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Mankovskii G, Hysi E. Photoacoustic Imaging of Metabolic Activities across Biological Length Scales. Physiology (Bethesda) 2025; 40:0. [PMID: 39706684 DOI: 10.1152/physiol.00010.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/28/2024] [Accepted: 07/01/2024] [Indexed: 12/23/2024] Open
Abstract
Imaging is ubiquitous with biomedical research and discovery. This article surveys the role of imaging in our understanding of metabolism and introduces photoacoustic imaging as a compelling candidate for providing high-resolution, label-free, and real-time insights into metabolic processes. As a rapidly evolving modality, photoacoustics holds promising preclinical and clinical potential in imaging of metabolism as well as metabolism-related changes.
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Affiliation(s)
- Gabriella Mankovskii
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
| | - Eno Hysi
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Insitute for Biomedical Engineering, Science and Technology, a partnership between Toronto Metropolitan University and St. Michael's Hospital, Toronto, Ontario, Canada
- Department of Physics, Faculty of Science, Toronto Metropolitan University, Toronto, Ontario, Canada
- Banting & Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
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2
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Lee Y, Jin C, Ohgaki R, Xu M, Ogasawara S, Warshamanage R, Yamashita K, Murshudov G, Nureki O, Murata T, Kanai Y. Structural basis of anticancer drug recognition and amino acid transport by LAT1. Nat Commun 2025; 16:1635. [PMID: 39952931 PMCID: PMC11828871 DOI: 10.1038/s41467-025-56903-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 01/31/2025] [Indexed: 02/17/2025] Open
Abstract
LAT1 (SLC7A5) transports large neutral amino acids and plays pivotal roles in cancer proliferation, immune response and drug delivery. Despite recent advances in structural understanding of LAT1, how it discriminates substrates and inhibitors including the clinically relevant drugs remains elusive. Here we report six structures of LAT1 across three conformations with bound ligands, elucidating its substrate transport and inhibitory mechanisms. JPH203 (also known as nanvuranlat or KYT-0353), an anticancer drug in clinical trials, traps LAT1 in an outward-facing state with a U-shaped conformer, with its amino-phenylbenzoxazol moiety pushing against transmembrane helix 3 (TM3) and bending TM10. Physiological substrates like ʟ-Phe lack such effects, whereas melphalan poses steric hindrance, explaining its inhibitory activity. The "classical" system L inhibitor BCH induces an occluded state critical for transport, confirming its substrate-like behavior. These findings provide a structural basis for substrate recognition and inhibition of LAT1, guiding future drug design.
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Affiliation(s)
- Yongchan Lee
- Department of Structural Biology, Max Planck Institute of Biophysics, 60438, Frankfurt, Germany.
- Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa, 230-0045, Japan.
| | - Chunhuan Jin
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Ryuichi Ohgaki
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan
| | - Minhui Xu
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Satoshi Ogasawara
- Graduate School of Science, Chiba University, Chiba, 263-8522, Japan
| | - Rangana Warshamanage
- Scientific Computing Department, UKRI Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Campus, Didcot, OX11 0FA, UK
| | - Keitaro Yamashita
- Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK
| | - Garib Murshudov
- Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK
| | - Osamu Nureki
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Takeshi Murata
- Graduate School of Science, Chiba University, Chiba, 263-8522, Japan
| | - Yoshikatsu Kanai
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan.
- Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Osaka, 565-0871, Japan.
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Tamer F, Yararbas U. A New Perspective on the Effectiveness of FDG PET/CT in Predicting KRAS Mutation in Colon Cancer Cases. Cancer Biother Radiopharm 2024; 39:664-672. [PMID: 38726607 DOI: 10.1089/cbr.2024.0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2024] Open
Abstract
Aim: The main aim of this study was to evaluate the effectiveness of 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computerized tomography (PET/CT) parameters in predicting the Kristen rat sarcoma viral oncogene(KRAS) mutation status of patients with colon cancer. Materials and Methods: Between April 2013 and December 2020, 79 patients who were diagnosed with colon cancer by colonoscopy underwent staging 18FDG PET/CT with this diagnosis and met all the inclusion criteria were included in this study. Clinical and prognostic features and also imaging (18FDG PET/CT and magnetic resonance imaging) reports of the patients were collected and analyzed retrospectively. Results: KRAS mutation was seen in 32 of patients (40.5%). No significant difference was observed between KRAS mutant and wild-type patients in terms of clinical features (tumor location, findings regarding metastasis, T stage, and tumor differentiation grade in patients who underwent surgery) and overall survival. Progression-free survival was significantly shorter in KRAS mutant patients (p = 0.018). Primary tumor standardized uptake value (SUVmean) was significantly higher in KRAS mutant cases in the whole group (p = 0.024) and in patients in whom KRAS analysis was performed only in the primary lesion (p = 0.036). The cutoff value for predicting KRAS mutation status was 7.01 g/mL (area under the curve [AUC]: 0.650, confidence interval [CI] 95%, 0.56-0.74). Conclusions: When colon and rectal cancer cases were evaluated separately, the primary tumor SUVmean value was significantly higher in KRAS mutant colon cancer cases. However, its effectiveness in predicting KRAS mutation status was low, similar to other parameters in the literature.
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Affiliation(s)
- Fatih Tamer
- Department of Nuclear Medicine, Niğde Ömer Halisdemir University Training and Research Hospital, Niğde, Turkey
| | - Ulkem Yararbas
- Department of Nuclear Medicine, Ege University Medical Faculty, Izmir, Turkey
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Komarova AD, Sinyushkina SD, Shchechkin ID, Druzhkova IN, Smirnova SA, Terekhov VM, Mozherov AM, Ignatova NI, Nikonova EE, Shirshin EA, Shimolina LE, Gamayunov SV, Shcheslavskiy VI, Shirmanova MV. Insights into metabolic heterogeneity of colorectal cancer gained from fluorescence lifetime imaging. eLife 2024; 13:RP94438. [PMID: 39197048 PMCID: PMC11357354 DOI: 10.7554/elife.94438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2024] Open
Abstract
Heterogeneity of tumor metabolism is an important, but still poorly understood aspect of tumor biology. Present work is focused on the visualization and quantification of cellular metabolic heterogeneity of colorectal cancer using fluorescence lifetime imaging (FLIM) of redox cofactor NAD(P)H. FLIM-microscopy of NAD(P)H was performed in vitro in four cancer cell lines (HT29, HCT116, CaCo2 and CT26), in vivo in the four types of colorectal tumors in mice and ex vivo in patients' tumor samples. The dispersion and bimodality of the decay parameters were evaluated to quantify the intercellular metabolic heterogeneity. Our results demonstrate that patients' colorectal tumors have significantly higher heterogeneity of energy metabolism compared with cultured cells and tumor xenografts, which was displayed as a wider and frequently bimodal distribution of a contribution of a free (glycolytic) fraction of NAD(P)H within a sample. Among patients' tumors, the dispersion was larger in the high-grade and early stage ones, without, however, any association with bimodality. These results indicate that cell-level metabolic heterogeneity assessed from NAD(P)H FLIM has a potential to become a clinical prognostic factor.
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Affiliation(s)
- Anastasia D Komarova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical UniversityNizhny NovgorodRussian Federation
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny NovgorodNizhny NovgorodRussian Federation
| | - Snezhana D Sinyushkina
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical UniversityNizhny NovgorodRussian Federation
| | - Ilia D Shchechkin
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical UniversityNizhny NovgorodRussian Federation
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny NovgorodNizhny NovgorodRussian Federation
| | - Irina N Druzhkova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical UniversityNizhny NovgorodRussian Federation
| | - Sofia A Smirnova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical UniversityNizhny NovgorodRussian Federation
| | - Vitaliy M Terekhov
- Nizhny Novgorod Regional Oncologic HospitalNizhny NovgorodRussian Federation
| | - Artem M Mozherov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical UniversityNizhny NovgorodRussian Federation
| | - Nadezhda I Ignatova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical UniversityNizhny NovgorodRussian Federation
| | - Elena E Nikonova
- Laboratory of Clinical Biophotonics, Sechenov First Moscow State Medical UniversityMoscowRussian Federation
| | - Evgeny A Shirshin
- Laboratory of Clinical Biophotonics, Sechenov First Moscow State Medical UniversityMoscowRussian Federation
- Faculty of Physics, Lomonosov Moscow State UniversityMoscowRussian Federation
| | - Liubov E Shimolina
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical UniversityNizhny NovgorodRussian Federation
| | - Sergey V Gamayunov
- Nizhny Novgorod Regional Oncologic HospitalNizhny NovgorodRussian Federation
| | - Vladislav I Shcheslavskiy
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical UniversityNizhny NovgorodRussian Federation
- Becker&Hickl GmbHBerlinGermany
| | - Marina V Shirmanova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical UniversityNizhny NovgorodRussian Federation
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5
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Kaneko K, Nagao M, Ueda K, Yamamoto A, Sakai S. Simultaneous evaluation of brain metastasis and thoracic cancer using semiconductor 11C-methionine PET/CT imaging. Ann Nucl Med 2024; 38:278-287. [PMID: 38386272 DOI: 10.1007/s12149-024-01908-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 12/27/2023] [Indexed: 02/23/2024]
Abstract
OBJECTIVE To investigate the potential of whole-body digital 11C-methionine (MET) PET/CT imaging for simultaneous evaluation of thoracic cancer patients suspected of local recurrence (LR) after stereotactic radiosurgery (SRS) for brain metastasis. METHODS A total of 45 lung or breast cancer patients suspected of LR after SRS were investigated using brain and whole-body MET-PET/CT scans. We compared the tumor-to-normal ratio (TNR) and maximum standardized uptake values (SUVmax) between patients with LR and radiation necrosis (RN) and performed receiver operating characteristic (ROC) analyses. We also investigated associations among extracranial recurrence, intracranial recurrence, primary site, and initial treatment type. RESULTS A total of 44 LR and 14 RN lesions were analyzed. In the ROC analyses for differentiating LR from RN, TNR showed higher area under the curve (AUC) (0.82) than SUVmax (0.79), and the cutoff TNR value (2.12) was higher than current cutoff values of conventional PET systems. The whole-body scans detected extracranial recurrences in 31.1% of the patients. Recurrence rates were not significantly correlated with existence of intracranial recurrence or primary site, but patients who underwent non-surgical treatment (consisting of stage III/ IV patients according to the Union for International Cancer Control TNM classification or small-cell lung cancer patients) showed significantly higher recurrence than the surgically treated patients (68.8% vs. 10.3%, p = 0.0001). CONCLUSION In digital MET-PET/CT imaging, TNR was a more useful parameter to differentiate LR from RN than SUVmax, and the cutoff value was higher than those with conventional PET systems. Additional whole-body scans could detect extracranial recurrence and would be especially useful for advanced thoracic cancer patients who underwent non-surgical treatment.
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Affiliation(s)
- Koichiro Kaneko
- Department of Diagnostic Imaging & Nuclear Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
| | - Michinobu Nagao
- Department of Diagnostic Imaging & Nuclear Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Kaori Ueda
- Department of Diagnostic Imaging & Nuclear Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Atsushi Yamamoto
- Department of Diagnostic Imaging & Nuclear Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Shuji Sakai
- Department of Diagnostic Imaging & Nuclear Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
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6
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Rodríguez-Laval V, Lumbreras-Fernández B, Aguado-Bueno B, Gómez-León N. Imaging of Multiple Myeloma: Present and Future. J Clin Med 2024; 13:264. [PMID: 38202271 PMCID: PMC10780302 DOI: 10.3390/jcm13010264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/18/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
Multiple myeloma (MM) is the second most common adult hematologic malignancy, and early intervention increases survival in asymptomatic high-risk patients. Imaging is crucial for the diagnosis and follow-up of MM, as the detection of bone and bone marrow lesions often dictates the decision to start treatment. Low-dose whole-body computed tomography (CT) is the modality of choice for the initial assessment, and dual-energy CT is a developing technique with the potential for detecting non-lytic marrow infiltration and evaluating the response to treatment. Magnetic resonance imaging (MRI) is more sensitive and specific than 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for the detection of small focal lesions and diffuse marrow infiltration. However, FDG-PET/CT is recommended as the modality of choice for follow-up. Recently, diffusion-weighted MRI has become a new technique for the quantitative assessment of disease burden and therapy response. Although not widespread, we address current proposals for structured reporting to promote standardization and diminish variations. This review provides an up-to-date overview of MM imaging, indications, advantages, limitations, and recommended reporting of each technique. We also cover the main differential diagnosis and pitfalls and discuss the ongoing controversies and future directions, such as PET-MRI and artificial intelligence.
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Affiliation(s)
- Víctor Rodríguez-Laval
- Department of Radiology, University Hospital La Princesa, IIS-Princesa, Calle Diego de León 62, 28005 Madrid, Spain; (B.L.-F.); (N.G.-L.)
