• cancer
• emission
• hypoxia
• positron
• tomography

• Humans
• Radioactive Tracers
• Animals
• Fluorodeoxyglucose F18
• Neoplasms/diagnostic imaging
• Neoplasms/metabolism
• Cell Hypoxia
• Hypoxia/diagnostic imaging
• Nitroimidazoles

• Brain metastasis
• Copper-64
• Cu-ATSM
• HIF
• Hypoxia
• Imaging
• Lung cancer
• Oxidative stress
• PET
• Preclinical
• Proteomic
• Rodent

• ANR-11-LABEX-0018-01 Agence Nationale de la Recherche
• ANR-11-LABEX-0018-01 Agence Nationale de la Recherche
• RIN HYPOTHERA Région Normandie
• RIN HYP-IRON2 Région Normandie
• RIN HYPOTHERA Région Normandie
• RIN HYP-IRON2 Région Normandie
• Université de Caen Normandie
• Centre National de la Recherche Scientifique

• carcinogenesis
• hypoxia
• magnetic resonance imaging
• positron emission tomography
• treatment resistance

• OE-MRI
• [18F]-FAZA
• [18F]-FMISO
• [64Cu]-ATSM
• cancer
• hypoxia

• COVID-19
• cancer
• immunity
• patient care
• vaccine

• 18F-FDG
• PET
• lung cancer
• radiotracer
• tyrosine kinases inhibitor

Targeted radionuclide theranostics is becoming more and more prominent in clinical oncology. Currently, most nuclear medicine compounds researched for cancer theranostics are directed towards targets expressed in only a small subset of cancer types, limiting clinical applicability. The identification of cancer-specific targets that are (more) universally expressed will allow more cancer patients to benefit from these personalized nuclear medicine–based interventions. A tumor is not merely a collection of cancer cells, it also comprises supporting stromal cells embedded in an altered extracellular matrix (ECM), together forming the tumor microenvironment (TME). Since the TME is less genetically unstable than cancer cells, and TME phenotypes can be shared between cancer types, it offers targets that are more universally expressed. The TME is characterized by the presence of altered processes such as hypoxia, acidity, and increased metabolism. Next to the ECM, the TME consists of cancer-associated fibroblasts (CAFs), macrophages, endothelial cells forming the neo-vasculature, immune cells, and cancer-associated adipocytes (CAAs). Radioligands directed at the altered processes, the ECM, and the cellular components of the TME have been developed and evaluated in preclinical and clinical studies for targeted radionuclide imaging and/or therapy. In this review, we provide an overview of the TME targets and their corresponding radioligands. In addition, we discuss what developments are needed to further explore the TME as a target for radionuclide theranostics, with the hopes of stimulating the development of novel TME radioligands with multi-cancer, or in some cases even pan-cancer, application.

• Cancer stroma
• Pan-cancer therapy
• Radionuclide imaging and therapy
• Theranostics
• Tumor microenvironment

• PET
• dual-tracer separation
• network

• Cancers
• Clinical trial
• Molecular imaging
• Precision medicine

• Brain/pathology
• Breast Neoplasms/drug therapy
• Breast Neoplasms/therapy
• Humans
• Lung/pathology
• Male
• Molecular Imaging/methods
• Precision Medicine/methods
• Prostate/pathology

Metabolic reprogramming is recognized as one of the hallmarks of cancer. Alterations in the micro-environmental metabolic characteristics are recognized as important tools for cancer cells to interact with the resident and infiltrating T-cells within this tumor microenvironment. Cancer-induced metabolic changes in the micro-environment also affect treatment outcomes. In particular, immune therapy efficacy might be blunted because of somatic mutation-driven metabolic determinants of lung cancer such as acidity and oxygenation status. Based on these observations, new onco-immunological treatment strategies increasingly include drugs that interfere with metabolic pathways that consequently affect the composition of the lung cancer tumor microenvironment (TME). Positron emission tomography (PET) imaging has developed a wide array of tracers targeting metabolic pathways, originally intended to improve cancer detection and staging. Paralleling the developments in understanding metabolic reprogramming in cancer cells, as well as its effects on stromal, immune, and endothelial cells, a wave of studies with additional imaging tracers has been published. These tracers are yet underexploited in the perspective of immune therapy. In this review, we provide an overview of currently available PET tracers for clinical studies and discuss their potential roles in the development of effective immune therapeutic strategies, with a focus on lung cancer. We report on ongoing efforts that include PET/CT to understand the outcomes of interactions between cancer cells and T-cells in the lung cancer microenvironment, and we identify areas of research which are yet unchartered. Thereby, we aim to provide a starting point for molecular imaging driven studies to understand and exploit metabolic features of lung cancer to optimize immune therapy.

