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Tumor volume. Bar graph showing tumor volume calculation of 4T1 tumor-bearing mice over time for control, doxorubicin-treated, and dichloroacetate-treated groups (mean ± SD). Two-way ANOVA Bonferroni post, * p = 0.0002, ** p < 0.0001
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PurposeTriple-negative breast cancer (TNBC) patients have usually poor outcome after chemotherapy and early prediction of therapeutic response would be helpful. [18F]F-FDG-PET/CT acquisitions are often carried out to monitor variation in metabolic activity associated with response to the therapy, despite moderate accuracy and radiation exposure lim...
Contexts in source publication
Context 1
... and width of the tumors were measured using a caliper three times a week starting from baseline up to 26 days and the volumes were calculated using the equation (width 2 × length)/2. Figure S1 in the ESM shows a graphical representation of the experimental setup. Mice were randomly divided into two cohorts of three groups for each MRI and PET imaging experiments. ...
Context 2
... volume reduction in doxorubicin-treated mice compared to control mice was already observed 5 days after treatment (19 days post-implantation, Fig. 1). Differences in tumor volumes between the two groups of mice became more evident and statistically significant after the second doxorubicin dose (292 mm 3 and 188 mm 3 , P = 0.0004; 430 mm 3 and 302 mm 3 , P < 0.0001; 628 mm 3 and 321 mm 3 , P < 0.0001 for control and treated mice, after 21, 24, and 26 days post-tumor implantation, ...
Citations
... Numerous studies show the use of 18 F-FDG-PET for the monitoring of cancer cell response to targeted therapies in the Wilms mouse tumor model [51]. In other studies, we can find a comparison of GlucoCEST MRI and 18 F-FDG-PET to assess the response to chemotherapy and metabolic therapies in breast cancer studies in mice, with the studies confirming that glucoCEST can be a sensitive technique for monitoring metabolic pathways [52]. Also, Kristian et al. presented the use of dynamic 18 F-FDG-PET to study glucose distribution in tissues in order to monitor the effects of therapy. ...
The aim of the study was to investigate the effect of Trastuzumab on the MCF-7 and CRL-2314 breast cancer cell lines. Additionally, an attempt was made to optimize magnetic resonance spectroscopy (MRS) for cell culture studies, with particular emphasis on the impact of treatment with Trastuzumab. The research materials included MCF-7 and CRL-2314 breast cancer cell lines. The study examined the response of these cell lines to treatment with Trastuzumab. The clinical magnetic resonance imaging (MRI) system, OPTIMA MR360 manufactured by GEMS, with a magnetic field induction of 1.5 T, was used. Due to the nature of the tested objects, their size and shape, it was necessary to design and manufacture additional receiving coils. They were used to image the tested cell cultures and record the spectroscopic signal. The spectra obtained by MRS were confirmed by NMR using a 300 MHz NMR Fourier 300 with the TopSpin 3.1 system from Bruker. The designed receiving coils allowed for conducting experiments with the cell lines in a satisfactory manner. These tests would not be possible using factory-delivered coils due to their parameters and the size of the test objects, whose volume did not exceed 1 mL. MRS studies revealed an increase in the metabolite at 1.9 ppm, which indicates the induction of histone acetylation. Changes in histone acetylation play a very important role in both cell development and differentiation processes. The use of Trastuzumab therapy in breast cancer cells increases the levels of acetylated histones. MRS studies and spectra obtained from the 300 MHz NMR system are consistent with the specificity inherent in both systems.
... This is significantly earlier than in a study evaluating treatment response to ICI with 18 F-FDG-PET in a mouse model of hepatocellular carcinoma, with the first significant changes in metabolism observed after fourteen days [33]. While a decrease in glucose metabolism, assessed by CEST-MRI, has also been observed as sign of successful response to chemotherapy [34], the increase in creatine metabolism detected by CEST-MRI appears to be attributable to the pronounced intratumoral T-cell infiltration after ICI therapy, a specific hallmark for successful anticancer immunotherapy [11]. The effects of ICI therapy on amide proton metabolism showed clear differences between the two tumor models: ICI-treated 4T1 tumors demonstrated elevated amide proton metabolism compared to control groups, whereas 67NR tumors showed decreased values after therapy. ...
