, the need for new blood vessels arises. The formation of new blood vessels is achieved through angiogenesis, a multistep process that relies on the tumor-driven production of proangiogenic factors. These resulting new blood vessels, however, are structurally and functionally deficient when compared with normal ones. They are disorganized, tortuous, and leaky, leading to heterogeneous blood flow, hypoxia, acidosis, and elevated interstitial fluid pressure, with a disturbed tumor microenvironment as a result (1). Nevertheless, this neovascularization allows the tumor to grow and plays an important role in tumor invasiveness and metastasis. Given the importance of angiogenesis, several therapeutic strategies rely on the selective inhibition of angiogenesis and destruction of tumor vasculature. In several types of cancer, antiangiogenic therapy alone or in combination with standard chemotherapeutic strategies has led to an improvement of survival (2,3). As the importance of these therapies increases, noninvasive methods are needed to provide a reliable assessment of tumor vasculature and thus a means for the management and planning of antiangiogenic therapy.A possible mechanism to target tumor vas...

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“…It is already proven with numerous antibodies (39,(70)(71)(72)(73)(74) and other proteins (75,76) through the efforts of groups in The Netherlands where it has been developed in both preclinical and, with good manufacturing practices (GMP) production for tracer production and validation, in clinical settings. Although Zr-89 does have an extraneous high-energy gamma ray (909 keV), the image quality is good and the overall radiation burden is well tolerated (77).…”

Section: The Advent Of Zirconium-89mentioning

confidence: 99%

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

Williams¹

2012

AAPS J

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Abstract. Molecular imaging techniques for protein therapeutics rely on reporter labels, especially radionuclides or sometimes near-infrared fluorescent moieties, which must be introduced with minimal perturbation of the protein's function in vivo and are detected non-invasively during whole-body imaging. PET is the most sensitive whole-body imaging technique available, making it possible to perform biodistribution studies in humans with as little as 1 mg of injected antibody carrying 1 mCi (37 MBq) of zirconium-89 radiolabel. Different labeling chemistries facilitate a variety of optical and radionuclide methods that offer complementary information from microscopy and autoradiography and offer some trade-offs in whole-body imaging between cost and logistic difficulty and image quality and sensitivity (how much protein needs to be injected). Interpretation of tissue uptake requires consideration of label that has been catabolized and possibly residualized. Image contrast depends as much on background signal as it does on tissue uptake, and so the choice of injected dose and scan timing guides the selection of a suitable label and helps to optimize image quality. Although only recently developed, zirconium-89 PET techniques allow for the most quantitative tomographic imaging at millimeter resolution in small animals and they translate very well into clinical use as exemplified by studies of radiolabeled antibodies, including trastuzumab in breast cancer patients, in The Netherlands.

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VEGF-PET Imaging Is a Noninvasive Biomarker Showing Differential Changes in the Tumor during Sunitinib Treatment

Cited by 103 publications

References 35 publications

⁸⁹Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

⁸⁹Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

^99mTc-Labeled Tricarbonyl His-CNA35 as an Imaging Agent for the Detection of Tumor Vasculature

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

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VEGF-PET Imaging Is a Noninvasive Biomarker Showing Differential Changes in the Tumor during Sunitinib Treatment

Cited by 103 publications

References 35 publications

89Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

89Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

99mTc-Labeled Tricarbonyl His-CNA35 as an Imaging Agent for the Detection of Tumor Vasculature

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

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Product

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⁸⁹Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

⁸⁹Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

^99mTc-Labeled Tricarbonyl His-CNA35 as an Imaging Agent for the Detection of Tumor Vasculature