• T-cells (or lymphocytes)
• immunotherapy
• lung cancer
• metabolism
• molecular imaging
• tumor microenvironment

In recent years, copper-64 and copper-67 have been considered as a useful theranostic pair in nuclear medicine, due to their favourable and complementary decay properties. As ⁶⁷Cu and ⁶⁴Cu are chemically identical, development of both existing and new bifunctional chelators for ⁶⁴Cu imaging agents can be readily adapted for the ⁶⁷Cu-radionuclide. In this study, we explored the use of photoactivatable copper chelators based on the asymmetric bis(thiosemicarbazone) scaffold, H₂ATSM/en, for the photoradiolabelling of protein. Photoactivatable ⁶⁴CuATSM-derivatives were prepared by both direct synthesis and transmetallation from the corresponding ^natZn complex. Then, irradiation with UV light in the presence of a protein of interest in a pH buffered aqueous solution afforded the ⁶⁴Cu-labelled protein conjugates in decay-corrected radiochemical yield of 86.9 ± 1.0% via the transmetallation method and 35.3 ± 1.7% from the direct radiolabelling method. This study successfully demonstrates the viability of photochemically induced conjugation methods for the development of copper-based radiotracers for potential applications in diagnostic positron emission tomography (PET) imaging and targeted radionuclide therapy.

In recent years, copper-64 and copper-67 have been considered as a useful theranostic pair in nuclear medicine. Here, we report a photochemically-mediated approach for radiolabelling biologically relevant protein with copper radionuclides.

• Chelating Agents/chemistry
• Copper Radioisotopes/chemistry
• Positron-Emission Tomography/methods
• Radiopharmaceuticals/chemistry
• Thiosemicarbazones/chemistry

• H2020 European Research Council
• Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

The hypoxic state in a solid tumor refers to the internal hypoxic environment that appears as the tumor volume increases (the maximum radius exceeds 180-200 microns). This state can promote angiogenesis, destroy the balance of the cell’s internal environment, and lead to resistance to radiotherapy and chemotherapy, as well as poor prognostic factors such as metastasis and recurrence. Therefore, accurate quantification, mapping, and monitoring of hypoxia, targeted therapy, and improvement of tumor hypoxia are of great significance for tumor treatment and improving patient survival. Despite many years of development, PET-based hypoxia imaging is still the most widely used evaluation method. This article provides a comprehensive overview of tumor hypoxia imaging using radionuclide-labeled PET tracers. We introduced the mechanism of tumor hypoxia and the reasons leading to the poor prognosis, and more comprehensively included the past, recent and ongoing studies of PET radiotracers for tumor hypoxia imaging. At the same time, the advantages and disadvantages of mainstream methods for detecting tumor hypoxia are summarized.

• cancer
• hypoxia
• imaging
• positron emission tomography (PET)
• radiotracer

• 2-deoxy-2-[18F]fluoro-D-glucose
• Hypoxia
• Lung cancer
• Positron emission tomography
• Radiotherapy
• [18F]fluoromisonidasole

Hypoxia correlates with poor prognosis in several cancer types, including lung cancer. Prolyl hydroxylase domain proteins (PHDs) belong to an evolutionarily conserved superfamily of dioxygenases that play a role in cell oxygen sensing and homeostasis. In this study, we evaluated PHD1, PHD2 and PHD3 mRNA expression in 60 NSCLC tumours and compared it to that in normal lungs and evaluated the prognostic significance of these differences for distinguishing the survival of NSCLC patients treated with radical surgery. Our results showed that the mRNA expression PHD1 and PHD2 in NSCLC primary tumours was decreased, which correlated with larger tumour size and poor prognosis of patients. PHD1 also showed borderline independent prognostic value in multivariate analysis. In contrast, we found no associations between PHD3 expression and any of the observed parameters. Our results suggest that loss of PHD1 and PHD2 expression is associated with the development and progression of NSCLC, whereas PHD1 could be further assessed as a prognostic marker in NSCLC.