- Department of Medicine, Autonomous University of Madrid, Calle del Arzobispo Morcillo 4, 28029 Madrid, Spain
| | - Blanca Lumbreras-Fernández
- Department of Radiology, University Hospital La Princesa, IIS-Princesa, Calle Diego de León 62, 28005 Madrid, Spain; (B.L.-F.); (N.G.-L.)
| | - Beatriz Aguado-Bueno
- Department of Hematology, University Hospital La Princesa, IIS-Princesa, Calle Diego de León 62, 28005 Madrid, Spain;
| | - Nieves Gómez-León
- Department of Radiology, University Hospital La Princesa, IIS-Princesa, Calle Diego de León 62, 28005 Madrid, Spain; (B.L.-F.); (N.G.-L.)
- Department of Medicine, Autonomous University of Madrid, Calle del Arzobispo Morcillo 4, 28029 Madrid, Spain
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7
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Hakobyan NR, Yavroyan ZV, Hovhannisyan AG, Gevorgyan ES. Cisplatin and progesterone separate and combined action on rat brain nuclear phospholipids content. Prostaglandins Other Lipid Mediat 2023; 168:106750. [PMID: 37247723 DOI: 10.1016/j.prostaglandins.2023.106750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 05/31/2023]
Abstract
The antitumor agent cisplatin and steroid hormone progesterone separate and combined action on content of total phospholipids and their individual classes in nuclei from rat brain cells were investigated. Cisplatin and progesterone exhibit their own characteristic properties, when used separately. Cisplatin reduces, and progesterone, on the contrary, increases the content of total phospholipids. When used together, the effects of these drugs are summed up. Cisplatin reduces the content of all 7 individual phospholipids found in rat brain nuclear preparations. Progesterone, on the other hand, increases the content of 5 classes of phospholipids. The combined use of cisplatin and progesterone restores 5 classes of nuclear phospholipids to the baseline level, and increases the quantity of 2 classes. The obtained results are discussed in terms of antagonistic effects of studied drugs, which can help in reducing undesirable side effects of cisplatin in case of combined use of antitumor drug and steroid.
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Affiliation(s)
- N R Hakobyan
- Faculty of Biology, Yerevan State University, Armenia.
| | - Zh V Yavroyan
- Faculty of Biology, Yerevan State University, Armenia
| | | | - E S Gevorgyan
- Faculty of Biology, Yerevan State University, Armenia
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8
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Li KP, Gleba JJ, Parent EE, Knight JA, Copland JA, Cai H. Radiosynthesis and Preliminary Evaluation of [ 11C]SSI-4 for the Positron Emission Tomography Imaging of Stearoyl CoA Desaturase 1. Mol Pharm 2023; 20:4129-4137. [PMID: 37409698 DOI: 10.1021/acs.molpharmaceut.3c00273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
Stearoyl CoA desaturase 1 (SCD1) is the rate-limiting enzyme for converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs) and plays a key role in endogenous (de novo) fatty acid metabolism. Given that this pathway is broadly upregulated across many tumor types with an aggressive phenotype, SCD1 has emerged as a compelling target for cancer imaging and therapy. The ligand 2-(4-(2-chlorophenoxy)piperidine-1-carboxamido)-N-methylisonicotinamide (SSI-4) was identified as a potent and highly specific SCD1 inhibitor with a strong binding affinity for SCD1 at our laboratory. We herein report the radiosynthesis of [11C]SSI-4 and the preliminary biological evaluation including in vivo PET imaging of SCD1 in a human tumor xenograft model. Radiotracer [11C]SSI-4 was labeled at the carbamide position via the direct [11C]CO2 fixation on the Synthra MeIplus module in high molar activity and good radiochemical yield. In vitro cell uptake assays were performed with three hepatocellular carcinoma (HCC) cell lines and three renal cell carcinoma (RCC) cell lines. Additionally, in vivo small animal PET/CT imaging with [11C]SSI-4 and the biodistribution were carried out in a mouse model bearing HCC xenografts. Radiotracer [11C]SSI-4 afforded a 4.14 ± 0.44% (decay uncorrected, n = 10) radiochemical yield based on starting [11]CO2 radioactivity. The [11C]SSI-4 radiosynthesis time including HPLC purification and SPE formulation was 25 min from the end of bombardment to the end of synthesis (EOS). The radiochemical purity of [11C]SSI-4 was 98.45 ± 1.43% (n = 10) with a molar activity of 225.82 ± 33.54 GBq/μmol (6.10 ± 0.91 Ci/μmol) at the EOS. In vitro cell uptake study indicated all SSI-4 responsive HCC and RCC cell line uptakes demonstrate specific uptake and are blocked by standard compound SSI-4. Preliminary small animal PET/CT imaging study showed high specific uptake and block of [11C]SSI-4 uptake with co-injection of cold SSI-4 in high SCD1-expressing organs including lacrimal gland, brown fat, liver, and tumor. In summary, novel radiotracer [11C]SSI-4 was rapidly and automatedly radiosynthesized by direct [11C]CO2 fixation. Our preliminary biological evaluation results suggest [11C]SSI-4 could be a promising radiotracer for PET imaging of SCD1 overexpressing tumor tissues.
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Affiliation(s)
- Kang-Po Li
- Department of Radiology, Mayo Clinic, Jacksonville, Florida 32224, United States
| | - Justyna J Gleba
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida 32224, United States
| | - Ephraim E Parent
- Department of Radiology, Mayo Clinic, Jacksonville, Florida 32224, United States
| | - Joshua A Knight
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida 32224, United States
| | - John A Copland
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida 32224, United States
| | - Hancheng Cai
- Department of Radiology, Mayo Clinic, Jacksonville, Florida 32224, United States
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9
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Kilicoglu O, Sepay N, Ozgenc E, Gundogdu E, Kara U, Alomairy S, Al-Buriahi M. Evaluation of F-18 FDG radiopharmaceuticals through Molecular Docking and radiation effects. Appl Radiat Isot 2022; 191:110553. [DOI: 10.1016/j.apradiso.2022.110553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 10/23/2022] [Accepted: 11/02/2022] [Indexed: 11/08/2022]
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10
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Zhang Q, Shao J, Wang J, Gong XJ, Liu WX, Wang S, Zhang Y, Yang S, Zhang QS, Wei JX, Tian JL. Antitumor effects of new glycoconjugated Pt II agents dual-targeting GLUT1 and Pgp proteins. Dalton Trans 2022; 51:16082-16092. [PMID: 36178270 DOI: 10.1039/d2dt02455a] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A novel and highly efficient dual-targeting PtII system was designed to improve the drug delivery capacity and selectivity in cancer treatment. The dual-targeting monofunctional PtII complexes (1-8) having glycosylated pendants as tridentated ligand were achieved by introducing glycosylation modification in the thioaminocarbazone compounds with potential lysosomal targeting ability. The structures and stability of 1-8 were further established by various techniques. Molecular docking studies showed that 2 was efficiently docked into glucose transporters protein 1 (GLUT1) and P-glycoprotein (Pgp) proteins with the optimal CDocker-interaction-energy of -64.84 and -48.85 kcal mol-1. Complex 2 with higher protein binding capacity demonstrated significant and broad-spectrum antitumor efficacy in vitro, even exhibiting a half maximal inhibitory concentration (IC50) value (∼10 μM) than cisplatin (∼17 μM) against human lung adenocarcinoma cells (A549). The inhibitor experiment revealed GLUT-mediated uptake of 2, and the subcellular localization experiment in A549 also proved that 2 could be localized in the lysosome, thereby causing cell apoptosis. Moreover, cellular thermal shift assay (CETSA) confirmed the binding of 2 with the target proteins of GLUT1 and Pgp. The above results indicated that 2 represents a potential anticancer candidate with dual-targeting functions.
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Affiliation(s)
- Qiang Zhang
- College of Chemistry, Nankai University, Tianjin 300071, PR China.
| | - Jia Shao
- Department of Pharmacy, Tianjin First Central Hospital, Tianjin 300192, PR China. .,National Health Commission's Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300192, PR China
| | - Jin Wang
- Outpatient Office, Tianjin First Central Hospital, Tianjin 300192, PR China
| | - Xian-Jin Gong
- College of Chemistry, Nankai University, Tianjin 300071, PR China.
| | - Wei-Xing Liu
- College of Chemistry, Nankai University, Tianjin 300071, PR China.
| | - Shan Wang
- Department of Pharmacy, Tianjin First Central Hospital, Tianjin 300192, PR China.
| | - Yi Zhang
- Department of Pharmacy, Tianjin First Central Hospital, Tianjin 300192, PR China. .,National Health Commission's Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300192, PR China
| | - Shuang Yang
- Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin 300071, PR China
| | - Quan-Sheng Zhang
- Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, PR China
| | - Jin-Xia Wei
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
| | - Jin-Lei Tian
- College of Chemistry, Nankai University, Tianjin 300071, PR China.
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11
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Halogenation of tyrosine perturbs large-scale protein self-organization. Nat Commun 2022; 13:4843. [PMID: 35977922 PMCID: PMC9385671 DOI: 10.1038/s41467-022-32535-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 08/04/2022] [Indexed: 11/08/2022] Open
Abstract
Protein halogenation is a common non-enzymatic post-translational modification contributing to aging, oxidative stress-related diseases and cancer. Here, we report a genetically encodable halogenation of tyrosine residues in a reconstituted prokaryotic filamentous cell-division protein (FtsZ) as a platform to elucidate the implications of halogenation that can be extrapolated to living systems of much higher complexity. We show how single halogenations can fine-tune protein structures and dynamics of FtsZ with subtle perturbations collectively amplified by the process of FtsZ self-organization. Based on experiments and theories, we have gained valuable insights into the mechanism of halogen influence. The bending of FtsZ structures occurs by affecting surface charges and internal domain distances and is reflected in the decline of GTPase activities by reducing GTP binding energy during polymerization. Our results point to a better understanding of the physiological and pathological effects of protein halogenation and may contribute to the development of potential diagnostic tools.
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12
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Davidson SM, Schmidt DR, Heyman JE, O'Brien JP, Liu AC, Israelsen WJ, Dayton TL, Sehgal R, Bronson RT, Freinkman E, Mak HH, Fanelli GN, Malstrom S, Bellinger G, Carracedo A, Pandolfi PP, Courtney KD, Jha A, DePinho RA, Horner JW, Thomas CJ, Cantley LC, Loda M, Vander Heiden MG. Pyruvate Kinase M1 Suppresses Development and Progression of Prostate Adenocarcinoma. Cancer Res 2022; 82:2403-2416. [PMID: 35584006 PMCID: PMC9256808 DOI: 10.1158/0008-5472.can-21-2352] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 04/19/2022] [Accepted: 05/11/2022] [Indexed: 01/07/2023]
Abstract
SIGNIFICANCE Differential expression of PKM1 and PKM2 impacts prostate tumorigenesis and suggests a potential therapeutic vulnerability in prostate cancer.
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Affiliation(s)
- Shawn M. Davidson
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Broad Institute of MIT and Harvard University, Cambridge, Massachusetts.,Corresponding Authors: Matthew G. Vander Heiden, Koch Institute/Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. E-mail: ; and Shawn M. Davidson,
| | - Daniel R. Schmidt
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Broad Institute of MIT and Harvard University, Cambridge, Massachusetts.,Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Julia E. Heyman
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - James P. O'Brien
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Amy C. Liu
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - William J. Israelsen
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Talya L. Dayton
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | | | - Roderick T. Bronson
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | | | - Howard H. Mak
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Giuseppe Nicolò Fanelli
- Weill Cornell Medical College, New York, New York.,Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Scott Malstrom
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Gary Bellinger
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | | | | | | | | | | | | | - Craig J. Thomas
- National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland
| | - Lewis C. Cantley
- Beth Israel Deaconess Medical Center, Boston, Massachusetts.,Weill Cornell Medical College, New York, New York
| | - Massimo Loda
- Weill Cornell Medical College, New York, New York.,Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Matthew G. Vander Heiden
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Broad Institute of MIT and Harvard University, Cambridge, Massachusetts.,Dana-Farber Cancer Institute, Boston, Massachusetts.,Corresponding Authors: Matthew G. Vander Heiden, Koch Institute/Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. E-mail: ; and Shawn M. Davidson,
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13
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Scott NP, Teoh EJ, Flight H, Jones BE, Niederer J, Mustata L, MacLean GM, Roy PG, Remoundos DD, Snell C, Liu C, Gleeson FV, Harris AL, Lord SR, McGowan DR. Characterising 18F-fluciclovine uptake in breast cancer through the use of dynamic PET/CT imaging. Br J Cancer 2022; 126:598-605. [PMID: 34795409 PMCID: PMC8854436 DOI: 10.1038/s41416-021-01623-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 10/25/2021] [Accepted: 10/29/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND 18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades. METHODS Thirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters. RESULTS A reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation. CONCLUSIONS 18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake. CLINICAL TRIAL REGISTRATION NCT03036943.
