Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Sarrett SM

PROVIDER: S-EPMC10915790 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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

Sarrett Samantha M SM Rodriguez Cindy C Delaney Samantha S Hosny Meena M MM Sebastiano Joni J Santos-Coquillat Ana A Keinänen Outi M OM Carter Lukas M LM Lastwika Kristin J KJ Lampe Paul D PD Zeglis Brian M BM

Molecular pharmaceutics 20240208 3

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 ...[more]

PMID: 38331430

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Project description:BackgroundIt has been proven that the treatment window of small cell lung cancer (SCLC) is short, so it is vital to find other possible therapeutic targets. CD39 inhibits natural killer (NK) cells and promotes the occurrence and metastasis of tumors. There has been little research about the role of CD39 in SCLC, so we explored the correlation between CD39 and other surface antigens, and its association with survival in SCLC.MethodsThis study included 75 patients with SCLC from Shanghai Pulmonary Hospital. After paraffin embedding and sectioning, immunohistochemistry (IHC) was applied. Then we identify cutoff value for CD39 and other surface antigens based on the analysis of ROC curve in RFS by SPSS. All statistical analyses were based on SPSS and Graphpad Prism8. Chi-square test, Kendall's tau-b correlation analysis, Logistic regression analysis, Kaplan-Meier method, univariate and multivariate Cox regression analysis were conducted. In all analyses, P = 0.05 distinguished whether they had statistical significance.ResultsOf the 75 SCLC patients enrolled in this study, 61.33% positively expressed CD39. A correlation between CD39 and programmed cell death-ligand 1 (PD-L1) (P=0.007), CD3 (P<0.001), CD4 (P<0.001), CD8 (P<0.001), and forkhead box P3 (FOXP3) (P<0.001) on tumor-infiltrating lymphocytes (TILs) was identified by correlation analysis and logistic regression analysis. Based on Kaplan-Meier survival analysis, we found that CD39 affected relapse-free survival (RFS) [negative vs. positive, 95% confidence interval (CI): 0.2765-0.9862, P=0.0390]. SCLC patients with high-expressed CD39 and low-expressed PD-L1 had poor prognosis (P<0.001). Positive expression of CD39 and negative expression of CD3, CD4, CD8, and FOXP3 also indicated shorter RFS (P=0.0409). Univariate and multivariate Cox regression analysis was performed to confirm the factors that influenced RFS.ConclusionsCD39, programmed cell death-1 (PD-1), and PD-L1 expressed on TILs but not on tumor cells. CD39 has a significant association with PD-L1, CD3, CD4, CD8, and FOXP3 on TILs. The positive expression of CD39 predicts poor prognosis. SCLC patients with low expression of CD39 combined with high expression of PD-L1 or CD3, CD4, CD8, and FOXP3 have a more favorable prognosis.

Project description:BackgroundMaintenance of cancer stem-like cell (CSC) stemness supported by aberrantly regulated cancer cell metabolism is critical for CSC self-renewal and tumor progression. As a key glycolytic enzyme, hexokinase 2 (HK2) plays an instrumental role in aerobic glycolysis and tumor progression. However, whether HK2 directly contribute to CSC stemness maintenance in small cell lung cancer (SCLC) is largely unclear. In this study, we aimed to investgate whether HK2 independent of its glycolytic activity is directly involved in stemness maintenance of CSC in SCLC.MethodsImmunoblotting analyses were conducted to determine the expression of HK2 in SCLC CSCs and their differentiated counterparts. CSC-like properties and tumorigenesis of SCLC cells with or without HK2 depletion or overexpression were examined by sphere formation assay and xenograft mouse model. Immunoprecipitation and mass spectrometry analyses were performed to identify the binding proteins of CD133. The expression levels of CD133-associated and CSC-relevant proteins were evaluated by immunoblotting, immunoprecipitation, immunofluorescence, and immunohistochemistry assay. RNA expression levels of Nanog, POU5F1, Lin28, HK2, Prominin-1 were analyzed through quantitative reverse transcription PCR. Polyubiquitination of CD133 was examined by in vitro or in vivo ubiquitination assay. CD133+ cells were sorted by flow cytometry using an anti-CD133 antibody.ResultsWe demonstrated that HK2 expression was much higher in CSCs of SCLC than in their differentiated counterparts. HK2 depletion inhibited CSC stemness and promoted CSC differentiation. Mechanistically, non-mitochondrial HK2 directly interacted with CD133 and enhanced CD133 expression without affecting CD133 mRNA levels. The interaction of HK2 and CD133 promoted the binding of the deubiquitinase ubiquitin-specific protease 11 (USP11) to CD133, thereby inhibiting CD133 polyubiquitylation and degradation. HK2-mediated upregulation of CD133 expression enhanced the expression of cell renewal regulators, SCLC cell stemness, and tumor growth in mice. In addition, HK2 expression was positively correlated with CD133 expression in human SCLC specimens, and their expression levels were associated with poor prognosis of SCLC patients.ConclusionsThese results revealed a critical non-metabolic function of HK2 in promotion of cancer cell stemness. Our findings provided new insights into the multifaceted roles of HK2 in tumor development.

Dataset Information

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

Publications

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

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