Background: Hypoxia correlates with poor prognosis in several cancer types, including lung cancer. Prolyl hydroxylase domain proteins (PHDs) play a role in cell oxygen sensing, negatively regulating the hypoxia-inducible factor (HIF) pathway. Our study aim was to evaluate PHD1, PHD2 and PHD3 mRNA expression levels in primary tumours and normal lungs of non-small-cell lung cancer (NSCLC) patients and to correlate it with selected regulators of HIF signalling, with clinicopathological characteristics and overall survival (OS). Methods: Tumour tissue samples were obtained from 60 patients with surgically resected NSCLC who were treated with radical surgery. In 22 out of 60 cases, matching morphologically normal lung tissue was obtained. PHD1, PHD2 and PHD3 mRNA expressions were measured using RT-qPCR. Results: The PHD1 and PHD2 mRNA levels in primary tumours were significantly decreased compared to those in normal lungs (both p < 0.0001). PHD1 and PHD2 expression in tumours was positively correlated (r_s = 0.82; p < 0.0001) and correlated well with HIF pathway downstream genes HIF1A, PKM2 and PDK1. Decreased PHD1 and PHD2 were associated with larger tumour size, higher tumour stage (PHD1 only) and squamous cell carcinoma. Patients with low PHD1 and patients with low PHD2 expression had shorter OS than patients with high PHD1 (p = 0.02) and PHD2 expression (p = 0.01). PHD1 showed borderline independent prognostic values in multivariate analysis (p = 0.06). In contrast, we found no associations between PHD3 expression and any of the observed parameters. Conclusions: Our results show that reduced expression of PHD1 and PHD2 is associated with the development and progression of NSCLC. PHD1 could be further assessed as a prognostic marker in NSCLC.

• mRNA expression
• non-small-cell lung cancer
• prognosis
• prolyl hydroxylase domain proteins

• amyotrophic lateral sclerosis
• iron
• magnetic resonance imaging
• quantitative susceptibility mapping
• susceptibility weighted imaging

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the coronavirus family, which causes coronavirus disease 2019 (COVID-19). The phenotype of the disease varies from asymptomatic, to a mild phenotype, through to the severe form of acute respiratory distress syndrome (ARDS), which often leads to death, especially in those with underlying diseases. It has been reported that those who suffer from cancer (especially lung cancer and hematological malignancies) are at higher risk of serious complications and death from COVID-19. Some cancer treatments such as CAR T cell therapy can produce a cytokine storm, which is also a hallmark of severe COVID-19. Therefore, patients receiving CAR T cells are at higher risk if they become infected with COVID-19, and could be treated with anti-cytokine approaches.

Hypoxia is the most common microenvironment feature of lung cancer tumors, which affects cancer progression, metastasis and metabolism. Oxygen induces both proteomic and genomic changes within tumor cells, which cause many alternations in the tumor microenvironment (TME). This review defines current knowledge in the field of tumor hypoxia in non-small cell lung cancer (NSCLC), including biology, biomarkers, in vitro and in vivo studies and also hypoxia imaging and detection. While classic two-dimensional (2D) in vitro research models reveal some hypoxia dependent manifestations, three-dimensional (3D) cell culture models more accurately replicate the hypoxic TME. In this study, a systematic review of the current NSCLC 3D models that have been able to mimic the hypoxic TME is presented. The multicellular tumor spheroid, organoids, scaffolds, microfluidic devices and 3D bioprinting currently being utilized in NSCLC hypoxia studies are reviewed. Additionally, the utilization of 3D in vitro models for exploring biological and therapeutic parameters in the future is described.