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Affiliation(s)
- N P Scott
- Department of Oncology, University of Oxford, Oxford, UK
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - E J Teoh
- Department of Oncology, University of Oxford, Oxford, UK
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Blue Earth Diagnostics Ltd, Oxford Science Park, Oxford, UK
| | - H Flight
- Department of Oncology, University of Oxford, Oxford, UK
| | - B E Jones
- Royal Berkshire NHS Foundation Trust, Reading, UK
| | - J Niederer
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - L Mustata
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - G M MacLean
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - P G Roy
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - D D Remoundos
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - C Snell
- Mater Research, University of Queensland, Brisbane, QLD, Australia
- Mater Pathology, Mater Hospital Brisbane, Brisbane, QLD, Australia
| | - C Liu
- Mater Pathology, Mater Hospital Brisbane, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - F V Gleeson
- Department of Oncology, University of Oxford, Oxford, UK
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - A L Harris
- Department of Oncology, University of Oxford, Oxford, UK
- MRC Weatherall Institute of Molecular Medicine, Oxford, UK
| | - S R Lord
- Department of Oncology, University of Oxford, Oxford, UK
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - D R McGowan
- Department of Oncology, University of Oxford, Oxford, UK.
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
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14
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Li Q, Chen Q, Yang X, Zhang Y, Lv L, Zhang Z, Zeng S, Lv J, Liu S, Fu B. Cocktail strategy based on a dual function nanoparticle and immune activator for effective tumor suppressive. J Nanobiotechnology 2022; 20:84. [PMID: 35177088 PMCID: PMC8851817 DOI: 10.1186/s12951-022-01241-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/02/2022] [Indexed: 11/26/2022] Open
Abstract
Background Immune checkpoint inhibitor-mediated immunotherapy cannot be carried out on a large scale clinically due to its low universality. In recent years, cyclic guanosine monophosphate synthase/interferon gene stimulating factor (cGAS/STING)-mediated innate immune signaling pathway-mediated immunotherapy has attracted more and more attention. In addition, metabolic inhibitors also show good effects on tumor treatment, but their application is often limited because of their large first pass effect or difficult administration. Methods The particle size and potential parameters were measured by DLS. In order to determine the optimal ratio of the two drugs, we calculated the CI value of different nanoparticles through MTT experiment, and simulated their synergistic effect through Gaussian software. Then the morphology and crystal form of the best proportion of drugs were studied by TEM and XRD. The anti-tumor mechanism of composite nanoparticles was confirmed by the determination of metabolic related indexes, Q-PCR and WB. The antitumor effect and immune activation effect were comprehensively evaluated by in vivo and in vitro experiments. Results Here, we found and synthesized BCP nanoparticles ((BPA + CPI) @ PLGA NPs) which can effectively reduce the metabolism of tumor cells and inhibit cell proliferation. At the same time, the release of mitochondrial DNA (mtDNA) caused by mitochondrial metabolism disorder further activated the cGAS/STING signal pathway in Hepa1–6 cells. We found that the drug-treated Hepa1–6 cells had obvious TBK1 phosphorylation and STING dimerization. Combined with STING agonist, it could effectively promote the activation of CD8 T cells and enhanced the therapeutic effect on liver cancer. Conclusion Our results showed that PLGA nanocarrier can successfully improve the dosage forms of two metabolic inhibitors and show the effect of synergistic therapy. BCP nanoparticles can also activate the innate immunity of tumor cells and significantly enhance tumor inhibition after combined with STING agonists. This study has high reference and transformation value for the combined treatment of immunosuppression and metabolic inhibition. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12951-022-01241-y.
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Affiliation(s)
- Qian Li
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China
| | - Qiubing Chen
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xue Yang
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yuelan Zhang
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Linyue Lv
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhuyou Zhang
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shaowei Zeng
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jiaxi Lv
- Department of Clinical Medicine, Fourth Clinical Medical College, Capital Medical University, Beijing, People's Republic of China
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
| | - Bishi Fu
- Department of Paediatrics, State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China. .,Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China. .,Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China.
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15
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Zhu Z, Li W, Lai Y, Carter O, Banerjee S, Sadler PJ, Huang H. Photocatalytic glucose-appended bio-compatible Ir(III) anticancer complexes. Dalton Trans 2022; 51:10875-10879. [DOI: 10.1039/d2dt01134d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Rationally-designed glucose-appended Ir(III) photo-catalysts ([Ir(N,C)2(N,N-Glc)]+, Ir1-Ir3) show visible light-induced catalytic NAD(P)H oxidation in aqueous solution. Highly in-vivo biocompatible complex, Ir3, shows lysosome and mitochondria targeting necro-apoptotic photo-cytotoxicity against various cancer...
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16
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Cho SG, Kim M, Lee SH, Park KS, Kim J, Moon JB, Song HC. Evaluation of Non-infarct-Related Arteries Using C-11 Acetate PET in STEMI With Multivessel Disease. J Cardiovasc Imaging 2022; 30:169-180. [PMID: 35879252 PMCID: PMC9314231 DOI: 10.4250/jcvi.2021.0189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/14/2022] [Accepted: 02/17/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND We analyzed whether C-11 acetate positron emission tomography (PET) can be used for the evaluation of non-infarct-related artery (NIRA) in patients with ST-elevation myocardial infarction (STEMI) and multivessel disease. METHODS We prospectively enrolled 31 patients with STEMI and at least one NIRA stenosis (diameter stenosis [DS] ≥ 50%). C-11 acetate PET was performed after successful revascularization for the infarct-related artery (IRA). Myocardial blood flow (MBF) and oxidative metabolism (kmono) were measured and compared between NIRA vs. IRA, stenotic (DS ≥ 50%) vs. non-stenotic (DS < 50%) NIRAs, and NIRAs with significant stenosis (DS ≥ 70% or fractional flow reserve [FFR] ≤ 0.80) vs. those without (neither DS ≥ 70% nor FFR ≤ 0.80). The correlations between PET and angiographic parameters were also analyzed. RESULTS MBF and kmono were significantly higher in NIRAs than those in IRAs. Stenotic NIRAs showed significantly reduced stress MBF, myocardial flow reserve (MFR), relative flow reserve (RFR) (0.72 ± 0.12 vs. 0.82 ± 0.14; p = 0.001), and stress kmono, as compared to those in non-stenotic NIRAs. NIRAs with significant stenosis had significantly lower stress MBF, MFR, and RFR (0.70 ± 0.10 vs. 0.80 ± 0.14; p = 0.001). RFR showed the best, but modest linear correlation with DS of NIRA stenosis (r = −0.429, p = 0.001). RFR > 0.81 could effectively exclude the presence of significant NIRA stenosis. CONCLUSIONS C-11 acetate PET could be a feasible alternative noninvasive modality in patients with STEMI and multivessel disease, by excluding the presence of significant NIRA stenosis.
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Affiliation(s)
- Sang-Geon Cho
- Department of Nuclear Medicine, Chonnam National University Hospital, Gwangju, Korea
| | - Minchul Kim
- Department of Cardiology, Chonnam National University Hospital, Gwangju, Korea
| | - Seung Hun Lee
- Department of Cardiology, Chonnam National University Hospital, Gwangju, Korea
| | - Ki Seong Park
- Department of Nuclear Medicine, Chonnam National University Hospital, Gwangju, Korea
| | - Jahae Kim
- Department of Nuclear Medicine, Chonnam National University Hospital, Gwangju, Korea
| | - Jang Bae Moon
- Department of Nuclear Medicine, Chonnam National University Hospital, Gwangju, Korea
| | - Ho-Chun Song
- Department of Nuclear Medicine, Chonnam National University Hospital, Gwangju, Korea
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17
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Lecouvet FE, Vekemans MC, Van Den Berghe T, Verstraete K, Kirchgesner T, Acid S, Malghem J, Wuts J, Hillengass J, Vandecaveye V, Jamar F, Gheysens O, Vande Berg BC. Imaging of treatment response and minimal residual disease in multiple myeloma: state of the art WB-MRI and PET/CT. Skeletal Radiol 2022; 51:59-80. [PMID: 34363522 PMCID: PMC8626399 DOI: 10.1007/s00256-021-03841-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/28/2021] [Accepted: 06/06/2021] [Indexed: 02/02/2023]
Abstract
Bone imaging has been intimately associated with the diagnosis and staging of multiple myeloma (MM) for more than 5 decades, as the presence of bone lesions indicates advanced disease and dictates treatment initiation. The methods used have been evolving, and the historical radiographic skeletal survey has been replaced by whole body CT, whole body MRI (WB-MRI) and [18F]FDG-PET/CT for the detection of bone marrow lesions and less frequent extramedullary plasmacytomas.Beyond diagnosis, imaging methods are expected to provide the clinician with evaluation of the response to treatment. Imaging techniques are consistently challenged as treatments become more and more efficient, inducing profound response, with more subtle residual disease. WB-MRI and FDG-PET/CT are the methods of choice to address these challenges, being able to assess disease progression or response and to detect "minimal" residual disease, providing key prognostic information and guiding necessary change of treatment.This paper provides an up-to-date overview of the WB-MRI and PET/CT techniques, their observations in responsive and progressive disease and their role and limitations in capturing minimal residual disease. It reviews trials assessing these techniques for response evaluation, points out the limited comparisons between both methods and highlights their complementarity with most recent molecular methods (next-generation flow cytometry, next-generation sequencing) to detect minimal residual disease. It underlines the important role of PET/MRI technology as a research tool to compare the effectiveness and complementarity of both methods to address the key clinical questions.
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Affiliation(s)
- Frederic E. Lecouvet
- Radiology Department, Institut de Recherche Expérimentale et Clinique (IREC), Cliniques Universitaires Saint-Luc, UCLouvain, Hippocrate Avenue 10, 1200 Brussels, Belgium
| | - Marie-Christiane Vekemans
- Haematology Unit, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique (IREC), 1200 Brussels, Belgium
| | - Thomas Van Den Berghe
- Radiology Department, Universiteit Ghent, Sint-Pietersnieuwstraat 33, 9000 Gent, Belgium
| | - Koenraad Verstraete
- Radiology Department, Universiteit Ghent, Sint-Pietersnieuwstraat 33, 9000 Gent, Belgium
| | - Thomas Kirchgesner
- Radiology Department, Institut de Recherche Expérimentale et Clinique (IREC), Cliniques Universitaires Saint-Luc, UCLouvain, Hippocrate Avenue 10, 1200 Brussels, Belgium
| | - Souad Acid
- Radiology Department, Institut de Recherche Expérimentale et Clinique (IREC), Cliniques Universitaires Saint-Luc, UCLouvain, Hippocrate Avenue 10, 1200 Brussels, Belgium
| | - Jacques Malghem
- Radiology Department, Institut de Recherche Expérimentale et Clinique (IREC), Cliniques Universitaires Saint-Luc, UCLouvain, Hippocrate Avenue 10, 1200 Brussels, Belgium
| | - Joris Wuts
- Department of Electronics and Informatics (ETRO), Vrije Universiteit Brussel, Avenue du Laerbeek 101, 1090 Jette, Belgium
| | - Jens Hillengass
- Departement of Medicine, Myeloma Unit, Park Comprehensive Cancer Center, Buffalo, NY USA
| | - Vincent Vandecaveye
- Radiology Department, Katholieke Univesiteit Leuven, Oude Markt, 13, 3000 Leuven, Belgium
| | - François Jamar
- Nuclear Medicine Department, Institut de Recherche Expérimentale et Clinique (IREC), Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Olivier Gheysens
- Nuclear Medicine Department, Institut de Recherche Expérimentale et Clinique (IREC), Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Bruno C. Vande Berg
- Radiology Department, Institut de Recherche Expérimentale et Clinique (IREC), Cliniques Universitaires Saint-Luc, UCLouvain, Hippocrate Avenue 10, 1200 Brussels, Belgium
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Enhancing the accumulation level of 3-[ 18F]fluoro-L-α-methyltyrosine in tumors by preloading probenecid. Nucl Med Biol 2021; 104-105:47-52. [PMID: 34896813 DOI: 10.1016/j.nucmedbio.2021.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 11/24/2021] [Accepted: 11/29/2021] [Indexed: 11/23/2022]
Abstract
INTRODUCTION 3-[18F]fluoro-α-methyl-L-tyrosine ([18F]FAMT) is a promising amino acid tracer targeting L-type amino acid transporter 1 (LAT1). One concern regarding the diagnosis using [18F]FAMT is the possibility of false-negative findings because of its relatively low accumulation level even in malignant tumors. Moreover, preloading probenecid, an organic anion transporter inhibitor, markedly increased the tumor accumulation level of radioiodine-labeled α-methyltyrosine. In this study, we evaluated the usefulness of preloading probenecid in improving the tumor-imaging capability of [18F]FAMT. METHODS Three biodistribution studies of [18F]FAMT were conducted in normal mice to elucidate the usefulness of probenecid preloading. Later, a biodistribution study and positron emission tomography (PET) imaging of [18F]FAMT were conducted with or without probenecid injection in tumor-bearing mice. RESULTS Probenecid preloading significantly delayed blood clearance and consequently enhanced the accumulation of [18F]FAMT in the pancreas, a LAT1-positive organ. The effects of probenecid preloading were independent of the administration route. Tumor accumulation level in the biodistribution study and the maximum standardized uptake value in tumors on PET imaging of the probenecid preloading group were significantly higher than those of the control (without probenecid injection) group in tumor-bearing mice. CONCLUSIONS Preloading probenecid significantly delayed blood clearance and consequently enhanced the accumulation of [18F]FAMT in tumors. These results indicate that preloading probenecid could improve the diagnostic accuracy of [18F]FAMT.
