Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma

The introduction of targeted therapy represents a major advance in the treatment of tumor progression. Targeted agents are a novel therapeutic approach developed to disrupt different cellular signaling pathways. The tyrosine kinase inhibitor sunitinib specifically blocks multiple tyrosine kinase receptors that are involved in the progression of many tumors. Sunitinib is the current standard of care in first-line treatment of advanced renal cell carcinoma, and it is approved in imatinib-intolerant and imatinib-refractory gastrointestinal stromal tumors. However, it is increasingly evident that sunitinib may display collateral effects on other proteins beyond its main target receptors, eliciting undesirable and unexpected adverse events. A better understanding of the molecular mechanisms underlying these undesirable sunitinib-associated side effects will help physicians to maximize efficacy of sunitinib and minimize adverse events. Here, we focus on new insights into molecular mechanisms that may mediate sunitinib-associated adverse events. Mol Cancer Ther; 10(12); 2215-23. Ó2011 AACR.

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“…50 represents the concentration of a drug that is required to achieve 50% inhibition of the enzyme in a biochemical assay.…”

Section: Disclosure Of Potential Conflicts Of Interestmentioning

confidence: 99%

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

Aparicio-Gallego

Blanco

Figueroa

et al. 2011

Molecular Cancer Therapeutics

106

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“…The purpose of the present study was to longitudinally assess the effects of repeated administration of sunitinib, an antiangiogenic receptor tyrosine kinase inhibitor (25)(26)(27), on the uptake of 18 F-fluciclatide in glioblastoma xenograft tumor-bearing mice.…”

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confidence: 99%

Monitoring Tumor Response to Antiangiogenic Sunitinib Therapy with ¹⁸F-Fluciclatide, an ¹⁸F-Labeled α_Vβ₃-Integrin and α_Vβ₅-Integrin Imaging Agent

Battle¹,

Goggi²,

Allen³

et al. 2011

J Nucl Med

108

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Arginine-glycine-aspartate (RGD)-binding a V b 3 -integrin and a V b 5 -integrin play key roles in tumor angiogenesis. We examined an 18 F-labeled small peptide (fluciclatide [United States Adopted Name (ASAN)-approved, International Nonproprietary Name (INN)-proposed name], previously referred to as AH111585) containing an RGD sequence. Fluciclatide binds with a high (nM) affinity to a V b 3 -integrin and a V b 5 -integrin, which are highly expressed on tumors and the tumor neovasculature. In this study, 18 F-fluciclatide was used to examine the response of human glioblastoma xenografts to treatment with the antiangiogenic agent sunitinib. Methods: U87-MG tumor uptake of 18 F-fluciclatide was determined by small-animal PET after longitudinal administration of the antiangiogenic agent sunitinib (a 2-wk dosing regimen). Tumor sizes were measured throughout the study, and tumor volumes were calculated. Tumor microvessel density (MVD) after therapy was also analyzed. Results: Dynamic small-animal PET of 18 F-fluciclatide uptake after administration of the clinically relevant antiangiogenic agent sunitinib revealed a reduction in the tumor uptake of 18 F-fluciclatide compared with that in vehicle-treated controls over the 2-wk dosing regimen. Skeletal muscle, used as a reference tissue, showed equivalent 18 F-fluciclatide uptake in both therapy and control groups. A reduction in tumor MVD was also observed after treatment with the antiangiogenic agent. No significant changes in tumor volume were observed in the 2 groups. Conclusion: The data demonstrated that 18 F-fluciclatide detected changes in tumor uptake after acute antiangiogenic therapy markedly earlier than any significant volumetric changes were observable. These results suggest that this imaging agent may provide clinically important information for guiding patient care and monitoring the response to antiangiogenic therapy. Int egrins are a family of cell adhesion molecules consisting of 2 noncovalently bound transmembrane subunits, a and b, that form heterodimers with distinct adhesive capabilities (1). In mammals, 18 a and 8 b subunits assemble into 24 different receptors. Integrins play important roles in several pathologic processes, such as inflammation, fibrosis, tumor metastasis, and angiogenesis (2,3).Angiogenesis, the process of forming new blood vessels from existing vessels (4), is central to normal biologic processes, such as embryogenesis, tissue remodeling, inflammation, and wound healing, and is present in numerous disease states, including rheumatoid arthritis, psoriasis, restenosis, diabetic retinopathy, and tumor growth (5-7). The interest in angiogenesis research has been fueled by the potential to develop antiangiogenic drugs as novel therapeutic agents for targeting tumors and several nononcologic diseases. a V b 3 -integrin and a V b 5 -integrin act as receptors for a variety of proteins expressing the exposed arginine-glycineaspartate (RGD) tripeptide sequence, such as vitronectin, fibronectin, fibrinogen, laminin, collagen, Von Will...

