Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR.
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ABSTRACT:
SUBMITTER: Behr SC
PROVIDER: S-EPMC6238742 | biostudies-other | 2018 Nov
REPOSITORIES: biostudies-other
Publications
Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR.
Behr Spencer C SC Villanueva-Meyer Javier E JE Li Yan Y Wang Yung-Hua YH Wei Junnian J Moroz Anna A Lee Julia Kl JK Hsiao Jeffrey C JC Gao Kenneth T KT Ma Wendy W Cha Soonmee S Wilson David M DM Seo Youngho Y Nelson Sarah J SJ Chang Susan M SM Evans Michael J MJ
JCI insight 20181102 21
Noninvasive tools that target tumor cells could improve the management of glioma. Cancer generally has a high demand for Fe(III), an essential nutrient for a variety of biochemical processes. We tested whether 68Ga-citrate, an Fe(III) biomimetic that binds to apo-transferrin in blood, detects glioma in preclinical models and patients using hybrid PET/MRI. Mouse PET/CT studies showed that 68Ga-citrate accumulates in subcutaneous U87MG xenografts in a transferrin receptor-dependent fashion within ...[more]
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Project description:AbstractHigh-grade gliomas are among the deadliest of all cancers despite standard treatments, and new therapeutic strategies are needed to improve patient outcome. Targeting the altered metabolic state of tumors with traditional chemotherapeutic agents has a history of success, and our increased understanding of cellular metabolism in the past 2 decades has reinvigorated the concept of novel metabolic therapies in brain tumors. Here we highlight metabolic alterations in advanced gliomas and their translation into clinical trials using both novel agents and already established drugs repurposed for cancer treatment in an effort to improve outcome for these deadly diseases.
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Project description:PurposeGDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. Because these two targets alter tumor vascularity and metabolism, respectively, we hypothesized multiparametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas.Patients and methodsMultiparametric advanced MR-PET imaging was performed to evaluate physiologic response in a first-in-man, multicenter, phase I, dose-escalation study of GDC-0084 (NCT01547546) in 47 patients with recurrent malignant glioma.ResultsMeasured maximum concentration (C max) was associated with a decrease in enhancing tumor volume (P = 0.0287) and an increase in fractional anisotropy (FA; P = 0.0418). Posttreatment tumor volume, 18F-FDG uptake, Ktrans, and relative cerebral blood volume (rCBV) were all correlated with C max. A linear combination of change in 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp, and rCBV was able to estimate both C max (R2 = 0.4113; P < 0.0001) and drug exposure (AUC; R2 = 0.3481; P < 0.0001). Using this composite multiparametric MR-PET imaging response biomarker to predict PK, patients with an estimated C max > 0.1 μmol/L and AUC > 1.25 μmol/L*hour demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure (P = 0.0039 and P = 0.0296, respectively).ConclusionsResults from this study suggest composite biomarkers created from multiparametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies.
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Project description:BACKGROUND:Prosthetic joint infections may lead to failures of total joint arthroplasty. Radionuclide imaging can play a diagnostic role in identifying such infections, which require two-stage exchange arthroplasty (instead of simple revision surgery performed in non-infected cases). Although 18F-FDG PET/CT has emerged as a novel diagnostic tool in this setting, the clinical usefulness of 68Ga-citrate PET/CT has not been previously investigated. This single-center prospective study was designed to address this issue. METHODS:Between January 2016 and October 2017, we examined 34 patients with clinically proven or suspected prosthetic hip/knee joint infections scheduled to undergo surgery. All patients underwent 68Ga-citrate PET/CT scans and sequential 18F-FDG PET/CT imaging for comparative purposes. Intraoperative findings and the results of microbiological analyses of surgical specimens served as gold standard. The diagnostic results were examined according to (1) image interpretation based on radiotracer uptake patterns and (2) quantitative analysis using volumes of interest (VOIs) to calculate standard uptake values (SUVs) and metabolic volumes (MVs). RESULTS:A total of 26 (76%) patients were diagnosed as having infections. Based on radiotracer uptake pattern criteria, the sensitivity, specificity, and accuracy of 68Ga-citrate PET/CT and 18F-FDG PET/CT were 92%, 88%, and 91% and 100%, 38%, and 85%, respectively. MV was significantly higher in the infected group when 68Ga-citrate PET/CT was used (422.45 vs. 303.65 cm3, p?=?0.027), whereas no significant differences were observed on 18F-FDG PET/CT. According to receiver operating characteristic (ROC) curve analysis, a cut-off value of 370.86 for MV resulted in a sensitivity of 61.5% and a specificity of 87.5% (area under curve: 0.75, 95% confidence interval: 0.57-0.88, p?=?0.035). CONCLUSIONS:Subject to future confirmation, our data provide preliminary evidence that 68Ga-citrate PET/CT may have a complimentary role to 18F-FDG PET/CT in detecting prosthetic joint infections, being characterized by a higher specificity and the possibility to discriminate between an infectious condition and sterile inflammation. TRIAL REGISTRATION:This prospective study was registered at clinicaltrials.gov (registration number: NCT02855190 ).