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19
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Zhang Z, Liu S, Ma H, Xiang X, Nie D, Hu P, Tang G. Propionic Acid-Based PET Imaging of Prostate Cancer. Mol Imaging Biol 2021; 23:836-845. [PMID: 33876336 DOI: 10.1007/s11307-021-01608-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 04/08/2021] [Accepted: 04/12/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE This study aimed to evaluate the potential value of 2-[18F]fluoropropionic acid ([18F]FPA) for PET imaging of prostate cancer (PCa) and to explore the relationship between [18F]FPA accumulation and fatty acid synthase (FASN) levels in PCa models. The results of the first [18F]FPA PET study of a PCa patient are reported. PROCEDURES The LNCaP, PC-3 cell lines with high FASN expression, and DU145 cell lines with low FASN expression were selected for cell culture. A PET imaging comparison of [18F]FDG and [18F]FPA was performed in LNCaP, PC-3, and DU145 tumors. Additionally, in vivo inhibition experiments in those models were conducted with orlistat. In a human PET study, a patient with PCa before surgery was examined with [18F]FPA PET and [18F]FDG PET. RESULTS The uptake of [18F]FPA in the LNCaP and PC-3 tumors was higher than that of [18F]FDG (P<0.05 and P<0.05), but was lower in DU145 tumors (P<0.05). The accumulation (% ID/g) of [18F]FPA in the LNCaP, PC-3, and DU145 tumors decreased by 27.6, 40.5, and 11.7 %, respectively, after treatment with orlistat. The [18F]FPA showed higher radioactive uptake than [18F]FDG in the first PCa patient. CONCLUSIONS The [18F]FPA uptake in PCa models may be varies with fatty acid synthase activity and could be reduced after administration of a single FASN inhibitor, albeit the activity that is not measured directly. The [18F]FPA seems to be a potential broad-spectrum PET imaging agent and may serve as a valuable tool in the diagnosis of PCa in humans.
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Affiliation(s)
- Zhanwen Zhang
- Department of Nuclear Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China
- Department of Nuclear Medicine and Medical Imaging, Guangdong Engineering Research Center for Translational Application of Medical Radiopharmaceuticals, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Shaoyu Liu
- Department of Nuclear Medicine and Medical Imaging, Guangdong Engineering Research Center for Translational Application of Medical Radiopharmaceuticals, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- Department of Nuclear Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Hui Ma
- Department of Nuclear Medicine and Medical Imaging, Guangdong Engineering Research Center for Translational Application of Medical Radiopharmaceuticals, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xianhong Xiang
- Department of Nuclear Medicine and Medical Imaging, Guangdong Engineering Research Center for Translational Application of Medical Radiopharmaceuticals, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Dahong Nie
- Department of Nuclear Medicine and Medical Imaging, Guangdong Engineering Research Center for Translational Application of Medical Radiopharmaceuticals, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ping Hu
- Department of Nuclear Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.
| | - Ganghua Tang
- Department of Nuclear Medicine and Medical Imaging, Guangdong Engineering Research Center for Translational Application of Medical Radiopharmaceuticals, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
- Nanfang PET Center and Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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20
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Lin L, Xiang X, Su S, Liu S, Xiong Y, Ma H, Yuan G, Nie D, Tang G. Biological Evaluation of [ 18F]AlF-NOTA-NSC-GLU as a Positron Emission Tomography Tracer for Hepatocellular Carcinoma. Front Chem 2021; 9:630452. [PMID: 33937189 PMCID: PMC8085524 DOI: 10.3389/fchem.2021.630452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/23/2021] [Indexed: 12/29/2022] Open
Abstract
Purpose: N-(2-[18F]fluoropropionyl)-L-glutamate ([18F]FPGLU) for hepatocellular carcinoma (HCC) imaging has been performed in our previous studies, but its radiosynthesis method and stability in vivo need to be improved. Hence, we evaluated the synthesis and biological properties of a simple [18F]-labeled glutamate analog, [18F]AlF-1,4,7-triazacyclononane-1,4,7-triacetic-acid-2-S-(4-isothiocyanatobenzyl)-l-glutamate ([18F]AlF-NOTA-NSC-GLU), for HCC imaging. Procedures: [18F]AlF-NOTA-NSC-GLU was synthesized via a one-step reaction sequence from NOTA-NSC-GLU. In order to investigate the imaging value of [18F]AlF-NOTA-NSC-GLU in HCC, we conducted positron emission tomography/computed tomography (PET/CT) imaging and competitive binding of [18F]AlF-NOTA-NSC-GLU in human Hep3B tumor-bearing mice. The transport mechanism of [18F]AlF-NOTA-NSC-GLU was determined by competitive inhibition and protein incorporation experiments in vitro. Results: [18F]AlF-NOTA-NSC-GLU was prepared with an overall radiochemical yield of 29.3 ± 5.6% (n = 10) without decay correction within 20 min. In vitro competitive inhibition experiments demonstrated that the Na+-dependent systems XAG-, B0+, ASC, and minor XC- were involved in the uptake of [18F]AlF-NOTA-NSC-GLU, with the Na+-dependent system XAG- possibly playing a more dominant role. Protein incorporation studies of the Hep3B human hepatoma cell line showed almost no protein incorporation. Micro-PET/CT imaging with [18F]AlF-NOTA-NSC-GLU showed good tumor-to-background contrast in Hep3B human hepatoma-bearing mouse models. After [18F]AlF-NOTA-NSC-GLU injection, the tumor-to-liver uptake ratio of [18F]AlF-NOTA-NSC-GLU was 2.06 ± 0.17 at 30 min post-injection. In vivo competitive binding experiments showed that the tumor-to-liver uptake ratio decreased with the addition of inhibitors to block the XAG system. Conclusions: We have successfully synthesized [18F]AlF-NOTA-NSC-GLU as a novel PET tracer with good radiochemical yield and high radiochemical purity. Our findings indicate that [18F]AlF-NOTA-NSC-GLU may be a potential candidate for HCC imaging. Also, a further biological evaluation is underway.
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Affiliation(s)
- Liping Lin
- Department of Radiology Intervention and Medical Imaging, Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xianhong Xiang
- Department of Radiology Intervention and Medical Imaging, Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shu Su
- Department of Radiology Intervention and Medical Imaging, Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shaoyu Liu
- Department of Radiology Intervention and Medical Imaging, Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ying Xiong
- Department of Radiology Intervention and Medical Imaging, Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Ma
- Department of Radiology Intervention and Medical Imaging, Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Gongjun Yuan
- Department of Radiology Intervention and Medical Imaging, Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dahong Nie
- Department of Radiology Intervention and Medical Imaging, Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Radiotherapy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ganghua Tang
- Department of Radiology Intervention and Medical Imaging, Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Nanfang PET Center, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
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21
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Samim A, Tytgat GA, Bleeker G, Wenker ST, Chatalic KL, Poot AJ, Tolboom N, van Noesel MM, Lam MG, de Keizer B. Nuclear Medicine Imaging in Neuroblastoma: Current Status and New Developments. J Pers Med 2021; 11:jpm11040270. [PMID: 33916640 PMCID: PMC8066332 DOI: 10.3390/jpm11040270] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 04/01/2021] [Indexed: 12/20/2022] Open
Abstract
Neuroblastoma is the most common extracranial solid malignancy in children. At diagnosis, approximately 50% of patients present with metastatic disease. These patients are at high risk for refractory or recurrent disease, which conveys a very poor prognosis. During the past decades, nuclear medicine has been essential for the staging and response assessment of neuroblastoma. Currently, the standard nuclear imaging technique is meta-[123I]iodobenzylguanidine ([123I]mIBG) whole-body scintigraphy, usually combined with single-photon emission computed tomography with computed tomography (SPECT-CT). Nevertheless, 10% of neuroblastomas are mIBG non-avid and [123I]mIBG imaging has relatively low spatial resolution, resulting in limited sensitivity for smaller lesions. More accurate methods to assess full disease extent are needed in order to optimize treatment strategies. Advances in nuclear medicine have led to the introduction of radiotracers compatible for positron emission tomography (PET) imaging in neuroblastoma, such as [124I]mIBG, [18F]mFBG, [18F]FDG, [68Ga]Ga-DOTA peptides, [18F]F-DOPA, and [11C]mHED. PET has multiple advantages over SPECT, including a superior resolution and whole-body tomographic range. This article reviews the use, characteristics, diagnostic accuracy, advantages, and limitations of current and new tracers for nuclear medicine imaging in neuroblastoma.
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Affiliation(s)
- Atia Samim
- Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (A.S.); (G.A.M.T.); (S.T.M.W.); (K.L.S.C.); (A.J.P.); (N.T.); (M.M.v.N.)
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht/Wilhelmina Children’s Hospital, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands;
| | - Godelieve A.M. Tytgat
- Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (A.S.); (G.A.M.T.); (S.T.M.W.); (K.L.S.C.); (A.J.P.); (N.T.); (M.M.v.N.)
| | - Gitta Bleeker
- Department of Radiology and Nuclear Medicine, Northwest Clinics, Wilhelminalaan 12, 1815 JD Alkmaar, The Netherlands;
| | - Sylvia T.M. Wenker
- Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (A.S.); (G.A.M.T.); (S.T.M.W.); (K.L.S.C.); (A.J.P.); (N.T.); (M.M.v.N.)
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht/Wilhelmina Children’s Hospital, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands;
| | - Kristell L.S. Chatalic
- Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (A.S.); (G.A.M.T.); (S.T.M.W.); (K.L.S.C.); (A.J.P.); (N.T.); (M.M.v.N.)
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht/Wilhelmina Children’s Hospital, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands;
| | - Alex J. Poot
- Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (A.S.); (G.A.M.T.); (S.T.M.W.); (K.L.S.C.); (A.J.P.); (N.T.); (M.M.v.N.)
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht/Wilhelmina Children’s Hospital, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands;
| | - Nelleke Tolboom
- Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (A.S.); (G.A.M.T.); (S.T.M.W.); (K.L.S.C.); (A.J.P.); (N.T.); (M.M.v.N.)
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht/Wilhelmina Children’s Hospital, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands;
| | - Max M. van Noesel
- Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (A.S.); (G.A.M.T.); (S.T.M.W.); (K.L.S.C.); (A.J.P.); (N.T.); (M.M.v.N.)
| | - Marnix G.E.H. Lam
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht/Wilhelmina Children’s Hospital, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands;
| | - Bart de Keizer
- Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (A.S.); (G.A.M.T.); (S.T.M.W.); (K.L.S.C.); (A.J.P.); (N.T.); (M.M.v.N.)
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht/Wilhelmina Children’s Hospital, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands;
- Correspondence: ; Tel.: +31-887-571-794
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22
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Singh N, Miner A, Hennis L, Mittal S. Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:17-43. [PMID: 34337348 PMCID: PMC8319838 DOI: 10.20517/cdr.2020.79] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months. Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy. Temozolomide (TMZ) is the first-choice chemotherapeutic agent in GBM; however, the development of resistance to TMZ often becomes the limiting factor in effective treatment. While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance, many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathways, autophagy, epigenetic modifications, microRNAs, and extracellular vesicle production. This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance.
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Affiliation(s)
- Neha Singh
- Division of Neurosurgery, Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA.,Fralin Biomedical Research Institute at VTC, Roanoke, VA 24014, USA
| | - Alexandra Miner
- Division of Neurosurgery, Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA.,Fralin Biomedical Research Institute at VTC, Roanoke, VA 24014, USA
| | - Lauren Hennis
- Division of Neurosurgery, Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA.,Fralin Biomedical Research Institute at VTC, Roanoke, VA 24014, USA
| | - Sandeep Mittal
- Division of Neurosurgery, Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA.,Fralin Biomedical Research Institute at VTC, Roanoke, VA 24014, USA.,Carilion Clinic - Neurosurgery, Roanoke, VA 24014, USA
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23
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The Intratumoral Heterogeneity of Cancer Metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1311:149-160. [PMID: 34014541 DOI: 10.1007/978-3-030-65768-0_11] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancer is one of the deadliest diseases in the world, causing over half a million deaths a year in the USA alone. Despite recent advances made in the field of cancer biology and the therapies that have been developed [1, 2], it is clear that more advances are necessary for us to classify cancer as curable. The logical question that arises is simple: Why, despite all the technologies and medical innovations of our time, has a complete cure eluded us? This chapter sheds light on one of cancer's most impactful attributes: its heterogeneity and, more specifically, the intratumoral heterogeneity of cancer metabolism. Simply put, what makes cancer one of the deadliest diseases is its ability to change and adapt. Cancer cells' rapid evolution, coupled with their irrepressible ability to divide, gives most of them the advantage over our immune systems. In this chapter, we delve into the complexities of this adaptability and the vital role that metabolism plays in the rise and progression of this heterogeneity.