... Since 4T1 and 67NR tumors differ in their PD-L1 expression [35], these differences might potentially indicate different activation patterns of the intratumoral T-cells; however, further investigation of this hypothesis is needed. Previous CEST-MRI studies were also able to detect changes in individual metabolites after different cancer therapies [34,36,37]. However, these changes of tumor metabolism have mainly been shown after size-reduction of tumors due to cytostatic chemotherapeutics. ...
Background:
With metabolic alterations of the tumor microenvironment (TME) contributing to cancer progression, metastatic spread and response to targeted therapies, non-invasive and repetitive imaging of tumor metabolism is of major importance. The purpose of this study was to investigate whether multiparametric chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI) allows to detect differences in the metabolic profiles of the TME in murine breast cancer models with divergent degrees of malignancy and to assess their response to immunotherapy.
Methods:
Tumor characteristics of highly malignant 4T1 and low malignant 67NR murine breast cancer models were investigated, and their changes during tumor progression and immune checkpoint inhibitor (ICI) treatment were evaluated. For simultaneous analysis of different metabolites, multiparametric CEST-MRI with calculation of asymmetric magnetization transfer ratio (MTRasym) at 1.2 to 2.0 ppm for glucose-weighted, 2.0 ppm for creatine-weighted and 3.2 to 3.6 ppm for amide proton transfer- (APT-) weighted CEST contrast was conducted. Ex vivo validation of MRI results was achieved by 1H nuclear magnetic resonance spectroscopy, matrix-assisted laser desorption/ionization mass spectrometry imaging with laser postionization and immunohistochemistry.
Results:
During tumor progression, the two tumor models showed divergent trends for all examined CEST contrasts: While glucose- and APT-weighted CEST contrast decreased and creatine-weighted CEST contrast increased over time in the 4T1 model, 67NR tumors exhibited increased glucose- and APT-weighted CEST contrast during disease progression, accompanied by decreased creatine-weighted CEST contrast. Already three days after treatment initiation, CEST contrasts captured response to ICI therapy in both tumor models.
Conclusion:
Multiparametric CEST-MRI enables non-invasive assessment of metabolic signatures of the TME, allowing both for estimation of the degree of tumor malignancy and for assessment of early response to immune checkpoint inhibition.
... Tumor lesions have common characteristics among different types of cancer, including genetic mutations, altered metabolism, hypoxia, and extracellular acidosis. Furthermore, treatment in a triple-negative breast cancer murine model with no changes in tumor acidification [44]. ...
The tumor microenvironment acidification confers treatment resistance; therefore, the interference with pH regulating systems is considered a new therapeutic strategy. In this study, two human prostate cancer cell lines, PC3 and LNCaP, have been treated in vitro with proton pump inhibitors (PPIs), namely Lansoprazole, Esomeprazole (V-ATPases-inhibitors), Cariporide, and Amiloride (NHE1-inhibitors). The cell viability and pH were assessed at several drug concentrations either at normoxic or hypoxic conditions. Since Esomeprazole showed the highest toxicity towards the PC3 cancer cells compared to LNCaP ones, athymic nude mice bearing subcutaneous or orthotopic PC3 tumors were treated with Esomeprazole (dose: 2.5 mg/kg body weight) for a period of three weeks-and tumor growth was monitored. MRI-CEST tumor pH imaging with Iopamidol was performed upon treatment at 3 h, 1 week (in combination with FDG-PET), and after 2 weeks for evaluating acute, early, and late responses. Although acute tumor pH changes were observed in vivo, long-term studies on both PC3 prostate cancer models did not provide any significant change in tumor acidosis or tumor growth. In conclusion, this work shows that MRI-CEST tumor pH imaging is a valuable tool for assessing the in vivo treatment response to PPIs.
... Capozza et al. believed that cervical cancer was one of the earliest malignant tumors with clinical staging. Its history could be traced back to 1928 [7]. Reinhold et al. believed that the clinical staging classification was born in the context of radiotherapy as the main treatment for cervical cancer [8]. ...
In order to understand the problems of the application of MRI and CT images in the early cervical cancer surgery, a method that the application of MRI imaging and CT images in early cervical cancer surgery was proposed. For the cervical cancer in clinical practice, the applications of the modern imaging examination and the clinical staging classification were investigated and analyzed. Compared with the surgical pathology results, the application value of common modern imaging in clinical staging of cervical cancer was evaluated. It was found that the sensitivity of MRI and CT in diagnosing lymph node metastasis was 56% and 58%, and the specificity was 93% and 92%, respectively. The experiment proved the application value of MRI and CT in clinical staging of cervical cancer.
