There is a need to measure tumor hypoxia in assessing the aggressiveness of tumor and predicting the outcome of therapy. A number of invasive and noninvasive techniques have been exploited to measure tumor hypoxia, including polarographic needle electrodes, immunohistochemical staining, radionuclide imaging (positron emission tomography [PET] and single-photon emission computed tomography [SPECT]), magnetic resonance imaging (MRI), optical imaging (bioluminescence and fluorescence), and so on. This review article summarizes and discusses the pros and cons of each currently available method for measuring tissue oxygenation. Special emphasis was placed on noninvasive imaging hypoxia with emerging new agents and new imaging technologies to detect the molecular events that are relevant to tumor hypoxia.
1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1617-1625.
Two major treatment strategies employed in non-small cell lung cancer, NSCLC, are tyrosine kinase inhibitors, TKIs, and immune checkpoint inhibitors, ICIs. The choice of strategy is based on heterogeneous biomarkers that can dynamically change during therapy. Thus, there is a compelling need to identify comprehensive biomarkers that can be used longitudinally to help guide therapy choice. Herein, we report a 18F-FDG-PET/CT-based deep learning model, which demonstrates high accuracy in EGFR mutation status prediction across patient cohorts from different institutions. A deep learning score (EGFR-DLS) was significantly and positively associated with longer progression free survival (PFS) in patients treated with EGFR-TKIs, while EGFR-DLS is significantly and negatively associated with higher durable clinical benefit, reduced hyperprogression, and longer PFS among patients treated with ICIs. Thus, the EGFR-DLS provides a non-invasive method for precise quantification of EGFR mutation status in NSCLC patients, which is promising to identify NSCLC patients sensitive to EGFR-TKI or ICI-treatments.
Using X-ray as the irradiation source, a photodynamic therapy process can be initiated from under deep tissues. This technology, referred to as X-ray induced PDT, or X-PDT, holds great potential to treat tumors at internal organs. To this end, one question is how to navigate the treatment to tumors with accuracy with external irradiation. Herein we address the issue with a novel, LiGa5O8: Cr (LGO:Cr)-based nanoscintillator, which emits persistent, near-infrared X-ray luminescence. This permits deep-tissue optical imaging that can be employed to guide irradiation. Specifically, we encapsulated LGO:Cr nanoparticles and a photosensitizer, 2,3-naphthalocyanine, into mesoporous silica nanoparticles. The nanoparticles were conjugated with cetuximab and systemically injected into H1299 orthotopic non-small cell lung cancer tumor models. The nanoconjugates can efficiently home to tumors in the lung, confirmed by monitoring X-ray luminescence from LGO:Cr. Guided by the imaging, external irradiation was applied, leading to efficient tumor suppression while minimally affecting normal tissues. To the best of our knowledge, the present study is the first to demonstrate, with systematically injected nanoparticles, that X-PDT can suppress growth of deep-seated tumors. The imaging guidance is also new to X-PDT, and is significant to the further transformation of the technology.
Purpose: To show the relationship between antibody delivery and therapeutic efficacy in head and neck cancers, in this study we evaluated the pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR)-targeted immunotherapy and radioimmunotherapy by quantitative positron emission tomography (PET) imaging.Experimental Design: EGFR expression on UM-SCC-22B and SCC1 human head and neck squamous cell cancer (HNSCC) cells were determined by flow cytometry and immunostaining. Tumor delivery and distribution of cetuximab in tumor-bearing nude mice were evaluated with small animal PET using 64 Cu-DOTA-cetuximab. The in vitro toxicity of cetuximab to HNSCC cells was evaluated by MTT assay. The tumor-bearing mice were then treated with four doses of cetuximab at 10 mg/kg per dose, and tumor growth was evaluated by caliper measurement. FDG PET was done after the third dose of antibody administration to evaluate tumor response. Apoptosis and tumor cell proliferation after cetuximab treatment were analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki-67 staining. Radioimmunotherapy was done with 90 Y-DOTA-cetuximab. Results: EGFR expression on UM-SCC-22B cells is lower than that on SCC1 cells. However, the UM-SCC-22B tumors showed much higher 64 Cu-DOTA-cetuximab accumulation than the SCC1 tumors.Cetuximab-induced apoptosis in SCC1 tumors and tumor growth was significantly inhibited, whereas an agonistic effect of cetuximab on UM-SCC-22B tumor growth was observed. After cetuximab treatment, the SCC1 tumors showed decreased FDG uptake, and the UM-SCC-22B tumors had increased FDG uptake. UM-SCC-22B tumors are more responsive to 90 Y-DOTA-cetuximab treatment than SCC1 tumors, partially due to the high tumor accumulation of the injected antibody. Conclusion: Cetuximab has an agonistic effect on the growth of UM-SCC-22B tumors, indicating that tumor response to cetuximab treatment is not necessarily related to EGFR expression and antibody delivery efficiency, as determined by PET imaging. Although PET imaging with antibodies as tracers has limited function in patient screening, it can provide guidance for targeted therapy using antibodies as delivery vehicles.
