title: Transcriptomic Signatures of Auger Electron Radioimmunotherapy Using Nuclear Targeting (111)In-Trastuzumab for Potential Combination Therapies.
abstract: (111)In-labeled trastuzumab modified with nuclear localizing signal (NLS) peptides ((111)In-trastuzumab-NLS) efficiently delivers an Auger electron (AE) emitter (111)In into the cell nucleus and is thus a promising radiopharmaceutical in AE radioimmunotherapy (AE-RIT) for targeted killing of HER2-positive cancer. However, further improvement of its therapeutic efficacy is required. In this study, the authors show a transcriptomic approach to identify potential targets for enhancing the cytotoxic effects of (111)In-trastuzumab-NLS. They generated two types of (111)In-trastuzumab-NLS harboring different numbers of NLS peptides, (111)In-trastuzumab-NLS-S and -L. These radioimmunoconjugates (230 and 460 kBq) showed a significant higher cytotoxicity to SKBR3 human breast cancer cells overexpressing HER2 compared to (111)In-trastuzumab. Microarray analysis revealed that NF-kB-related genes (38 genes) were significantly changed in transcription by (111)In trastuzumab-NLS-L (230 kBq) treatment. Quantitative reverse transcription polymerase chain reaction confirmed the microarray data by showing transcriptional alternation of selected NF-κB target genes in cells treated with (111)In-trastuzumab-NLS-L. Interestingly, bortezomib, a drug known as a NF-κB modulator, significantly enhanced the cytotoxicity of (111)In-trastuzumab-NLS-L in SKBR3 cells. Taken together, the transcriptome data suggest the possibility that the modulation of NF-kB signaling activity is a molecular signature of (111)In-trastuzumab-NLS and coadministration of bortezomib may be efficacious in enhancement of AE-RIT with (111)In-trastuzumab-NLS.
authors.affiliation: 1 Molecular Imaging Center, National Institute of Radiological Sciences , Chiba, Japan .|2 Graduate School of Medical and Pharmaceutical Sciences, Chiba University , Chiba, Japan .|3 Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan .
authors.forename: Huizi Keiko
authors.initials: HK
authors.lastname: Li
authors.affiliation: 1 Molecular Imaging Center, National Institute of Radiological Sciences , Chiba, Japan .
authors.forename: Yukie
authors.initials: Y
authors.lastname: Morokoshi
authors.affiliation: 4 Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan .
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Daino
authors.affiliation: 1 Molecular Imaging Center, National Institute of Radiological Sciences , Chiba, Japan .
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: 2 Graduate School of Medical and Pharmaceutical Sciences, Chiba University , Chiba, Japan .|3 Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan .
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kamada
authors.affiliation: 1 Molecular Imaging Center, National Institute of Radiological Sciences , Chiba, Japan .
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
authors.affiliation: 1 Molecular Imaging Center, National Institute of Radiological Sciences , Chiba, Japan .
authors.forename: Sumitaka
authors.initials: S
authors.lastname: Hasegawa
mesh_terms: D000069286:Bortezomib / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D004369:Pentetic Acid; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016499:Radioimmunotherapy / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects; D059467:Transcriptome; D000068878:Trastuzumab / Q000627:therapeutic use*
chemical_list: D000069286:Bortezomib; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D016328:NF-kappa B; D004369:Pentetic Acid; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Auger electron radioimmunotherapy; Bortezomib; DNA microarray; NF-κB