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“…Therefore, the group sizes in the present study are likely adequate for assessing reproducibility. In addition, U87MG subcutaneous xenografts of the size used in the present study are relatively homogenous histologically, are well vascularized, and exhibit relatively modest necrosis (35,36). Future studies are needed to assess the reproducibility of total cholineto-water ratios in xenografts of other tumor cell lines that may exhibit more necrosis and/or other tissue heterogeneities than U87MG tumors in the linear growth phase.…”

Section: Discussionmentioning

confidence: 93%

Reproducibility of total choline/water ratios in mouse U87MG xenograft tumors by ¹H‐MRS

Zhu

Fischl

Trowbridge

et al. 2012

Magnetic Resonance Imaging

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Purpose: To evaluate the reproducibility of the measurement of the total choline-to-water ratio, and the effect of repositioning the subject between scans, using 1 H-magnetic resonance spectroscopy in a mouse U87MG xenograft model. Materials and Methods:In vivo single-voxel MR spectra at 7T from xenograft tumors were obtained using both a water-suppressed and a nonwater-suppressed pointresolved spectroscopy (PRESS) sequence. Reproducibility of the total choline/water ratio was evaluated under the conditions of immediate rescan with no change in position of the animal or voxel, immediate reposition, and reposition after 1 or 7 days.Results: Total choline-to-water ratios in U87MG tumor xenografts averaged %0.018 across all of the groups. The average percent difference between the two scans in each condition was always less than %3.0%, and the coefficient of variation was always less than %12%. Bias was unrelated to the testing condition and relatively negligible in magnitude (<3%). Due to heteroscedasticity in the ratios, the limits of agreement were calculated after log transformation of the data and ranged from %12% when animals were maintained in the same position and immediately rescanned to %52% when the two scans were 7 days apart. Conclusion:The total choline-to-water ratio provides a reproducible measure of choline-containing metabolites in subcutaneous U87MG xenograft tumors in mice.

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Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma

Cited by 149 publications

References 33 publications

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

Monitoring Tumor Response to Antiangiogenic Sunitinib Therapy with ¹⁸F-Fluciclatide, an ¹⁸F-Labeled α_Vβ₃-Integrin and α_Vβ₅-Integrin Imaging Agent

Reproducibility of total choline/water ratios in mouse U87MG xenograft tumors by ¹H‐MRS

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Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma

Cited by 149 publications

References 33 publications

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

Monitoring Tumor Response to Antiangiogenic Sunitinib Therapy with 18F-Fluciclatide, an 18F-Labeled αVβ3-Integrin and αVβ5-Integrin Imaging Agent

Reproducibility of total choline/water ratios in mouse U87MG xenograft tumors by 1H‐MRS

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Monitoring Tumor Response to Antiangiogenic Sunitinib Therapy with ¹⁸F-Fluciclatide, an ¹⁸F-Labeled α_Vβ₃-Integrin and α_Vβ₅-Integrin Imaging Agent

Reproducibility of total choline/water ratios in mouse U87MG xenograft tumors by ¹H‐MRS