• hypoxia
• in vitro models
• lung cancer
• three-dimensional
• tumor microenvironment

• Bioprinting
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/pathology
• Humans
• Imaging, Three-Dimensional
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Models, Biological
• Tumor Hypoxia

• Dynamic barriers
• Functional barriers
• Hypoxia
• Imaging
• Immune exclusion
• Physical barriers
• Tumor microenvironment

• Cell Hypoxia
• Humans
• Hypoxia
• Immunotherapy
• Neoplasms
• T-Lymphocytes
• Tumor Microenvironment

Tumor hypoxia has been widely reported to promote metastasis. However, the molecular mechanisms underlying metastasis-associated hypoxia remain unclear. Formyl peptide receptor 1 (FPR1) has been reported to be highly expressed under hypoxic conditions. This study aimed to explore the role of FPR1 in tumor cells under hypoxic conditions.

The expressions of FPR1 and hypoxia-inducible factor 1α (HIF-1α) in A549 cells under hypoxic conditions were detected using western blot. The expression of FPR1 in A549 cells under hypoxic conditions was suppressed using the FPR1 antagonist Boc2. Wound-healing and Transwell assays were performed to investigate the migration and invasion of cells. Furthermore, the tumorigenicity of A549 cells was evaluated by constructing a hypoxic mouse model of lung adenocarcinoma. The expression levels of HIF-1α and FPR1 in tumors were measured by real-time polymerase chain reaction (PCR) and western blot.

The expression levels of FPR1 and HIF-1α increased in a time-dependent manner after exposure to hypoxic conditions. Wound-healing and Transwell assays showed that hypoxia promoted the migration and invasion abilities of A549 cells, whereas downregulation of FPR1 blocked the effects of hypoxia on A549 cells. Our in vivo results demonstrated that the tumor volumes and weights of mice exposed to hypoxic conditions were significantly higher than those of untreated mice. Furthermore, the downregulation of FPR1 blocked the effects of hypoxia in the mice. Meanwhile, the expressions of HIF-1α and FPR1 at the protein and mRNA levels were increased after hypoxic exposure, whereas FPR1 antagonist Boc2 suppressed the effect of hypoxia on the expression of FPR1.

Our results suggest that FPR1 could be a therapeutic target for suppressing the invasion and tumorigenicity of lung adenocarcinoma cells.

• Formyl peptide receptor 1 (FPR1)
• hypoxia
• invasion
• migration
• tumorigenicity

• 2-Nitroimidazole
• Click reaction
• Hypoxia imaging agent
• Radioiodination

Tumor hypoxia (low tissue oxygenation) is an adverse condition of the solid tumor environment, associated with malignant progression, radiotherapy resistance, and poor prognosis. One method to detect tumor hypoxia is by positron emission tomography (PET) with the tracer [⁶⁴Cu][Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)] ([⁶⁴Cu][Cu(ATSM)]), as demonstrated in both preclinical and clinical studies. In addition, emerging studies suggest using [⁶⁴Cu][Cu(ATSM)] for molecular radiotherapy, mainly due to the release of therapeutic Auger electrons from copper-64, making [⁶⁴Cu][Cu(ATSM)] a “theranostic” agent. However, the radiocopper retention based on a metal-ligand dissociation mechanism under hypoxia has long been controversial. Recent studies using ionic Cu(II) salts as tracers have raised further questions on the original mechanism and proposed a potential role of copper itself in the tracer uptake. We have reviewed the evidence of using the copper radiopharmaceuticals [^60/61/62/64Cu][Cu(ATSM)]/ionic copper salts for PET imaging of tumor hypoxia, their possible therapeutic applications, issues related to the metal-ligand dissociation mechanism, and possible explanations of copper trapping based on studies of the copper metabolism under hypoxia.

We found that hypoxia selectivity of [⁶⁴Cu][Cu(ATSM)] has been clearly demonstrated in both preclinical and clinical studies. Preclinical therapeutic studies in mice have also demonstrated promising results, recently reporting significant tumor volume reductions and improved survival in a dose-dependent manner. Cu(II)-[Cu(ATSM)] appears to be accumulated in regions with substantially higher CD133⁺ expression, a marker for cancer stem cells. This, combined with the reported requirement of copper for activation of the hypoxia inducible factor 1 (HIF-1), provides a possible explanation for the therapeutic effects of [⁶⁴Cu][Cu(ATSM)]. Comparisons between [⁶⁴Cu][Cu(ATSM)] and ionic Cu(II) salts have showed similar results in both imaging and therapeutic studies, supporting the argument for the central role of copper itself in the retention mechanism.

