Patterns of αvβ3 Expression in Primary and Metastatic Human Breast Cancer as Shown by 18F-Galacto-RGD PET

Beer, Ambros J.; Niemeyer, Markus; Carlsen, Janette; Sarbia, Mario; Nährig, Jörg; Watzlowik, Petra; Wester, Hans‐Jürgen; Harbeck, Nadia; Schwaiger, Markus

doi:10.2967/jnumed.107.045526

Cited by 161 publications

(128 citation statements)

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“…Previous studies demonstrated the utility of RGD-based radioligands for the noninvasive assessment of tumor vascularity and for assessment of the efficacy of single-dose antitumor therapy (17,19,21,32,33). However, relatively little attention has been focused on the ability of these radiotracers to monitor the response of tumors to therapies that target the vasculature longitudinally.…”

Section: Discussionmentioning

confidence: 99%

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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

Battle¹,

Goggi²,

Allen³

et al. 2011

J Nucl Med

107

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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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Section: Discussionmentioning

confidence: 99%

“…Others have shown that RGD peptides can serve as targeting biomolecules for carrying a range of radionuclides (e.g., 18 F, 99m Tc, and 64 Cu) to RGD-binding integrins (such as a V b 3 -integrin) that are upregulated in cancer (16)(17)(18)(19)(20)(21). The PET tracer 18 F-fluciclatide is an 18 F-radiolabeled small peptide containing the RGD sequence.…”

mentioning

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

107

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“…However, in human cases, 58% of pancreatic carcinomas showed positive staining and the frequency was significantly higher in primary tumors with lymph node metastasis (5). Recently, integrin α V β 3 was also studied as a target molecule for imaging diagnosis in mammary carcinoma (23), and this BOP-induced hamster model may aid in the pre-clinical screening of integrin α V β 3 and other molecular-targeted probes and/or medicines. kallikrein 7 is a chymotrypsin-like serine protease, originally purified from human skin, which is specifically expressed in keratinizing squamous epithelia (24), and is involved in cell invasion by cleavage of the extracellular domain of adhesion molecules, such as E-cadherin.…”

Section: Discussionmentioning

confidence: 99%

Novel immunohistochemical marker, integrin αVβ3, for BOP-induced early lesions in hamster pancreatic ductal carcinogenesis

Kitahashi¹,

Yoshimoto²,

Imai³

2011

Oncology Letters

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Abstract. N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic ductal carcinomas and early ductal lesions in Syrian hamsters have been reported to show histopathological resemblance to those in humans. Specific protein expression profiles have been found in human carcinomas, but a detailed molecular approach regarding the dissection of BOP-induced pancreatic carcinogenesis has yet to be determined. The present immunohistochemical study of early and advanced hamster lesions focused on five proteins reported to be overexpressed in human patients, to clarify interspecies phenotype similarity. Integrin α V β 3 was found to be overexpressed in the epithelial cells of 13 of 14 atypical hyperplasias and 6 of 6 adenocarcinomas. This overexpression was more frequent than in the remaining four proteins. However, immunoreactivity for α-enolase in epithelial cells and for kallikrein 7 and galectin-1/3 in both epithelial and stromal cells was also evident at various frequencies. Thus, similarities of tumor-associated protein expression between human and hamster pancreatic ductal lesions were confirmed, and integrin α V β 3 was identified as a potentially useful immunohistochemical marker for early lesions in hamsters. IntroductionPancreatic cancer is among the 10 most frequently occurring type of cancer. In Japan, pancreatic cancer is ranked fifth as a cause of cancer-related mortality. The mortality rate associated with this type of cancer also ranks high in other developed countries (1,2). The detection of pancreatic cancer at early operable stages is difficult, combined with the lack of curative treatment approaches other than complete surgical removal; thus, 5-year relative survival rates are less than 6% (3,4). Therefore, it is crucial to develop new diagnostic and preventive methods to complement any improvements in therapeutic methods for the reduction of mortality and morbidity, and to explore specific proteins overexpressed in early lesions during pancreatic carcinogenesis.Specific protein expression profiles revealed by immunohistochemical and proteomic analyses are currently employed in the application of individualized therapy of advanced human pancreatic carcinomas (5-8). Consequently, a number of candidates of prognostic and/or predictive markers have been established (9,10). Examples expressed in early lesions show potential for the development of novel diagnostic and preventive strategies.Chemically induced and transgenic animal models for pancreatic ductal carcinogenesis have been the target of investigation of the impact of environmental factors and the role of specific gene alterations in multistage carcinogenesis (11)(12)(13)(14)(15). Among the models established thus far, the N-nitrosobis(2-oxopropyl)amine (BOP)-induced hamster model is the first and most widely utilized based on similarities to human diseases in the morphological characteristics of, not only advanced cancers, but also early ductal lesions, as well as pivotal genetic alterations, including K-ras and p16 (13,(16)(17)(18). In particular...