... As a consequence, it is widely used as a surrogate for late-stage triple-negative breast cancer (TNBC) in humans due to its highly invasive potential and substantial molecular similarity (lack of Esr1, Erbb2, and Pgr expression) [11]. As a human TNBC model, 4T1-related tumors in mice have shown intense 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake; thus, 18 F-FDG PET is often used as a comparator in preclinical imaging studies [12]. Due to the recent development of therapeutics, several molecular alternatives investigating nonglycolytic pathways have been researched for breast cancer imaging [13,14]. ...
64CuCl2 is an economic radiotracer for oncologic PET investigations. In the present study, we characterized the uptake of 64CuCl2 in vivo by µPET/CT in an allograft 4T1-related mouse model (BALB/c) of advanced breast cancer. 18F-FDG was used as a comparator. Twenty-two animals were imaged 7–9 days following 4T1-cell implantation inside mammary glands. Dynamic 64CuCl2 µPET/CT acquisition or iterative static images up to 8 h p.i. were performed. Animal biodistribution and tumor uptake were first evaluated in vivo by µPET analysis and then assessed on tissue specimens. Concerning 18F-FDG µPET, a static acquisition was performed at 15 min and 60 min p.i. Tumor 64CuCl2 accumulation increased from 5 min to 4 h p.i., reaching a maximum value of 5.0 ± 0.20 %ID/g. Liver, brain, and muscle 64CuCl2 accumulation was stable over time. The tumor-to-muscle ratio remained stable from 1 to 8 h p.i., ranging from 3.0 to 3.7. Ex vivo data were consistent with in vivo estimations. The 18F-FDG tumor accumulation was 8.82 ± 1.03 %ID/g, and the tumor-to-muscle ratio was 4.54 ± 1.11. 64CuCl2 PET/CT provides good characterization of the 4T1-related breast cancer model and allows for exploration of non-glycolytic cellular pathways potentially of interest for theragnostic strategies.
... Thus, Capozza et al. investigated whether the glucoCEST approach can monitor the metabolic response to anticancer therapies in a breast murine cancer model and compared the results with those obtained with the 18 F-FDG-PET approach [52]. In this study the metastasizing triple negative breast tumor 4T1-bearing mice were treated for two weeks with i) a conventional chemotherapeutic drug (doxorubicin) or ii) with dichloroacetate (DCA) that targets tumor metabolism by reversing the Warburg effect [53]. ...
Cancer is one of the most devastating diseases that the world is currently facing, accounting for 10 million deaths in 2020 (WHO). In the last two decades, advanced medical imaging has played an ever more important role in the early detection of the disease, as it increases the chances of survival and the potential for full recovery. To date, dynamic glucose-enhanced (DGE) MRI using glucose-based chemical exchange saturation transfer (glucoCEST) has demonstrated the sensitivity to detect both d -glucose and glucose analogs, such as 3-oxy-methyl- d -glucose (3OMG) uptake in tumors. As one of the recent international efforts aiming at pushing the boundaries of translation of the DGE MRI technique into clinical practice, a multidisciplinary team of eight partners came together to form the “glucoCEST Imaging of Neoplastic Tumors (GLINT)” consortium, funded by the Horizon 2020 European Commission. This paper summarizes the progress made to date both by these groups and others in increasing our knowledge of the underlying mechanisms related to this technique as well as translating it into clinical practice.
Background
Triple-negative breast cancer (TNBC) includes approximately 20% of all breast cancer and is characterized by its aggressive nature, high recurrence rates, and visceral metastasis. Pathological complete response (pCR) is an established surrogate endpoint for survival. The window of opportunity studies provide valuable information on the disease biology prior to definitive treatment.
Objectives
To study the association of dynamic change in pathological, imagining, and genomic biomarkers that can prognosticate pCR. The study aims to develop a composite prognostic score.
Design
Clinical, interventional, and prognostic biomarker study using the novel window of opportunity design.
Methods
The study aims to enroll 80 treatment-naïve, pathologically confirmed TNBC patients, administering a single dose of paclitaxel and carboplatin during the window period before neoadjuvant chemotherapy (NACT). Tumor tissue will be obtained through a tru-cut biopsy, and positron emission tomography and computed tomography scans will be performed for each patient at two time points aiming to evaluate biomarker alterations. This will be followed by the administration of standard dose-dense NACT containing anthracyclines and taxanes, with the study culminating in surgery to assess pCR.