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24
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Jin C, Wei L, Ohgaki R, Tominaga H, Xu M, Okuda S, Okanishi H, Kawamoto Y, He X, Nagamori S, Kanai Y. Interaction of Halogenated Tyrosine/Phenylalanine Derivatives with Organic Anion Transporter 1 in the Renal Handling of Tumor Imaging Probes. J Pharmacol Exp Ther 2020; 375:451-462. [PMID: 32981893 DOI: 10.1124/jpet.120.000235] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 09/16/2020] [Indexed: 03/08/2025] Open
Abstract
Halogenated tyrosine/phenylalanine derivatives have been developed for use in tumor imaging and targeted alpha therapy. 3-Fluoro-α-methyl-l-tyrosine (FAMT), targeting amino acid transporter LAT1 (SLC7A5), is a cancer-specific positron emission tomography probe that exhibits high renal accumulation, which is supposed to be mediated by organic anion transporter OAT1 (SLC22A6). In the present study, we investigated the structural requirements of FAMT essential for interaction with OAT1. OAT1 transported FAMT with a K m of 171.9 μM. In structure-activity relationship analyses, removal of either the 3-halogen or 4-hydroxyl group from FAMT or its structural analog 3-iodo-α-methyl-l-tyrosine greatly decreased the interaction with OAT1, reducing the [14C]p-aminohippurate uptake inhibition and the efflux induction. By contrast, the α-methyl group, which is essential for LAT1 specificity, contributed to a lesser degree. In fluorinated tyrosine derivatives, fluorine at any position was accepted by OAT1 when there was a hydroxyl group at the ortho-position, whereas ortho-fluorine was less interactive when a hydroxyl group was at meta- or para-positions. The replacement of the ortho-fluorine with a bulky iodine atom greatly increased the interaction. In in vivo studies, probenecid decreased the renal accumulation (P < 0.001) and urinary excretion (P = 0.0012) of FAMT, whereas the plasma concentration was increased, suggesting the involvement of OAT1-mediated transepithelial organic anion excretion. LAT1-specific 2-fluoro-α-methyltyrosine, which had lower affinity for OAT1, exhibited lower renal accumulation (P = 0.0142) and higher tumor uptake (P = 0.0192) compared with FAMT. These results would provide a basis to design tumor-specific compounds that can avoid renal accumulation for tumor imaging and targeted alpha therapy. SIGNIFICANCE STATEMENT: We revealed the structural characteristics of halogenated tyrosine derivatives essential for interaction with the organic anion transporter responsible for their renal accumulation. We have confirmed that such interactions are important for renal handling and tumor uptake. The critical contribution of hydroxyl and halogen groups and their positions as well as the role of α-methyl group found in the present study may facilitate the development of tumor-specific compounds while avoiding renal accumulation for use in tumor imaging and targeted alpha therapy.
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Affiliation(s)
- Chunhuan Jin
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
| | - Ling Wei
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
| | - Ryuichi Ohgaki
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
| | - Hideyuki Tominaga
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
| | - Minhui Xu
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
| | - Suguru Okuda
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
| | - Hiroki Okanishi
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
| | - Yasuharu Kawamoto
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
| | - Xin He
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
| | - Shushi Nagamori
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
| | - Yoshikatsu Kanai
- Department of Bio-system Pharmacology, Graduate School of Medicine (C.J., L.W., R.O., M.X., S.O., H.O., Ya.K., Yo.K.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI) (Yo.K.), Osaka University, Osaka, Japan; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan (H.T.); School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China (L.W., X.H.); and Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan (S.N.)
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25
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Delayed 18F-FDG PET/CT Appearance of Urachal Adenocarcinomas. CONTRAST MEDIA & MOLECULAR IMAGING 2020; 2020:3216179. [PMID: 33013244 PMCID: PMC7509541 DOI: 10.1155/2020/3216179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 07/05/2020] [Accepted: 08/28/2020] [Indexed: 12/27/2022]
Abstract
Background Urachal carcinoma is a rare urological malignancy. Use of 18F-FDG PET/CT in urological oncology has developed slowly because of the urinary elimination of 18F-FDG. We investigated whether delayed postdiuretic 18F-FDG PET/CT could be used for diagnosing urachal carcinoma. Methods This retrospective study included 6 patients who underwent delayed postdiuretic 18F-FDG PET/CT for the evaluation of urachal carcinoma. The delayed postdiuretic PET/CT parameters and clinical characteristics of urachal carcinoma were investigated. Results There was no significant difference in the SUVmax between the primary tumors and the urine in the bladder before delayed diuresis (25.4 ± 19.5 vs. 42.9 ± 31.1, P=0.18). However, the SUVmax of the primary tumors was significantly higher than the SUVmax of urine after delayed diuresis (25.4 ± 19.5 vs. 3.5 ± 1.6, P=0.002). Diuretic 18F-FDG PET/CT was positive in all patients when compared with normal liver tissues or urine after delayed diuresis. The SUVmax, TLR, and TUR of the primary tumors were 25.4 (range: 7.2–58.9), 7.0 (range: 1.8–14.7), and 6.8 (range: 3.8–11.3), respectively. Delayed postdiuretic 18F-FDG PET/CT had a negative predictive value of 100% (5/5) for predicting lymph node metastasis. One patient received chemotherapy after radical resection of urachal carcinoma because 18F-FDG PET/CT found lung metastases, and one patient only received chemotherapy because PET/CT found peritoneal and skeletal metastases. Conclusions Delayed postdiuretic 18F-FDG PET/CT is a useful tool for the preoperative evaluation of urachal carcinoma. 18F-FDG PET/CT may improve clinical decision making and management of urachal carcinomas.
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Chan AT, Fox J, Perez Johnston R, Kim J, Brouwer LR, Grizzard J, Kim RJ, Matasar M, Shia J, Moskowitz CS, Steingart R, Weinsaft JW. Late Gadolinium Enhancement Cardiac Magnetic Resonance Tissue Characterization for Cancer-Associated Cardiac Masses: Metabolic and Prognostic Manifestations in Relation to Whole-Body Positron Emission Tomography. J Am Heart Assoc 2020; 8:e011709. [PMID: 31072171 PMCID: PMC6585339 DOI: 10.1161/jaha.118.011709] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Background Cardiac magnetic resonance (CMR) differentiates neoplasm from thrombus via contrast enhancement; positron emission tomography (PET) assesses metabolism. The relationship between CMR contrast enhancement and metabolism on PET is unknown. Methods and Results The population included 121 cancer patients undergoing CMR and 18F‐fluorodeoxyglucose (18F‐FDG)–PET, including 66 with cardiac masses and cancer‐matched controls. Cardiac mass etiology (neoplasm, thrombus) on CMR was defined by late gadolinium enhancement; PET was read blinded to CMR for diagnostic performance, then colocalized to measure FDG avidity. Of CMR‐evidenced thrombi (all nonenhancing), none were detected by PET. For neoplasm, PET yielded reasonable sensitivity (70–83%) and specificity (75–88%). Lesions undetected by PET were more likely to be highly mobile (P=0.001) despite similar size (P=0.33). Among nonmobile neoplasms, PET sensitivity varied in relation to extent of CMR‐evidenced avascularity; detection of diffusely enhancing or mixed lesions was higher versus predominantly avascular neoplasms (87% versus 63%). Colocalized analyses demonstrated 2‐ to 4‐fold higher FDG uptake in neoplasm versus thrombus (P<0.001); FDG uptake decreased stepwise when neoplasms were partitioned based on extent of avascularity on late gadolinium enhancement CMR (P≤0.001). Among patients with neoplasm, signal‐to‐noise ratio on late gadolinium enhancement CMR moderately correlated with standardized uptake values on PET (r=0.42–0.49, P<0.05). Mortality was higher among patients with CMR‐evidenced neoplasm versus controls (hazard ratio: 1.99 [95% CI, 1.1–3.6]; P=0.03) despite nonsignificant differences when partitioned via FDG avidity (hazard ratio: 1.56 [95% CI, 0.85–2.74]; P=0.16). Among FDG‐positive neoplasms detected concordantly with CMR, mortality risk versus cancer‐matched controls was equivalently increased (hazard ratio: 2.12 [95% CI, 1.01–4.44]; P=0.047). Conclusions CMR contrast enhancement provides a criterion for neoplasm that parallels FDG‐evidenced metabolic activity and stratifies prognosis. Extent of tissue avascularity on late gadolinium enhancement CMR affects cardiac mass identification by FDG‐PET.
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Affiliation(s)
- Angel T Chan
- 1 Department of Medicine Memorial Sloan Kettering Cancer Center New York NY.,2 Department of Radiology Memorial Sloan Kettering Cancer Center New York NY.,5 Department of Medicine Icahn School of Medicine at Mt. Sinai New York NY
| | - Josef Fox
- 2 Department of Radiology Memorial Sloan Kettering Cancer Center New York NY
| | | | - Jiwon Kim
- 6 Departments of Medicine and Radiology Weill Cornell Medical College New York NY
| | - Lillian R Brouwer
- 6 Departments of Medicine and Radiology Weill Cornell Medical College New York NY
| | - John Grizzard
- 7 Department of Radiology Virginia Commonwealth University Richmond VA
| | - Raymond J Kim
- 8 Duke Cardiovascular Magnetic Resonance Center Durham NC
| | - Mathew Matasar
- 1 Department of Medicine Memorial Sloan Kettering Cancer Center New York NY
| | - Jinru Shia
- 3 Department of Pathology Memorial Sloan Kettering Cancer Center New York NY
| | - Chaya S Moskowitz
- 4 Department of Epidemiology/Biostatistics Memorial Sloan Kettering Cancer Center New York NY
| | - Richard Steingart
- 1 Department of Medicine Memorial Sloan Kettering Cancer Center New York NY
| | - Jonathan W Weinsaft
- 1 Department of Medicine Memorial Sloan Kettering Cancer Center New York NY.,2 Department of Radiology Memorial Sloan Kettering Cancer Center New York NY.,6 Departments of Medicine and Radiology Weill Cornell Medical College New York NY
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27
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Ellingson BM, Yao J, Raymond C, Nathanson DA, Chakhoyan A, Simpson J, Garner JS, Olivero AG, Mueller LU, Rodon J, Gerstner E, Cloughesy TF, Wen PY. Multiparametric MR-PET Imaging Predicts Pharmacokinetics and Clinical Response to GDC-0084 in Patients with Recurrent High-Grade Glioma. Clin Cancer Res 2020; 26:3135-3144. [PMID: 32269051 DOI: 10.1158/1078-0432.ccr-19-3817] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 02/14/2020] [Accepted: 04/03/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE GDC-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 METHODS Multiparametric 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. RESULTS Measured 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). CONCLUSIONS Results 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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Affiliation(s)
- Benjamin M Ellingson
- UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California. .,Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California.,Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.,Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.,UCLA Neuro-Oncology Program, University of California, Los Angeles, Los Angeles, California
| | - Jingwen Yao
- UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California.,Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.,Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California
| | - Catalina Raymond
- UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California.,Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - David A Nathanson
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Ararat Chakhoyan
- UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California.,Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Jeremy Simpson
- Kazia Therapeutics Limited, Sydney, New South Wales, Australia
| | - James S Garner
- Kazia Therapeutics Limited, Sydney, New South Wales, Australia
| | | | | | - Jordi Rodon
- Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Elizabeth Gerstner
- Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
| | - Timothy F Cloughesy
- UCLA Neuro-Oncology Program, University of California, Los Angeles, Los Angeles, California.,Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Patrick Y Wen
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
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Xin Y, Gao X, Liu L, Ge WP, Jain MK, Cai H. Evaluation of L-1-[ 18F]Fluoroethyl-Tryptophan for PET Imaging of Cancer. Mol Imaging Biol 2020; 21:1138-1146. [PMID: 30815792 DOI: 10.1007/s11307-019-01327-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE Fluorine-18 labeled tryptophan analog L-1-[18F]fluoroethyl-tryptophan (L-1-[18F]FETrp) was designed for positron emission tomography (PET) imaging of cancer by dual targeting of the overexpressed amino acid transporters and altered indoleamine 2,3-dioxygenase (IDO)-mediated kynurenine pathway of tryptophan metabolism. In our previous study, we described the radiosynthesis and preliminary evaluation of L-1-[18F]FETrp for PET imaging of breast cancer. The aim of this study was to investigate the in vivo imaging mechanism and further evaluate this radiotracer in more wide range types of cancers including prostate cancer, lung cancer, and glioma. PROCEDURES The mice bearing subcutaneous PC-3 prostate cancer, subcutaneous H2009 and H460 lung cancers, subcutaneous MDA-MB-231, orthotopic A549 lung cancer, and intracranial 73C glioma were employed to evaluate L-1-[18F]FETrp for PET imaging of cancer. The in vivo catabolism of L-1-[18F]FETrp in the tumor was studied by analysis of PC-3 extracts with radio-HPLC. RESULTS Small animal PET/CT imaging of L-1-[18F]FETrp visualized all tumors in these different mouse models with high accumulations of radioactivity in PC-3 (7.5 ± 0.6 % ID/g), H2009 (5.3 ± 0.8 % ID/g), H460 (9.0 ± 1.4 % ID/g), A549 (4.5 ± 0.5 % ID/g), and 73C (4.1 ± 0.7 % ID/g) tumors. The radio-HPLC analysis of PC-3 tumor extracts revealed that about 30 % of L-1-[18F]FETrp was converted into a highly polar radioactive metabolite. The uptake in H460 cancer was about 1.7-fold higher than that in H2009 cancer, which indicated L-1-[18F]FETrp could differentiate these subtypes of lung cancers (H2009 and H460) by imaging quantification. Furthermore, small animal PET/CT imaging in intracranial glioma revealed L-1-[18F]FETrp could pass blood-brain barrier (BBB) and accumulate in glioma with a favorable imaging contrast (tumor-to-brain 2.9). CONCLUSIONS L-1-[18F]FETrp highly accumulated in a wide range of malignancies including lung cancer, prostate cancer, and glioma. These results suggested that L-1-[18F]FETrp is a promising radiotracer for PET imaging of cancer.
