RESUMO
Intratumoral genetic heterogeneity and the role of metabolic reprogramming in renal cell carcinoma (RCC) have been extensively documented. However, the distribution of these metabolic changes within the tissue has not been explored. We report on the first-in-human in vivo non-invasive metabolic interrogation of RCC using hyperpolarized carbon-13 (13C) magnetic resonance imaging (HP-MRI) and describe the validation of in vivo lactate metabolic heterogeneity against multi-regional ex vivo mass spectrometry. HP-MRI provides an in vivo assessment of metabolism and provides a novel opportunity to safely and non-invasively assess cancer heterogeneity.
RESUMO
The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no noninvasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc - maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here, we show that tumor cell retention of a system xc --specific PET radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment. SIGNIFICANCE: [18F]FSPG PET imaging provides a sensitive noninvasive measure of tumor redox status and provides an early marker of tumor response to therapy.See related commentary by Lee et al., p. 701.
Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Cistadenocarcinoma Seroso/patologia , Radioisótopos de Flúor/metabolismo , Glutamatos/metabolismo , Neoplasias Ovarianas/patologia , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/metabolismo , Acetilcisteína/farmacologia , Animais , Apoptose , Proliferação de Células , Cistadenocarcinoma Seroso/diagnóstico por imagem , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Feminino , Sequestradores de Radicais Livres/farmacologia , Humanos , Metabolômica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Oxirredução , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , terc-Butil Hidroperóxido/farmacologiaRESUMO
UNLABELLED: Human epidermal growth factor receptor (HER2)-targeted Affibody molecules radiolabeled with (18)F allow the noninvasive assessment of HER2 status in vivo through PET imaging. Such agents have the potential to improve patient management by selecting individuals for HER2-targeted therapies and allowing therapy monitoring. The aim of this study was to assess different (18)F radiolabeling strategies of the HER2-specific Affibody molecule Z(HER2:2891), preclinically determine the biologic efficacy of the different radiolabel molecules, and select a preferred radiolabeling strategy to progress for automated manufacture. METHODS: Cysteine was added to the C terminus of the Affibody molecule for the coupling of maleimide linkers, and 3 radiolabeling strategies were assessed: silicon-fluoride acceptor approach ((18)F-SiFA), (18)F-AlF-NOTA, and 4-(18)F-fluorobenzaldehyde ((18)F-FBA). The biodistributions of the radiolabeled Affibody molecules were then determined in naïve CD-1 nude mice, and tumor targeting was assessed in CD-1 nude mice bearing high-HER2-expressing NCI-N87 tumors and low-HER2-expressing A431 tumors. The (111)In-ABY-025 compound, which has demonstrable clinical utility, served as a reference tracer. RESULTS: The non-decay-corrected radiochemical yields based on starting (18)F-fluoride using the (18)F-FBA, (18)F-SiFA, and (18)F-AlF-NOTA methods were 13% ± 3% (n = 5), 38% ± 2% (n = 3), and 11% ± 4% (n = 6), respectively. In naïve mice, both the (18)F-AlF-NOTA-Z(HER2:2891) and the (111)In-ABY-025 compounds showed a significant kidney retention (70.3 ± 1.3 and 73.8 ± 3.0 percentage injected dose [%ID], respectively, at 90 min after injection), which was not observed for (18)F-FBA-Z(HER2:2891) or (18)F-SiFA-Z(HER2:2891) (4.8 ± 0.6 and 10.1 ± 0.7 %ID, respectively, at 90 min). The (18)F-SiFA-Z(HER2:2891) conjugate was compromised by increasing bone retention over time (5.3 ± 1.0 %ID/g at 90 min after injection), indicating defluorination. All the radiolabeled Affibody molecules assessed showed significantly higher retention in NCI-N87 tumors than A431 tumors at all time points (P < 0.05), and PET/CT imaging of (18)F-FBA-Z(HER2:2891) in a dual NCI-N87/A431 xenograft model demonstrated high tumor-to-background contrast for NCI-N87 tumors. CONCLUSION: The HER2 Affibody molecule Z(HER2:2891) has been site-selectively radiolabeled by three (18)F conjugation methods. Preliminary biologic data have identified (18)F-FBA-Z(HER2:2891) (also known as GE226) as a favored candidate for further development and radiochemistry automation.