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“…a v b 3 integrin is a protein expressed on activated endothelial cells during angiogenesis. It is involved in tumor growth, local invasiveness, and metastatic spread [105]. Promising PET tracers have been developed to image this protein: 18 F-galacto-RGD is the most studied one [105][106][107].…”

Section: Changes In Tumor Blood Flow and Angiogenesismentioning

confidence: 99%

Role of Positron Emission Tomography for the Monitoring of Response to Therapy in Breast Cancer

et al. 2015

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This review considers the potential utility of positron emission tomography (PET) tracers in the setting of response monitoring in breast cancer, with a special emphasis on glucose metabolic changes assessed with 18 F-fluorodeoxyglucose (FDG). In the neoadjuvant setting of breast cancer, the metabolic response can predict the final complete pathologic response after the first cycles of chemotherapy. Because tumor metabolic behavior highly depends on cancer subtype, studies are ongoing to define the optimal metabolic criteria of tumor response in each subtype.The recent multicentric randomized AVATAXHER trial has suggested, in the human epidermal growth factor 2-positive subtype, a clinical benefit of early tailoring the neoadjuvant treatment in women with poor metabolic response after the first course of treatment. In the bone-dominant metastatic setting, there is increasing clinical evidence that FDG-PET/computed tomography (CT) is the most accurate imaging modality for assessment of the tumor response to treatment when both metabolic information and morphologic information are considered. Nevertheless, there is a need to define standardized metabolic criteria of response, including the heterogeneity of response among metastases, and to evaluate the costs and health outcome of FDG-PET/CT compared with conventional imaging. New non-FDG radiotracers highlighting specific molecular hallmarks of breast cancer cells have recently emerged in preclinical and clinical studies. These biomarkers can take into account the heterogeneity of tumor biology in metastatic lesions. They may provide valuable clinical information for physicians to select and monitor the effectiveness of novel therapeutics targeting the same molecular pathways of breast tumor. The Oncologist 2015;20:94-104 Implications for Practice:18 F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is a molecular imaging exam. It can monitor breast cancer response to therapy earlier than the tumor shrinking observed with conventional imaging. This review focuses on the advantages and limits of FDG-PET for early determination of response, both in the neoadjuvant and metastatic settings. It discusses the different PET timing and metabolic criteria to define response that have been evaluated in previous studies. The development of new radiotracers of specific molecular pathways of breast cancer cells is also a challenging and promising research area to monitor the effectiveness of the new target treatments emerging in breast cancer.

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Patterns of α_vβ₃ Expression in Primary and Metastatic Human Breast Cancer as Shown by ¹⁸F-Galacto-RGD PET

Cited by 161 publications

References 13 publications

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

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

Novel immunohistochemical marker, integrin αVβ3, for BOP-induced early lesions in hamster pancreatic ductal carcinogenesis

Role of Positron Emission Tomography for the Monitoring of Response to Therapy in Breast Cancer

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Patterns of αvβ3 Expression in Primary and Metastatic Human Breast Cancer as Shown by 18F-Galacto-RGD PET

Cited by 161 publications

References 13 publications

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

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

Novel immunohistochemical marker, integrin αVβ3, for BOP-induced early lesions in hamster pancreatic ductal carcinogenesis

Role of Positron Emission Tomography for the Monitoring of Response to Therapy in Breast Cancer

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Patterns of α_vβ₃ Expression in Primary and Metastatic Human Breast Cancer as Shown by ¹⁸F-Galacto-RGD PET

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

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