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Affiliation(s)
- Yangchun Xin
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.,Katzin Diagnostic & Research PET/MR Center, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE, 19803, USA
| | - Xiaofei Gao
- Children's Research Institute, Department of Pediatrics, Neuroscience, Neurology & Neurotherapeutics, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Li Liu
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Woo-Ping Ge
- Children's Research Institute, Department of Pediatrics, Neuroscience, Neurology & Neurotherapeutics, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Manoj K Jain
- Department of Radiology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Hancheng Cai
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. .,Department of Radiology, Mayo Clinic, Jacksonville, FL, 32224, USA. .,Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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Shi Y, Chen R, Wang Y, Huang G, Xia Q, Liu J. Delayed post-diuretic 18F-FDG PET/CT for preoperative evaluation of renal pelvic cancer. J Cancer 2020; 11:3745-3750. [PMID: 32328179 PMCID: PMC7171487 DOI: 10.7150/jca.44512] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/28/2020] [Indexed: 11/18/2022] Open
Abstract
Background: Application of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in urological oncology was relatively slowly due to the urinary elimination of 18F-FDG. We investigated whether delayed post-diuretic 18F-FDG PET/CT could be used for diagnosing renal pelvic cancer. Methods: 51 patients were included who underwent delayed post-diuretic 18F-FDG PET/CT for detecting renal pelvic space-occupying lesions. The comparations of delayed PET/CT parameters and clinical characteristics between renal pelvic cancer and benign polyp were investigated. Results: Among the 51 patients, 47 were found to have renal pelvic urothelial carcinoma, and 4 had benign polyp. ROC analysis identified the lesion maximum standardized uptake value (SUVmax) of 6.2 as the optimal cut-off value to distinguish from renal pelvic urothelial carcinoma to benign polyp. With the SUVmax cut-off of 6.2, the sensitivity, and specificity for predicting of renal pelvic urothelial carcinoma were 91.5% (43/47), and 100% (4/4). We also found a significant difference in tumor size between the positive (SUVmax > 6.2) and negative (SUVmax ≤ 6.2) PET groups in renal pelvic cancers. In patients with tumor size < 1.1 cm, the probability of being in the negative PET group was 75%. In such patients, a substantial proportion of renal pelvic cancer demonstrated negative SUVmax similar to that in patients with benign polyp. Conclusion: Delayed 18F-FDG PET/CT could be used for differentiating renal pelvic cancer from benign polyp. In patients with small tumor size, renal pelvic cancer may present low 18F-FDG uptake, mimicking the metabolic phenotypes of patients with benign polyp.
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Affiliation(s)
- Yiping Shi
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ruohua Chen
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yining Wang
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Gan Huang
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qian Xia
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianjun Liu
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Liu J, Liao X, Xiong K, Kuang S, Jin C, Ji L, Chao H. Boosting two-photon photodynamic therapy with mitochondria-targeting ruthenium-glucose conjugates. Chem Commun (Camb) 2020; 56:5839-5842. [PMID: 32330213 DOI: 10.1039/d0cc01148g] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Herein, we present a series of dual-targeted ruthenium-glucose conjugates that can function as two-photon absorption (TPA) PDT agents to effectively destroy tumors by preferentially targeting both tumor cells and mitochondria. The in vivo experiments revealed an excellent tumor inhibitory efficiency of the dual-targeted TPA PSs.
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Affiliation(s)
- Jiangping Liu
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P. R. China.
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Zhang Y, Liu J, Sun Y, Yu X, Wang J, Dai D, Zhu Y, Song X, Zhu L, Li X, Xu W. Enhanced glucose metabolism mediated by CD147 is associated with 18 F-FDG PET/CT imaging in lung adenocarcinoma. Thorac Cancer 2020; 11:1245-1257. [PMID: 32162491 PMCID: PMC7180588 DOI: 10.1111/1759-7714.13383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 02/18/2020] [Accepted: 02/19/2020] [Indexed: 12/12/2022] Open
Abstract
Background Lung adenocarcinoma (LUAD) is one of the most deadly thoracic tumors. Reprogrammed glycolytic metabolism is a hallmark of cancer cells and significantly affects several cellular functions. In the current study, we aimed to investigate cluster of differentiation 147 (CD147)‐mediated glucose metabolic regulation in LUAD and its association with 18F‐FDG PET/CT imaging. Methods The expression profile and prognostic potential of CD147 in LUAD were analyzed using UALCAN and a Kaplan‐Meier plotter. Tissue immunohistochemical analyses and PET metabolic parameters were used to identify the relationship between CD147 expression and reprogrammed glycolysis. The role of CD147 in glucose metabolic reprogramming was assessed by radioactive uptake of 18F‐FDG through γ‐radioimmunoassays in vitro and micro‐PET/CT imaging in vivo. Western blotting assays were used to determine the expression level of monocarboxylate transporter 1 (MCT1) and MCT4 in established human LUAD cell lines (ie, HCC827 and H1975) with different CD147 expression levels via lentiviral transduction. Results CD147 was highly expressed in LUAD. A significant positive correlation existed between CD147 expression and PET metabolic parameters(SUVmax,SUVmean, SUVpeak). CD147 could promote radioactive uptake of 18F‐FDG in vitro and in vivo, suggesting the ability of CD147 to enhance glycolytic metabolism. Furthermore, as an obligate chaperone for MCT1 and MCT4, CD147 positively correlated with MCT1 and MCT4 expression in LUAD tissues and established cell lines with different CD147 expression. Conclusions Our study revealed that CD147 is a promising novel target for LUAD treatment and CD147‐mediated glucose metabolism demonstrated its contribution to the predictive role of 18F‐FDG PET/CT imaging for targeted therapeutic efficacy.
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Affiliation(s)
- Yufan Zhang
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jianjing Liu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yunchuan Sun
- Department of Nuclear Medicine, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
| | - Xiaozhou Yu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jian Wang
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Dong Dai
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yanjia Zhu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiuyu Song
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Lei Zhu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiaofeng Li
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wengui Xu
- Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
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Zhang Z, Liu S, Ma H, Nie D, Wen F, Zhao J, Sun A, Yuan G, Su S, Xiang X, Hu P, Tang G. Validation of R-2-[18F]Fluoropropionic Acid as a Potential Tracer for PET Imaging of Liver Cancer. Mol Imaging Biol 2019; 21:1127-1137. [PMID: 30847820 DOI: 10.1007/s11307-019-01346-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Mankoff DA, Pantel AR, Viswanath V, Karp JS. Advances in PET Diagnostics for Guiding Targeted Cancer Therapy and Studying In Vivo Cancer Biology. CURRENT PATHOBIOLOGY REPORTS 2019; 7:97-108. [PMID: 37092138 PMCID: PMC10117535 DOI: 10.1007/s40139-019-00202-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Purpose of the Review We present an overview of recent advances in positron emission tomography (PET) diagnostics as applied to the study of cancer, specifically as a tool to study in vivo cancer biology and to direct targeted cancer therapy. The review is directed to translational and clinical cancer investigators who may not be familiar with these applications of PET cancer diagnostics, but whose research might benefit from these advancing tools. Recent Findings We highlight recent advances in 3 areas: (1) the translation of PET imaging cancer biomarkers to clinical trials; (2) methods for measuring cancer metabolism in vivo in patients; and (3) advances in PET instrumentation, including total-body PET, that enable new methodologies. We emphasize approaches that have been translated to human studies. Summary PET imaging methodology enables unique in vivo cancer diagnostics that go beyond cancer detection and staging, providing an improved ability to guide cancer treatment and an increased understanding of in vivo human cancer biology.
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Affiliation(s)
- David A Mankoff
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Austin R Pantel
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Varsha Viswanath
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Joel S Karp
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Hanaoka H, Ohshima Y, Yamaguchi A, Suzuki H, Ishioka NS, Higuchi T, Arano Y, Tsushima Y. Novel 18F-Labeled α-Methyl-Phenylalanine Derivative with High Tumor Accumulation and Ideal Pharmacokinetics for Tumor-Specific Imaging. Mol Pharm 2019; 16:3609-3616. [DOI: 10.1021/acs.molpharmaceut.9b00446] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Hirofumi Hanaoka
- Department of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
| | - Yasuhiro Ohshima
- Project “Medical Radioisotope Application”, Department of Radiation-Applied Biology Research, Takasaki Advanced Radiation Research Institute, Quantum Beam Advanced Research Directorate, National Institutes for Quantum and Radiological Science and Technology (QST), Takasaki 370-1292, Japan
| | - Aiko Yamaguchi
- Department of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Science, Chiba University, Chiba 260-8675, Japan
| | - Noriko S. Ishioka
- Project “Medical Radioisotope Application”, Department of Radiation-Applied Biology Research, Takasaki Advanced Radiation Research Institute, Quantum Beam Advanced Research Directorate, National Institutes for Quantum and Radiological Science and Technology (QST), Takasaki 370-1292, Japan
| | - Tetsuya Higuchi
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
| | - Yasushi Arano
- Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Science, Chiba University, Chiba 260-8675, Japan
| | - Yoshito Tsushima
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
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Mirus M, Tokalov SV, Abramyuk A, Heinold J, Prochnow V, Zöphel K, Kotzerke J, Abolmaali N. Noninvasive assessment and quantification of tumor vascularization using [18F]FDG-PET/CT and CE-CT in a tumor model with modifiable angiogenesis-an animal experimental prospective cohort study. EJNMMI Res 2019; 9:55. [PMID: 31227938 PMCID: PMC6588673 DOI: 10.1186/s13550-019-0502-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 03/14/2019] [Indexed: 02/06/2023] Open
Abstract
Background This study investigated the noninvasive assessment of tumor vascularization with clinical F-18-fluorodeoxyglucose positron emission tomography/computed tomography and contrast-enhanced computed tomography ([18F]FDG-PET/CT and CE-CT) in experimental human xenograft tumors with modifiable vascularization and compared results to histology. Tumor xenografts with modifiable vascularization were established in 71 athymic nude rats by subcutaneous transplantation of human non-small-cell lung cancer (NSCLC) cells. Four different groups were transplanted with two different tumor cell lines (either A549 or H1299) alone or tumors co-transplanted with rat glomerular endothelial (RGE) cells, the latter to increase vascularization. Tumors were assessed noninvasively by [18F]FDG PET/CT and contrast-enhanced CT (CE-CT) using clinical scanners. This was followed by histological examinations evaluating tumor vasculature (CD-31 and intravascular fluorescent beads). Results In both tumor lines (A549 and H1299), co-transplantation of RGE cells resulted in faster growth rates [maximal tumor diameter of 20 mm after 22 (± 1.2) as compared to 45 (± 1.8) days, p < 0.001], higher microvessel density (MVD) determined histologically after CD-31 staining [171.4 (± 18.9) as compared to 110.8 (± 11) vessels per mm2, p = 0.002], and higher perfusion as indicated by the number of beads [1.3 (± 0.1) as compared to 1.1 (± 0.04) beads per field of view, p = 0.001]. In [18F]FDG-PET/CT, co-transplanted tumors revealed significantly higher standardized uptake values [SUVmax, 2.8 (± 0.2) as compared to 1.1 (± 0.1), p < 0.001] and larger metabolic active volumes [2.4 (± 0.2) as compared to 0.4 (± 0.2) cm3, p < 0.001] than non-co-transplanted tumors. There were significant correlations for vascularization parameters derived from histology and [18F]FDG PET/CT [beads and SUVmax, r = 0.353, p = 0.005; CD-31 and SUVmax, r = 0.294, p = 0.036] as well as between CE-CT and [18F]FDG PET/CT [contrast enhancement and SUVmax, r = 0.63, p < 0.001; vital CT tumor volume and metabolic PET tumor volume, r = 0.919, p < 0.001]. Conclusions In this study, a human xenograft tumor model with modifiable vascularization implementable for imaging, pharmacological, and radiation therapy studies was successfully established. Both [18F]FDG-PET/CT and CE-CT are capable to detect parameters closely connected to the degree of tumor vascularization, thus they can help to evaluate vascularization in tumors noninvasively. [18F]FDG-PET may be considered for characterization of tumors beyond pure glucose metabolism and have much greater contribution to diagnostics in oncology.
