CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer

Kunihiro, Andrew; Sarrett, Samantha M.; Lastwika, Kristin J.; Solan, Joell L.; Pisarenko, Tatyana; Keinänen, Outi; Rodríguez, Cindy Mariana Ariza; Taverne, Lydia R; Fitzpatrick, Annette L.; Li, Christopher I.; Houghton, A. McGarry; Zeglis, Brian M.; Lampe, Paul D.

doi:10.2967/jnumed.121.263511

Cited by 7 publications

(12 citation statements)

References 38 publications

(39 reference statements)

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“…However, it is nonetheless important to address the limitations of this work. First, the intrinsic heterogeneity of SCLC means that CD133 is unlikely to be a viable target in all cases of the disease; indeed, our previous work illustrated that CD133 was expressedboth at the transcript and protein levelsin ∼60% of SCLC cases . As a result, it is likely that serum autoantibody assays such as those described in our initial investigation will be highly valuable prior to initiating CD133-targeted immunoPET and radioimmunotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Imaging with a nonspecific, isotype control radioimmunoconjugate�[ 89 Zr]Zr-DFO-antihuman immunoglobulin G antibody�was previously performed in a subcutaneous model of SCLC to demonstrate the specificity of [ 89 Zr]Zr-DFO-αCD133, abrogating the need for such experiments in this investigation. 17 PET images of the mice bearing orthotopic xenografts were obtained using an Inveon PET/CT small animal imaging system (Siemens Medical Solutions; Malvern, PA, USA). Nude mice (n = 4) underwent static scans between 24 PET images of the mice bearing metastatic and PDXs were obtained using an Inveon PET/CT small animal imaging system.…”

Section: ■ Methods and Materialsmentioning

confidence: 99%

“…DFO-αCD133 was prepared as reported previously. , In brief, αCD133 (1.0 mg) in Chelex 100-treated (Bio-Rad Laboratories; Hercules, CA, USA) phosphate-buffered saline (Chelex-PBS, pH 7.4) was diluted to a final concentration of 1.0 mg/mL. The pH of the solution was adjusted to 8.8–9.0 with 0.1 M Na 2 CO 3 , 35 equiv of p -SCN-Bn-DFO (7.05 μL, 25 mg/mL in DMSO) were added in small aliquots, and the resulting solution was incubated on a ThermoMixer (37 °C, 500 rpm, 1 h).…”

Section: Methodsmentioning

confidence: 99%

“…The resulting images were processed using ASIPro VMTM software (Concorde Microsystems). Imaging with a nonspecific, isotype control radioimmunoconjugate[ 89 Zr]Zr-DFO-antihuman immunoglobulin G antibodywas previously performed in a subcutaneous model of SCLC to demonstrate the specificity of [ 89 Zr]Zr-DFO-αCD133, abrogating the need for such experiments in this investigation …”

Section: Methodsmentioning

confidence: 99%

“…Critically, healthy tissues express far lower levels of protein, making it a promising target for both imaging and therapy. We previously explored the potential of CD133 as a biomarker for the early diagnosis and molecular imaging of patients with SCLC . We found that CD133 is significantly overexpressed in patients with SCLC and that the expression rate of the protein does not vary with the stage of the disease.…”

Section: Introductionmentioning

confidence: 99%

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Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

Sarrett,

Rodriguez,

Delaney

et al. 2024

Mol. Pharmaceutics

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Despite decades of work, small-cell lung cancer (SCLC) remains a frustratingly recalcitrant disease. Both diagnosis and treatment are challenges: low-dose computed tomography (the approved method used for lung cancer screening) is unable to reliably detect early SCLC, and the malignancy’s 5 year survival rate stands at a paltry 7%. Clearly, the development of novel diagnostic and therapeutic tools for SCLC is an urgent, unmet need. CD133 is a transmembrane protein that is expressed at low levels in normal tissue but is overexpressed by a variety of tumors, including SCLC. We previously explored CD133 as a biomarker for a novel autoantibody-to-immunopositron emission tomography (PET) strategy for the diagnosis of SCLC, work that first suggested the promise of the antigen as a radiotheranostic target in the disease. Herein, we report the in vivo validation of a pair of CD133-targeted radioimmunoconjugates for the PET imaging and radioimmunotherapy of SCLC. To this end, [89Zr]Zr-DFO-αCD133 was first interrogated in a trio of advanced murine models of SCLCi.e., orthotopic, metastatic, and patient-derived xenograftswith the PET probe consistently producing high activity concentrations (>%ID/g) in tumor lesions combined with low uptake in healthy tissues. Subsequently, a variant of αCD133 labeled with the β-emitting radiometal 177Lu[177Lu]Lu-DTPA-A″-CHX-αCD133was synthesized and evaluated in a longitudinal therapy study in a subcutaneous xenograft model of SCLC, ultimately revealing that treatment with a dose of 9.6 MBq of the radioimmunoconjugate produced a significant increase in median survival compared to a control cohort. Taken together, these data establish CD133 as a viable target for the nuclear imaging and radiopharmaceutical therapy of SCLC.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Methods and Materialsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

Sarrett,

Rodriguez,

Delaney

et al. 2024

Mol. Pharmaceutics

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Radionuclide-based theranostics — a promising strategy for lung cancer

Zhu

Hsu

Guo

et al. 2023

Eur J Nucl Med Mol Imaging

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Construction of Prognostic Risk Model for Small Cell Lung Cancer Based on Immune-Related Genes

Deng

Feng

et al. 2022

Computational and Mathematical Methods in Medicine

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Small cell lung cancer (SCLC) is a highly invasive and fatal malignancy. Research at the present stage implied that the expression of immune-related genes is associated with the prognosis in SCLC. Accordingly, it is essential to explore effective immune-related molecular markers to judge prognosis and treat SCLC. Our research obtained SCLC dataset from Gene Expression Omnibus (GEO) and subjected mRNAs in it to differential expression analysis. Differentially expressed mRNAs (DEmRNAs) were intersected with immune-related genes to yield immune-related differentially expressed genes (DEGs). The functions of these DEGs were revealed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Thereafter, we categorized 3 subtypes of immune-related DEGs via K-means clustering. Kaplan-Meier curves analyzed the effects of 3 subtypes on SCLC patients’ survival. Single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE validated that the activation of different immune gene subtypes differed significantly. Finally, an immune-related-7-gene assessment model was constructed by univariate-Lasso-multiple Cox regression analyses. Riskscores, Kaplan-Meier curves, receiver operating characteristic (ROC) curves, and independent prognostic analyses validated the prognostic value of the immune-related-7-gene assessment model. As suggested by GSEA, there was a prominent difference in cytokine-related pathways between high- and low-risk groups. As the analysis went further, we discovered a statistically significant difference in the expression of human leukocyte antigen (HLA) proteins and costimulatory molecules expressed on the surface of CD274, CD152, and T lymphocytes in different groups. In a word, we started with immune-related genes to construct the prognostic model for SCLC, which could effectively evaluate the clinical outcomes and offer guidance for the treatment and prognosis of SCLC patients.

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CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer

Cited by 7 publications

References 38 publications

Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

Radionuclide-based theranostics — a promising strategy for lung cancer

Construction of Prognostic Risk Model for Small Cell Lung Cancer Based on Immune-Related Genes

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