We found promising evidence of using copper-64 radiopharmaceuticals for both PET imaging and treatment of hypoxic tumors. The Cu(II)-[Cu(ATSM)] retention mechanism remains controversial and future mechanistic studies should be focused on understanding the role of copper itself in the hypoxic tumor metabolism.

• Copper-64
• Metabolism
• Positron emission tomography
• Radiation
• Tumor hypoxia

• 18F-FDG-PET/CT
• Radiotherapy planning
• lung cancer
• motion artifacts
• new radiopharmaceuticals
• target volume definition

• Carcinoma, Non-Small-Cell Lung/diagnostic imaging
• Carcinoma, Non-Small-Cell Lung/radiotherapy
• Fluorodeoxyglucose F18
• Humans
• Lung Neoplasms/diagnostic imaging
• Lung Neoplasms/radiotherapy
• Molecular Imaging/methods
• Positron Emission Tomography Computed Tomography
• Radiopharmaceuticals
• Radiotherapy Planning, Computer-Assisted/methods

• Prolyl hydroxylase 3 (PHD3)
• hypoxia-inducible factor-1α (HIF-1α)
• lung cancer
• pyruvate kinase M2 (PKM2)

• maximum standardized uptake value
• non-small cell lung cancer
• platelet-to-lymphocyte ratio
• prognosis
• stereotactic body radiation therapy

• Cycling hypoxia
• Hypoxia
• MRI/EPR
• Optical imaging
• PET
• Quantification

• Atherosclerosis
• Clinical imaging
• Hypoxia
• Magnetic resonance imaging
• Oncology
• Positron emission tomography

• Humans
• Hypoxia/diagnosis
• Hypoxia/diagnostic imaging
• Hypoxia/pathology
• Myocardial Ischemia/diagnostic imaging
• Myocardial Ischemia/metabolism
• Myocardial Ischemia/pathology
• Neoplasms/diagnostic imaging
• Neoplasms/metabolism
• Neoplasms/pathology
• Oxygen/isolation & purification
• Oxygen/metabolism
• Positron-Emission Tomography
• Stroke/diagnostic imaging
• Stroke/metabolism
• Stroke/pathology

• FRET
• hypoxia
• metals in medicine
• molecular imaging
• oxygen sensing

• 18F-FDG PET/CT
• 62Cu-ATSM PET/CT
• Glioma
• Survival
• Tumor progression

• Antineoplastic Agents/pharmacology
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma, Non-Small-Cell Lung/diagnostic imaging
• Carcinoma, Non-Small-Cell Lung/radiotherapy
• Carcinoma, Non-Small-Cell Lung/secondary
• Clinical Trials as Topic
• Humans
• Lung Neoplasms/diagnostic imaging
• Lung Neoplasms/pathology
• Lung Neoplasms/radiotherapy
• Magnetic Resonance Imaging
• Positron-Emission Tomography
• Radiation-Sensitizing Agents/pharmacology
• Radiosurgery
• Tumor Hypoxia/drug effects
• Tumor Hypoxia/genetics

• 16465 Cancer Research UK
• 18097 Cancer Research UK
• 20465 Cancer Research UK
• 22746 Cancer Research UK

• 64Cu-ATSM
• angiogenesis
• bevacizumab
• hypoxia
• vascular decrease

• Hypoxia
• Hypoxia radiotracers
• MRI
• Positron emission tomography

• 16584 Cancer Research UK
• MR/N020782/1 Medical Research Council

• Aged
• Carcinoma, Non-Small-Cell Lung/diagnostic imaging
• Coordination Complexes
• Copper Radioisotopes
• Female
• Fractals
• Head and Neck Neoplasms/diagnostic imaging
• Humans
• Image Interpretation, Computer-Assisted/methods
• Lung Neoplasms/diagnostic imaging
• Male
• Middle Aged
• Organometallic Compounds
• Pilot Projects
• Positron Emission Tomography Computed Tomography/methods
• Positron Emission Tomography Computed Tomography/statistics & numerical data
• Radiopharmaceuticals
• Thiosemicarbazones