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Project description:BackgroundHigh-grade glioma (HGG) remains a recalcitrant clinical problem despite many decades of research. A major challenge in improving prognosis is the inability of current therapeutic strategies to address a clinically significant burden of infiltrating tumor cells that extend beyond the margins of the primary tumor mass. Such cells cannot be surgically excised nor efficiently targeted by radiation therapy. Therapeutic targeting of this tumor cell population is significantly hampered by the presence of an intact blood-brain barrier (BBB). In this study, we performed a preclinical investigation of the efficiency of MR-guided Focused Ultrasound (FUS) to temporarily disrupt the BBB to allow selective delivery of a tumor-targeting antibody to infiltrating tumor.MethodsStructural MRI, dynamic-contrast enhancement MRI, and histology were used to fully characterize the MR-enhancing properties of a patient-derived xenograft (PDX) orthotopic mouse model of HGG and to develop a reproducible, robust model of nonenhancing HGG. PET-CT imaging techniques were then used to evaluate the efficacy of FUS to increase 89Zr-radiolabeled antibody concentration in nonenhancing HGG regions and adjacent non-targeted tumor tissue.ResultsThe PDX mouse model of HGG has a significant tumor burden lying behind an intact BBB. Increased antibody uptake in nonenhancing tumor regions is directly proportional to the FUS-targeted volume. FUS locally increased antibody uptake in FUS-targeted regions of the tumor with an intact BBB, while leaving untargeted regions unaffected.ConclusionsFUS exposure successfully allowed temporary BBB disruption, localized to specifically targeted, nonenhancing, infiltrating tumor regions and delivery of a systemically administered antibody was significantly increased.
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Project description:Lower-grade glioma (LGG) is characterized by genetic and transcriptional heterogeneity, and a dismal prognosis. Iron metabolism is considered central for glioma tumorigenesis, tumor progression and tumor microenvironment, although key iron metabolism-related genes are unclear. Here we developed and validated an iron metabolism-related gene signature LGG prognosis. RNA-sequence and clinicopathological data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) were downloaded. Prognostic iron metabolism-related genes were screened and used to construct a risk-score model via differential gene expression analysis, univariate Cox analysis, and the Least Absolute Shrinkage and Selection Operator (LASSO)-regression algorithm. All LGG patients were stratified into high- and low-risk groups, based on the risk score. The prognostic significance of the risk-score model in the TCGA and CGGA cohorts was evaluated with Kaplan-Meier (KM) survival and receiver operating characteristic (ROC) curve analysis. Risk- score distributions in subgroups were stratified by age, gender, the World Health Organization (WHO) grade, isocitrate dehydrogenase 1 (IDH1) mutation status, the O6-methylguanine-DNA methyl-transferase (MGMT) promoter-methylation status, and the 1p/19q co-deletion status. Furthermore, a nomogram model with a risk score was developed, and its predictive performance was validated with the TCGA and CGGA cohorts. Additionally, the gene set enrichment analysis (GSEA) identified signaling pathways and pathological processes enriched in the high-risk group. Finally, immune infiltration and immune checkpoint analysis were utilized to investigate the tumor microenvironment characteristics related to the risk score. We identified a prognostic 15-gene iron metabolism-related signature and constructed a risk-score model. High risk scores were associated with an age of > 40, wild-type IDH1, a WHO grade of III, an unmethylated MGMT promoter, and 1p/19q non-codeletion. ROC analysis indicated that the risk-score model accurately predicted 1-, 3-, and 5-year overall survival rates of LGG patients in the both TCGA and CGGA cohorts. KM analysis showed that the high-risk group had a much lower overall survival than the low-risk group (P < 0.0001). The nomogram model showed a strong ability to predict the overall survival of LGG patients in the TCGA and CGGA cohorts. GSEA analysis indicated that inflammatory responses, tumor-associated pathways, and pathological processes were enriched in high-risk group. Moreover, a high risk score correlated with the infiltration immune cells (dendritic cells, macrophages, CD4+ T cells, and B cells) and expression of immune checkpoint (PD1, PDL1, TIM3, and CD48). Our prognostic model was based on iron metabolism-related genes in LGG, can potentially aid in LGG prognosis, and provides potential targets against gliomas.