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Affiliation(s)
- Martin Mirus
- Biological and Molecular Imaging, OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany.,Department of Anaesthesiology and Critical Care Medicine, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Institution under Public Law of the Free State of Saxony, Fetscherstraße 74, 01307, Dresden, Germany
| | - Sergey V Tokalov
- Biological and Molecular Imaging, OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany
| | - Andrij Abramyuk
- Biological and Molecular Imaging, OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany.,Department of Neuroradiology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany
| | - Jessica Heinold
- Biological and Molecular Imaging, OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany.,Municipal Hospital Dresden-Neustadt, Department of Neurology, Industriestraße 40, 01129, Dresden, Germany
| | - Vincent Prochnow
- Biological and Molecular Imaging, OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany.,Clinic for Obstetrics and Gynaecology, Klinikum Chemnitz, Flemmingstraße 4, 09116, Chemnitz, Germany
| | - Klaus Zöphel
- Department of Nuclear Medicine, University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307, Dresden, Germany
| | - Jörg Kotzerke
- Department of Nuclear Medicine, University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307, Dresden, Germany
| | - Nasreddin Abolmaali
- Biological and Molecular Imaging, OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany. .,Department of Radiology, Municipal Hospital and Academic Teaching Hospital of the Technical University Dresden, Dresden-Friedrichstadt, Friedrichstraße 41, 01067, Dresden, Germany.
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Ralph SJ, Nozuhur S, ALHulais RA, Rodríguez‐Enríquez S, Moreno‐Sánchez R. Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers. Med Res Rev 2019; 39:2397-2426. [DOI: 10.1002/med.21589] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 03/20/2019] [Accepted: 03/31/2019] [Indexed: 01/10/2023]
Affiliation(s)
- Stephen J. Ralph
- School of Medical ScienceGriffith University Southport Australia
| | - Sam Nozuhur
- School of Medical ScienceGriffith University Southport Australia
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Ntziachristos V, Pleitez MA, Aime S, Brindle KM. Emerging Technologies to Image Tissue Metabolism. Cell Metab 2019; 29:518-538. [PMID: 30269982 DOI: 10.1016/j.cmet.2018.09.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 07/24/2018] [Accepted: 09/02/2018] [Indexed: 12/19/2022]
Abstract
Due to the implication of altered metabolism in a large spectrum of tissue function and disease, assessment of metabolic processes becomes essential in managing health. In this regard, imaging can play a critical role in allowing observation of biochemical and physiological processes. Nuclear imaging methods, in particular positron emission tomography, have been widely employed for imaging metabolism but are mainly limited by the use of ionizing radiation and the sensing of only one parameter at each scanning session. Observations in healthy individuals or longitudinal studies of disease could markedly benefit from non-ionizing, multi-parameter imaging methods. We therefore focus this review on progress with the non-ionizing radiation methods of MRI, hyperpolarized magnetic resonance and magnetic resonance spectroscopy, chemical exchange saturation transfer, and emerging optoacoustic (photoacoustic) imaging. We also briefly discuss the role of nuclear and optical imaging methods for research and clinical protocols.
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Affiliation(s)
- Vasilis Ntziachristos
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, Neuherberg 85764, Germany; Chair of Biological Imaging, TranslaTUM, Technical University of Munich, Ismaningerstr. 22, Munich 81675, Germany.
| | - Miguel A Pleitez
- Institute of Biological and Medical Imaging, Helmholtz Zentrum München, Neuherberg 85764, Germany; Chair of Biological Imaging, TranslaTUM, Technical University of Munich, Ismaningerstr. 22, Munich 81675, Germany
| | - Silvio Aime
- Molecular Imaging Center, Department of Molecular Biotechnologies and Health Sciences, University of Turin, Turin 10126, Italy
| | - Kevin M Brindle
- Department of Biochemistry, University of Cambridge, Old Addenbrooke's Site, Cambridge CB2 1GA, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
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Integrating Small Animal Irradiators withFunctional Imaging for Advanced Preclinical Radiotherapy Research. Cancers (Basel) 2019; 11:cancers11020170. [PMID: 30717307 PMCID: PMC6406472 DOI: 10.3390/cancers11020170] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 01/23/2019] [Accepted: 01/29/2019] [Indexed: 12/16/2022] Open
Abstract
Translational research aims to provide direct support for advancing novel treatment approaches in oncology towards improving patient outcomes. Preclinical studies have a central role in this process and the ability to accurately model biological and physical aspects of the clinical scenario in radiation oncology is critical to translational success. The use of small animal irradiators with disease relevant mouse models and advanced in vivo imaging approaches offers unique possibilities to interrogate the radiotherapy response of tumors and normal tissues with high potential to translate to improvements in clinical outcomes. The present review highlights the current technology and applications of small animal irradiators, and explores how these can be combined with molecular and functional imaging in advanced preclinical radiotherapy research.
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Shukla SK, Mulder SE, Singh PK. Hypoxia-Mediated In Vivo Tumor Glucose Uptake Measurement and Analysis. Methods Mol Biol 2019; 1742:107-113. [PMID: 29330794 DOI: 10.1007/978-1-4939-7665-2_10] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Most solid tumors are hypoxic in nature due to the limited supply of oxygen to internal tissues. Hypoxia plays an important role in metabolic adaptations of tumors that contribute significantly to cancer pathogenesis. Among the several metabolic alterations induced by hypoxia, hypoxia-mediated increased glucose uptake serves as the hallmark of metabolic reprogramming. Hypoxia-mediated stabilization of hypoxia-inducible factor-1 alpha (HIF-1α) transcription factor leads to altered expression of several glycolytic genes and glucose transporters, which results in increased glucose uptake by tumor cells. Here we describe an easy and simple way of measuring the hypoxia-mediated tumor glucose uptake in vivo. The method is based on fluorescent imaging probe, RediJect 2-DG, which is a nonradioactive fluorescent-tagged glucose molecule. We have discussed orthotopic tumor implantation of HIF-1α knockdown and control pancreatic cancer cells and glucose uptake measurement in vivo by using IVIS imaging system along with reagent preparations.
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Affiliation(s)
- Surendra K Shukla
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Scott E Mulder
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pankaj K Singh
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
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Grkovski M, Gharzeddine K, Sawan P, Schöder H, Michaud L, Weber WA, Humm JL. 11C-Choline Pharmacokinetics in Recurrent Prostate Cancer. J Nucl Med 2018; 59:1672-1678. [PMID: 29626123 PMCID: PMC6225540 DOI: 10.2967/jnumed.118.210088] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 03/23/2018] [Indexed: 11/16/2022] Open
Abstract
The aim of this study was to investigate the value of pharmacokinetic modeling for quantifying 11C-choline uptake in patients with recurrent prostate cancer. Methods: In total, 194 patients with clinically suspected recurrence of prostate cancer underwent 11C-choline dynamic PET over the pelvic region (0-8 min), followed by a 6-min static acquisition at about 25 min after injection. Regions of interest were drawn over sites of disease identified by a radiologist with experience in nuclear medicine. 11C-choline uptake and pharmacokinetics were evaluated by SUV, graphical analysis (Patlak plot; KiP), and 1- and 2-compartment pharmacokinetic models (K1, K1/k2, k3, k4, and the macro parameter KiC). Twenty-four local recurrences, 65 metastatic lymph nodes, 19 osseous metastases, and 60 inflammatory lymph nodes were included in the analysis, which was subsequently repeated for regions of interest placed over the gluteus maximus muscle and adipose tissue as a control. Results: SUVmean and KiP were 3.60 ± 2.16 and 0.28 ± 0.22 min-1 in lesions, compared with 2.11 ± 1.33 and 0.15 ± 0.10 min-1 in muscle and 0.26 ± 0.07 and 0.02 ± 0.01 min-1 in adipose tissue. According to the Akaike information criterion, the 2-compartment irreversible model was most appropriate in 85% of lesions and resulted in a K1 of 0.79 ± 0.98 min-1 (range, 0.11-7.17 min-1), a K1/k2 of 2.92 ± 3.52 (range, 0.31-20.00), a k3 of 0.36 ± 0.30 min-1 (range, 0.00-1.00 min-1) and a KiC of 0.28 ± 0.22 min-1 (range, 0.00-1.33 min-1). The Spearman ρ between SUV and KiP, between SUV and KiC, and between KiP and KiC was 0.94, 0.91, and 0.97, respectively, and that between SUV and K1, between SUV and K1/k2, and between SUV and k3 was 0.70, 0.44, and 0.33, respectively. Malignant lymph nodes exhibited a higher SUV, KiP, and KiC than benign lymph nodes. Conclusion: Although 11C-choline pharmacokinetic modeling has potential to uncouple the contributions of different processes leading to intracellular entrapment of 11C-choline, the high correlation between SUV and both KiP and KiC supports the use of simpler SUV methods to evaluate changes in 11C-choline uptake and metabolism for treatment monitoring.
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Affiliation(s)
- Milan Grkovski
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Karem Gharzeddine
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Peter Sawan
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Heiko Schöder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York; and
| | - Laure Michaud
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Wolfgang A Weber
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York; and
- University Hospital Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - John L Humm
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
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Utility of FDG PET/CT in the Characterization of Sinonasal Neoplasms: Analysis of Standardized Uptake Value Parameters. AJR Am J Roentgenol 2018; 211:1354-1360. [PMID: 30300005 DOI: 10.2214/ajr.18.19501] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE We aimed to evaluate the contribution of different standardized uptake value (SUV) parameters generated from pretreatment 18F-FDG PET/CT in the characterization of sinonasal neoplasms with histopathologic correlations. MATERIALS AND METHODS This retrospective study included 97 consecutive patients (58 men, 39 women; age range, 20-93 years; mean age, 62 years) with pathologically proven untreated sinonasal neoplasms who underwent FDG PET/CT from February 2010 to August 2017. Semiquantitative analysis of primary tumors were performed to evaluate the maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), and the ratio of the SUVmax of the primary tumor to the SUVmean of mediastinal blood pool, which we refer to here as " SUVratio." Various sinonasal tumor histopathologic subgroups (n = 14) were analyzed. The Kruskal-Wallis test was used to compare the SUVmax, SUVmean, and SUVratio with the histopathologic diagnosis. RESULTS Mean values of SUVmax, SUVmean, and SUVratio for the sinonasal neoplasms were 16.6 ± 9.7 (SD), 8.6 ± 5.1, and 5.9 ± 3.7, respectively, and each parameter was significantly different between histopathologic types (p < 0.05). Mean values of SUVmax, SUVmean, and SUVratio were higher in sinonasal undifferentiated carcinoma (SNUC) than in olfactory neuroblastoma, metastasis, and adenoid cystic carcinoma (p < 0.05). Mean values of SUVmax and SUVmean were higher in squamous cell carcinoma (SCC) than in olfactory neuroblastoma and metastasis (p < 0.05). Also, mean SUVmax was higher in SCC and SNUC than in poorly differentiated carcinoma (p < 0.05). Mean SUVratio was higher in SCC than in small cell carcinoma, olfactory neuroblastoma, and adenoid cystic carcinoma (p < 0.05). CONCLUSION We conclude that different SUV parameters from FDG PET/CT can be used as so-called "metabolic biopsy" to categorize sinonasal neoplasms into different histopathologic subgroups because it can help in the characterization of some of the more common subgroups of sinonasal neoplasms. However, we found that there is overlap in FDG uptake values among some of the rare histologic subgroups; hence, surgical biopsy is still needed for differentiation of histologic subtypes of aggressive sinonasal masses.
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Pantel AR, Ackerman D, Lee SC, Mankoff DA, Gade TP. Imaging Cancer Metabolism: Underlying Biology and Emerging Strategies. J Nucl Med 2018; 59:1340-1349. [PMID: 30042161 PMCID: PMC6126440 DOI: 10.2967/jnumed.117.199869] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 06/18/2018] [Indexed: 12/22/2022] Open
Abstract
Dysregulated cellular metabolism is a characteristic feature of malignancy that has been exploited for both imaging and targeted therapy. With regard to imaging, deranged glucose metabolism has been leveraged using 18F-FDG PET. Metabolic imaging with 18F-FDG, however, probes only the early steps of glycolysis; the complexities of metabolism beyond these early steps in this single pathway are not directly captured. New imaging technologies-both PET with novel radiotracers and MR-based methods-provide unique opportunities to investigate other aspects of cellular metabolism and expand the metabolic imaging armamentarium. This review will discuss the underlying biology of metabolic dysregulation in cancer, focusing on glucose, glutamine, and acetate metabolism. Novel imaging strategies will be discussed within this biologic framework, highlighting particular strengths and limitations of each technique. Emphasis is placed on the role that combining modalities will play in enabling multiparametric imaging to fully characterize tumor biology to better inform treatment.