Objectives Labeling biomolecules with 18F is usually done through coupling with prosthetic groups, which requires several time-consuming radiosynthesis steps and therefore results in low labeling yield. In this study we designed a simple one-step 18F-labeling strategy to replace the conventional complex and long process of multiple-step radiolabeling procedure. Methods Both Monomeric and dimeric cyclic RGD peptides were modified to contain 4-NO2-3-CF3 arene as precursors for direct 18F labeling. Binding of the two functionalized peptides to integrin αvβ3 was tested in vitro using MDA-MB-435 human breast cell line. The most promising functionalized peptide, the dimeric cyclic RGD, was further evaluated in vivo in an orthotopic MDA-MB-435 tumor xenograft model. Results The use of relatively low amount of precursor (~0.5μmol), gave reasonable yield, ranging from 7–23% (decay corrected, calculated from start of synthesis) after HPLC purification. Overall reaction time was 40 min and the specific activity of the labeled peptide was high. Modification of RGD peptides did not significantly change the biological binding affinities of the modified peptides. Small animal PET and biodistribution studies revealed integrin specific tumor uptake and favorable biokinetics. Conclusions We have developed a novel one-step 18F radiolabeling strategy for peptides that contain a specific arene group, which shortens reaction time and labor significantly, requires low amount of precursor and results in specific activity of 79 ± 13 GBq/μmol. Successful introduction of 4-fluoro-3-trifluoromethylbenzamide into RGD peptides may be a general strategy applicable to other biologically active peptides and proteins.
Tumor heterogeneity and changes in epidermal growth factor receptor (EGFR) mutation status over time challenge the design of effective EGFR tyrosine kinase inhibitor (TKI) treatment strategies for non-small cell lung cancer (NSCLC). Therefore, there is an urgent need to develop techniques for comprehensive tumor EGFR profiling in real time, particularly in lung cancer precision medicine trials. We report a positron emission tomography (PET) tracer, -(3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-F-fluoroethoxy) ethoxy) ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (F-MPG), with high specificity to activating EGFR mutant kinase. We evaluate the feasibility of using F-MPG PET for noninvasive imaging and quantification of EGFR-activating mutation status in preclinical models of NSCLC and in patients with primary and metastatic NSCLC tumors.F-MPG PET in NSCLC animal models showed a significant correlation ( = 0.9050) between F-MPG uptake and activating EGFR mutation status. In clinical studies with NSCLC patients ( = 75), the concordance between the detection of EGFR activation by F-MPG PET/computed tomography (CT) and tissue biopsy reached 84.29%. There was a greater response to EGFR-TKIs (81.58% versus 6.06%) and longer median progression-free survival (348 days versus 183 days) in NSCLC patients whenF-MPG PET/CT SUV (maximum standard uptake value) was ≥2.23 versus <2.23. Our study demonstrates that F-MPG PET/CT is a powerful method for precise quantification of EGFR-activating mutation status in NSCLC patients, and it is a promising strategy for noninvasively identifying patients sensitive to EGFR-TKIs and for monitoring the efficacy of EGFR-TKI therapy.
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