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Project description:Pediatric high-grade glioma (HGG, WHO Grade III and IV) is a devastating brain tumor with a median survival of less than two years. PDGFRA is frequently mutated/ amplified in pediatric HGG, but the significance of this finding has not been fully characterized. We hypothesize that alterations of PDGFRA will promote distinct prognostic and treatment implications in pediatric HGG. In order to characterize the impact of PDGFR pathway alterations, we integrated genomic data from pediatric HGG patients (n=290) from multiple pediatric datasets and sequencing platforms. Integration of multiple human datasets showed that PDGFRA mutation, but not amplification, was associated with older age in pediatric HGG (P= <0.0001). In multivariate analysis, PDGFRA mutation was correlated with worse prognosis (P = 0.026), while PDGFRA amplification was not (P = 0.11). By Kaplan-Meier analysis, non-brainstem HGG with PDGFRA amplification carried a worse prognosis than non-brainstem HGG without PDGFRA amplification (P = 0.021). There were no pediatric patients with PDGFRA-amplified HGG that survived longer than two years. Additionally, we performed paired molecular profiling (germline / tumor / primary cell culture) and targeting of an infant thalamic HGG with amplification and outlier increased expression of PDGFRA. Dasatinib inhibited proliferation most effectively. In summary, integration of the largest genomic dataset of pediatric HGG to date, allowed us to highlight that PDGFRA mutation is found in older pediatric patients and that PDGFRA amplification is prognostic in non-brainstem HGG. Future precision-medicine based clinical trials for pediatric patients with PDGFRA-altered HGG should consider the optimized delivery of dasatinib.
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Project description:High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG). An important mechanism that mediates this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic adhesion molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway. However, the necessity of NLGN3 for glioma growth, the proteolytic mechanism of NLGN3 secretion, and the further molecular consequences of NLGN3 secretion in glioma cells remain unknown. Here we show that HGG growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of paediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent the release of NLGN3 into the tumour microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting NLGN3 secretion, which could prove transformative for HGG therapy.
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Project description:Recent exciting work partly through The Cancer Genome Atlas has implicated epigenetic mechanisms including histone modifications in the development of both pediatric and adult high-grade glioma (HGG). Histone lysine methylation has emerged as an important player in regulating gene expression and chromatin function. Lysine (K) 27 (K27) is a critical residue in all seven histone 3 variants and the subject of posttranslational histone modifications, as it can be both methylated and acetylated. In pediatric HGG, two critical single-point mutations occur in the H3F3A gene encoding the regulatory histone variant H3.3. These mutations occur at lysine (K) 27 (K27M) and glycine (G) 34 (G34R/V), both of which are involved with key regulatory posttranscriptional modifications. Therefore, these mutations effect gene expression, cell differentiation, and telomere maintenance. In recent years, alterations in histone acetylation have provided novel opportunities to explore new pharmacological targeting, with histone deacetylase (HDAC) overexpression reported in high-grade, late-stage proliferative tumors. HDAC inhibitors have shown promising therapeutic potential in many malignancies. This review focuses on the epigenetic mechanisms propagating pediatric and adult HGGs, as well as summarizing the current advances in clinical trials using HDAC inhibitors.