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Affiliation(s)
- Austin R Pantel
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Daniel Ackerman
- Penn Image-Guided Interventions Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania; and
| | - Seung-Cheol Lee
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David A Mankoff
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Terence P Gade
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Penn Image-Guided Interventions Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania; and
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania
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Ancey PB, Contat C, Meylan E. Glucose transporters in cancer - from tumor cells to the tumor microenvironment. FEBS J 2018; 285:2926-2943. [PMID: 29893496 DOI: 10.1111/febs.14577] [Citation(s) in RCA: 343] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 05/17/2018] [Accepted: 06/08/2018] [Indexed: 12/18/2022]
Abstract
Solute carriers of the glucose transporter (GLUT) family mediate the first step for cellular glucose usage. The upregulation of GLUTs has been reported in numerous cancer types as a result of perturbation of gene expression or protein relocalization or stabilization. Because they enable to sustain the energy demand required by tumor cells for various biochemical programs, they are promising targets for the development of anticancer strategies. Recently, important biological insights have come from the fine crystal structure determination of several GLUTs; these advances will likely catalyze the development of new selective inhibitory compounds. Furthermore, deregulated glucose metabolism of nontumor cells in the tumor mass is beginning to be appreciated and could have major implications for our understanding of how glucose uptake by specific cell types influences the behavior of neighboring cells in the same microenvironment. In this review, we discuss some of the deregulation mechanisms of glucose transporters, their genetic and pharmacological targeting in cancer, and new functions they may have in nontumor cells of the tumor environment or beyond glucose uptake for glycolysis.
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Affiliation(s)
- Pierre-Benoit Ancey
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Switzerland
| | - Caroline Contat
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Switzerland
| | - Etienne Meylan
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Switzerland
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Calais J, Cao M, Nickols NG. The Utility of PET/CT in the Planning of External Radiation Therapy for Prostate Cancer. J Nucl Med 2018; 59:557-567. [PMID: 29301928 PMCID: PMC6910632 DOI: 10.2967/jnumed.117.196444] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 12/01/2017] [Indexed: 12/25/2022] Open
Abstract
Radiotherapy and radical prostatectomy are the definitive treatment options for patients with localized prostate cancer. A rising level of prostate-specific antigen after radical prostatectomy indicates prostate cancer recurrence, and these patients may still be cured with salvage radiotherapy. To maximize chance for cure, the irradiated volumes should completely encompass the extent of disease. Therefore, accurate estimation of the location of disease is critical for radiotherapy planning in both the definitive and the salvage settings. Current first-line imaging for prostate cancer has limited sensitivity for detection of disease both at initial staging and at biochemical recurrence. Integration of PET into routine evaluation of prostate cancer patients may improve both staging accuracy and radiotherapy planning. 18F-FDG PET/CT is now routinely used in radiation planning for several cancer types. However, 18F-FDG PET/CT has low sensitivity for prostate cancer. Additional PET probes evaluated in prostate cancer include 18F-sodium fluoride, 11C-acetate, 11C- or 18F-choline, 18F-fluciclovine, and 68Ga- or 18F-labeled ligands that bind prostate-specific membrane antigen (PSMA). PSMA ligands appear to be the most sensitive and specific but have not yet received Food and Drug Administration New Drug Application approval for use in the United States. Retrospective and prospective investigations suggest a potential major impact of PET/CT on prostate radiation treatment planning. Prospective trials randomizing patients to routine radiotherapy planning versus PET/CT-aided planning may show meaningful clinical outcomes. Prospective clinical trials evaluating the addition of 18F-fluciclovine PET/CT for planning of salvage radiotherapy with clinical endpoints are under way. Prospective trials evaluating the clinical impact of PSMA PET/CT on prostate radiation planning are indicated.
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Affiliation(s)
- Jeremie Calais
- Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
| | - Minsong Cao
- Department of Radiation Oncology, UCLA, Los Angeles, California; and
| | - Nicholas G Nickols
- Department of Radiation Oncology, UCLA, Los Angeles, California; and
- Department of Radiation Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, California
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Lavallée E, Bergeron M, Buteau FA, Blouin AC, Duchesnay N, Dujardin T, Tiguert R, Lacombe L, Fradet V, Makao-Nguile M, Fradet Y, Beauregard JM, Pouliot F. Increased Prostate Cancer Glucose Metabolism Detected by 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Localised Gleason 8-10 Prostate Cancers Identifies Very High-risk Patients for Early Recurrence and Resistance to Castration. Eur Urol Focus 2018; 5:998-1006. [PMID: 29609897 DOI: 10.1016/j.euf.2018.03.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 02/19/2018] [Accepted: 03/14/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND The accuracy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to stage prostate cancer (PCa) is limited. However, Gleason 8-10 PCa and more aggressive metastatic PCa have been shown to exhibit a higher glycolytic activity. OBJECTIVE To evaluate the potential of intraprostatic FDG uptake to prognose Gleason 8-10 PCa patients prior to prostatectomy, based on tumour intrinsic biology. DESIGN, SETTING, AND PARTICIPANTS FDG-PET/CT and a bone scan were performed as a staging procedure prior to prostatectomy in 148 consecutive patients diagnosed with PCa with a Gleason sum of ≥8 at biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The FDG-PET/CT images were blind reviewed. Lymph node (LN) metastasis and intraprostatic FDG uptake were systematically recorded, and correlated with the patients' clinicopathological characteristics. RESULTS AND LIMITATIONS FDG-PET/CT detected foci of intraprostatic FDG uptake in 66% of patients. An intraprostatic FDG uptake of maximum intraprostatic standardised uptake value (SUVmax) of ≥4.6 was statistically significantly associated with a higher pathological Gleason ≥8, extracapsular extension, seminal vesicle invasion, and pathological LN metastasis. In multivariate analysis, an intraprostatic SUVmax of ≥4.6 was associated with a two-fold increased risk of biochemical recurrence in the year following surgery. Patients with an intraprostatic SUVmax of ≥4.6 had estimated median biochemical recurrence-free survival (BFS) of 11.3mo compared with 49.5mo for those with a lower SUVmax. Finally, high intraprostatic FDG uptake was associated with shorter time to castration resistance following radical prostatectomy (RP). CONCLUSIONS Preoperative intraprostatic FDG uptake is an integrator of adverse pathological prognostic factors, predicting BFS and castration resistance following RP in patients with a Gleason score ≥8 PCa at biopsy. These results support the use of preoperative FDG-PET/CT as a tool to distinguish at diagnosis very high-risk Gleason 8-10 PCa patients in whom novel neoadjuvant or adjuvant therapies should be explored. PATIENT SUMMARY This study shows that an increased use of glucose by prostate cancer cells detected by 18F-fluorodeoxyglucose positron emission tomography molecular imaging can identify aggressive prostate cancers.
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Affiliation(s)
- Etienne Lavallée
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Michelle Bergeron
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - François-Alexandre Buteau
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Annie-Claude Blouin
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Nicolas Duchesnay
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Thierry Dujardin
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Rabi Tiguert
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Louis Lacombe
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Vincent Fradet
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Molière Makao-Nguile
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Yves Fradet
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Jean-Mathieu Beauregard
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada
| | - Frédéric Pouliot
- Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Québec City, Canada; Division of Urology, Department of Surgery and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Québec City, Canada; Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec-Université Laval, Québec City, Canada.
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Evaluation of new 99mTc-labeled HYNIC-bombesin analogue for prostate cancer imaging. J Radioanal Nucl Chem 2018. [DOI: 10.1007/s10967-018-5819-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Shen LF, Zhao X, Zhou SH, Lu ZJ, Zhao K, Fan J, Zhou ML. In vivo evaluation of the effects of simultaneous inhibition of GLUT-1 and HIF-1α by antisense oligodeoxynucleotides on the radiosensitivity of laryngeal carcinoma using micro 18F-FDG PET/CT. Oncotarget 2018; 8:34709-34726. [PMID: 28410229 PMCID: PMC5471005 DOI: 10.18632/oncotarget.16671] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 03/15/2017] [Indexed: 12/27/2022] Open
Abstract
Purpose Hypoxia-inducible factor 1α (HIF-1α) and glucose transporter-1 (GLUT-1) are two important hypoxic markers associated with the radioresistance of cancers including laryngeal carcinoma. We evaluated whether the simultaneous inhibition of GLUT-1 and HIF-1α expression improved the radiosensitivity of laryngeal carcinoma. We explored whether the expression of HIF-1α and GLUT-1 was correlated with 2′-deoxy-2’-[18F]fluoro-D-glucose (18F-FDG) uptake and whether 18F-FDG positron emission tomography-computed tomography (PET/CT) was appropriate for early evaluation of the response of laryngeal carcinoma to targeted treatment in vivo. Materials and Methods To verify the above hypotheses, an in vivo model was applied by subcutaneously injecting Hep-2 (2 × 107/mL × 0.2 mL) and Tu212 cells (2 × 107/mL × 0.2 mL) into nude mice. The effects of HIF-1α antisense oligodeoxynucleotides (AS-ODNs) (100 μg) and GLUT-1 AS-ODNs (100 μg) on the radiosensitivity of laryngeal carcinoma were assessed by tumor volume and weight, microvessel density (MVD), apoptosis index (AI) and necrosis in vivo based on a full factorial (23) design. 18F-FDG-PET/CT was taken before and after the treatment of xenografts. The relationships between HIF-1α and GLUT-1 expression and 18F-FDG uptake in xenografts were estimated and the value of 18F-FDG-PET/CT was assessed after treating the xenografts. Results 10 Gy X-ray irradiation decreased the weight of Hep-2 xenografts 8 and 12 days after treatment, and the weights of Tu212 xenografts 8 days after treatment. GLUT-1 AS-ODNs decreased the weight of Tu212 xenografts 12 days after treatment. There was a synergistic interaction among the three treatments (GLUT-1 AS-ODNs, HIF-1α AS-ODNs and 10Gy X-ray irradiation) in increasing apoptosis, decreasing MVD, and increasing necrosis in Hep-2 xenografts 8 days after treatment (p < 0.05) and in Tu212 xenografts 12 days after treatment (p < 0.001). Standardized uptake value (tumor/normal tissue)( SUVmaxT/N) did not show a statistically significant correlation with GLUT1 and HIF-1α expression and therapeutic effect (necrosis, apoptosis). Conclusions Simultaneous inhibition of HIF-1α and GLUT-1 expression might increase the radiosensitivity of laryngeal carcinoma, decreasing MVD, and promoting apoptosis and necrosis. 18F-FDG-PET/CT wasn't useful in evaluating the therapeutic effect on laryngeal cancer in this animal study.
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Affiliation(s)
- Li-Fang Shen
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China
| | - Xin Zhao
- Center of PET/CT, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China
| | - Shui-Hong Zhou
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China
| | - Zhong-Jie Lu
- Department of Radiotherapy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China
| | - Kui Zhao
- Center of PET/CT, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China
| | - Jun Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China
| | - Min-Li Zhou
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, China
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Zhang Z, Liu S, Tang X, Nie D, Tang G, Sun A, Xiong Y, Ma H, Wen F, Hu P. Radiosynthesis and preliminary biological evaluation of the 2-[18F]fluoropropionic acid enantiomers for tumor PET imaging. J Radioanal Nucl Chem 2018. [DOI: 10.1007/s10967-018-5753-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Bandu R, Mok HJ, Kim KP. Phospholipids as cancer biomarkers: Mass spectrometry-based analysis. MASS SPECTROMETRY REVIEWS 2018; 37:107-138. [PMID: 27276657 DOI: 10.1002/mas.21510] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 05/19/2016] [Indexed: 05/02/2023]
Abstract
Lipids, particularly phospholipids (PLs), are key components of cellular membrane. PLs play important and diverse roles in cells such as chemical-energy storage, cellular signaling, cell membranes, and cell-cell interactions in tissues. All these cellular processes are pertinent to cells that undergo transformation, cancer progression, and metastasis. Thus, there is a strong possibility that some classes of PLs are expected to present in cancer cells and tissues in cellular physiology. The mass spectrometric soft-ionization techniques, electrospray ionization (ESI), and matrix-assisted laser desorption/ionization (MALDI) are well-established in the proteomics field, have been used for lipidomic analysis in cancer research. This review focused on the applications of mass spectrometry (MS) mainly on ESI-MS and MALDI-MS in the structural characterization, molecular composition and key roles of various PLs present in cancer cells, tissues, blood, and urine, and on their importance for cancer-related problems as well as challenges for development of novel PL-based biomarkers. The profiling of PLs helps to rationalize their functions in biological systems, and will also provide diagnostic information to elucidate mechanisms behind the control of cancer, diabetes, and neurodegenerative diseases. The investigation of cellular PLs with MS methods suggests new insights on various cancer diseases and clinical applications in the drug discovery and development of biomarkers for various PL-related different cancer diseases. PL profiling in tissues, cells and body fluids also reflect the general condition of the whole organism and can indicate the existence of cancer and other diseases. PL profiling with MS opens new prospects to assess alterations of PLs in cancer, screening specific biomarkers and provide a basis for the development of novel therapeutic strategies. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 37:107-138, 2018.
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Affiliation(s)
- Raju Bandu
- Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yong-in City, 446-701, Korea
| | - Hyuck Jun Mok
- Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yong-in City, 446-701, Korea
| | - Kwang Pyo Kim
- Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yong-in City, 446-701, Korea
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