Results
The study would develop a composite prognostic risk score derived from the dynamic change in the Ki-67, tumor-infiltrating lymphocytes, Standardized Uptake Value (SUV max), Standardized Uptake Value for lean body mass (SUL max), and gene expression level pre- and post-intervention during the window period prior to the start of definitive treatment. This outcome will aid in categorizing the disease biology into risk categories.
Trial registration
The current study is approved by the Institutional Ethics Committee [Ethics: Protocol. no. JIP/IEC/2020/019]. This study was registered with ClinicalTrials.gov [CTRI Registration: CTRI/2022/06/043109].
Conclusion
The validated biomarker score will help to personalize NACT protocols in patients in TNBC planned for definitive treatment.
After an initial response to chemotherapy, tumor relapse is frequent. This event is reflective of both the spatiotemporal heterogeneities of the tumor microenvironment as well as the evolutionary propensity of cancer cell populations to adapt to variable conditions. Since the cause of this adaptation could be genetic or epigenetic, studying phenotypic properties such as tumor metabolism is useful as it reflects molecular, cellular, and tissue-level dynamics. In Triple-Negative Breast Cancer (TNBC), the characteristic metabolic phenotype is a highly fermentative state. However, during treatment, the spatial and temporal dynamics of the metabolic landscape are highly unstable, with surviving populations taking on a variety of metabolic states. Thus, longitudinally imaging tumor metabolism provides a promising approach to inform therapeutic strategies, and to monitor treatment responses to understand and mitigate recurrence. Here we summarize some examples of the metabolic plasticity reported in TNBC following chemotherapy and review the current metabolic imaging techniques available in monitoring chemotherapy responses clinically and pre-clinically. The ensemble of imaging technologies we describe have distinct attributes that make them uniquely suited for a particular length scale, biological model, and/or features that can be captured. We focus on TNBC to highlight the potential of each of these technological advances in understanding evolution-based therapeutic resistance.
Les maladies neurodégénératives sont un enjeu de société majeur et leur détection précoce est essentielle pour mieux prendre en charge les patients et pour envisager l'application d'un traitement potentiel. L'un des biomarqueurs pour détecter la maladie avant même l'apparition de symptômes est la consommation cérébrale de glucose. En effet, le glucose est une molécule essentielle à la production d'énergie et notre cerveau est l'organe de notre corps qui en consomme le plus. Afin de mieux comprendre la physiopathologie de ces maladies, le recours aux modèles animaux est particulièrement intéressant car il permet, entre autres, d'étudier l'évolution de la maladie dès les premiers mois de vie des animaux. Cependant, les méthodes d'imagerie existantes, telles que la tomographie par émission de positrons ou l'autoradiographie ne sont pas adaptées au suivi longitudinal des nombreux modèles rongeurs existants du fait de leur manque de résolution spatiale ou de la nécessité de sacrifier l'animal. Afin de pallier ces inconvénients nous avons développé au cours de cette thèse l'imagerie de Transfert de Saturation par Échange chimique (CEST) du glucose dont l'objectif était de cartographier le métabolisme énergétique in vivo avec une très bonne résolution spatiale. L'objectif de ce travail de thèse a donc été d'optimiser, caractériser et évaluer le potentiel de l'imagerie glucoCEST pour l'investigation du métabolisme cérébral in vivo. Nous avons tout d'abord optimisé les paramètres de la séquence CEST afin d'être le plus sensible et spécifique possible au glucose et à ses différents analogues. Nous avons ensuite répondu à une question majeure qui est l'origine compartimentale du signal CEST en montrant qu'il provenait des compartiments extracellulaire et intracellulaire. A partir de ces résultats nous avons évalué le potentiel de l'imagerie CEST à suivre le métabolisme énergétique dans différentes structures cérébrales puis nous l'avons appliqué au suivi longitudinal de rats contrôles et de rats atteints de la maladie de Huntington. Nous avons ainsi pu observer des différences métaboliques entre ces cohortes. Enfin, nous avons travaillé sur la quantification du signal CEST. L'ensemble de ces résultats montre les applications de l'imagerie glucoCEST comme outil pertinent du suivi du métabolisme énergétique cérébral dans les modèles rongeurs.