| S-EPMC5368219 | biostudies-other
Project description:BackgroundArterial spin labeling is an MR imaging technique that measures cerebral blood flow (CBF) non-invasively. The aim of the study is to assess the diagnostic performance of arterial spin labeling (ASL) MR imaging for differentiation between high-grade glioma and low-grade glioma.MethodsCochrane Library, Embase, Medline, and Web of Science Core Collection were searched. Study selection ended November 2017. This study was prospectively registered in PROSPERO (CRD42017080885). Two authors screened all titles and abstracts for possible inclusion. Data were extracted independently by 2 authors. Bivariate random effects meta-analysis was used to describe summary receiver operating characteristics. Trial sequential analysis (TSA) was performed.ResultsIn total, 15 studies with 505 patients were included. The diagnostic performance of ASL CBF for glioma grading was 0.90 with summary sensitivity 0.89 (0.79-0.90) and specificity 0.80 (0.72-0.89). The diagnostic performance was similar between pulsed ASL (AUC 0.90) with a sensitivity 0.85 (0.71-0.91) and specificity 0.83 (0.69-0.92) and pseudocontinuous ASL (AUC 0.88) with a sensitivity 0.86 (0.79-0.91) and specificity 0.80 (0.65-0.87). In astrocytomas, the diagnostic performance was 0.89 with sensitivity 0.86 (0.79 to 0.91) and specificity 0.79 (0.63 to 0.89). Sensitivity analysis confirmed the robustness of the findings. TSA revealed that the meta-analysis was adequately powered.ConclusionArterial spin labeling MR imaging had an excellent diagnostic accuracy for differentiation between high-grade and low-grade glioma. Given its low cost, non-invasiveness, and efficacy, ASL MR imaging should be considered for implementation in the routine workup of patients with glioma.
| S-EPMC6176798 | biostudies-literature
Project description:UnlabelledThis work was designed to study the safety, biodistribution, and radiation dosimetry of a gastrin-releasing peptide receptor (GRPR)-targeting, (68)Ga-labeled bombesin (BBN) peptide derivative PET tracer, NOTA-Aca-BBN(7-14) (denoted as (68)Ga-BBN) in healthy volunteers and to assess the level of receptor expression in glioma patients.MethodsFour healthy volunteers (2 male and 2 female) underwent whole-body PET/CT at multiple time points after a bolus injection of (68)Ga-BBN (111 ± 148 MBq). Regions of interest were drawn manually over major organs, and time-activity curves were obtained. Dosimetry was calculated using the OLINDA/EXM software. Twelve patients with glioma diagnosed by contrast-enhanced MRI underwent PET/CT at 30-45 min after (68)Ga-BBN injection. Within 1 wk afterward, the tumor was surgically removed and immunohistochemical staining of tumor samples against GRPR was performed and correlated with the PET/CT results.Results(68)Ga-BBN was well tolerated in all healthy volunteers, with no adverse symptoms being noticed or reported. (68)Ga-BBN cleared rapidly from the circulation and was excreted mainly through the kidneys and urinary tract. The total effective dose equivalent and effective dose were 0.0335 ± 0.0079 and 0.0276 ± 0.0066 mSv/MBq, respectively. In glioma patients, all MRI-identified lesions showed high signal intensity on (68)Ga-BBN PET/CT. SUVmax and SUVmean were 2.08 ± 0.58 and 1.32 ± 0.37, respectively. With normal brain tissue as background, tumor-to-background ratios were 24.0 ± 8.85 and 13.4 ± 4.54 based on SUVmax and SUVmean, respectively. The immunohistochemical staining confirmed a positive correlation between SUV and GRPR expression level (r(2) = 0.71, P < 0.001).Conclusion(68)Ga-BBN is a PET tracer with favorable pharmacokinetics and a favorable dosimetry profile. It has the potential to evaluate GRPR expression in glioma patients and guide GRPR-targeted therapy of glioma.
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