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

Abstract

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...

Stratification of 18F-Labeled PET Imaging Agents for the Assessment of Antiangiogenic Therapy Responses in Tumors

“…39-Deoxy-39- 18 F-fluorothymidine ( 18 F-FLT) correlates with thymidine kinase 1 activity expressed during the DNA synthesis phase of the cell cycle, thus providing information on the proliferative potential of the tumor tissue (12,13). However, 18 F-FLT has proven to be an ineffective measure of therapy responses in some tumor types treated with antiangiogenic agents (14).…”

“…In this study, we compared the utility of the molecular imaging agents 18 F-FDG, 18 F-FLT, and 2-18 F-fluoroethyl-triazolyl conjugated c(RGDyK) peptide ( 18 F-FtRGD) for assessment of the early response to therapy with the multiple receptor tyrosine kinase inhibitor axitinib in rodent models of breast cancer and glioma. Our goal was to determine whether differences in tumor biology can affect patient management and the choice of an agent for the noninvasive monitoring of antiangiogenic treatment efficacy.…”

“…At present, 18 F-FDG PET imaging is used routinely to assess the efficacy of cancer treatments. The glucose analog 18 F-FDG provides a surrogate measure of glucose metabolism in the tumor and surrounding tissue accumulating in proportion to its metabolism (8).…”

“…These integrins act as receptors for proteins expressing the arginineglycine-aspartate (RGD) tripeptide sequence (16,17). Molecular imaging agents based on this RGD tripeptide sequence have been developed in a bid to improve the detection of both tumors and early therapeutic responses (18,19).…”

“…The glucose analog 18 F-FDG provides a surrogate measure of glucose metabolism in the tumor and surrounding tissue accumulating in proportion to its metabolism (8). However, the utility of 18 F-FDG for the assessment of therapy can be complicated by high 18 F-FDG uptake in surrounding tissue or other benign pathologies; therefore, low-grade or small tumors may exhibit little differential 18 F-FDG uptake (9,10).…”