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Transcriptomic signatures of Auger electron radioimmunotherapy using nuclear targeting 111In-trastuzumab for potential combination therapies

ABSTRACT: The aim of this study was to identify targetable molecular signatures for enhancing the cytotoxic effects of In-111-trastuzumab-NLS using microarray technology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE67193 | GEO | 2015/09/01

SECONDARY ACCESSION(S): PRJNA279237

REPOSITORIES: GEO

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Transcriptomic signatures of Auger electron radioimmunotherapy using nuclear targeting 111In-trastuzumab for potential combination therapies

Project description:The aim of this study was to identify targetable molecular signatures for enhancing the cytotoxic effects of In-111-trastuzumab-NLS using microarray technology. Changes in gene expression in SKBR3 cells untreated or treated with unlabeled or In-111-labeled antibodies for 7 days were measured. Three independent experiments in each condition were performed.

2015-09-01 | E-GEOD-67193 | biostudies-arrayexpress

A proteomic approach for characterizing trastuzumab-emtansine modified for nuclear directed localization that enhances cytotoxicity identifies regulatory nuclear transport receptor.

Project description:We used the approved antibody-drug conjugate trastuzumab-emtansine and the HER2+ cell line SKBR3. We also used a novel technology termed cell accumulator (Accum) that enables mAbs to escape endosome entrapment and localize to the cell nucleus without abrogating antibody affinity or specificity to target antigens. Accum harbors a well-known nuclear localization signal (NLS) sequence recognized by the classic nuclear transportation receptor (NTR) complex alpha-importin/importin-beta. Accum-modification of T-DM1 resulted in a significant increase in cytotoxic potency. We sought to understand the mechanisms through which Accum-T-DM1 localized to the nucleus and increased tumor cell killing effectiveness.

2021-09-08 | PXD014786 | Pride

RNA sequencing of BT474 cells treated with trastuzumab or trastuzumab + pertuzumab and BT474-derived cells resistant to trastuzumab or trastuzumab + pertuzumab

Project description:We sequenced untreated BT474 cells, BT474 cells treated for three days with trastuzumab or trastuzumab + pertuzumab, as well as two BT474-derived trastuzumab-resistant pools and two BT474-derived trastuzumab + pertuzumab resistant pools. Resistant pools were generated by culturing BT474 cells in gradually increasing doses of trastuzumab and trastuzumab + pertuzumab over the course of several months and continually maintained in drug.

2020-01-26 | GSE121105 | GEO

A Phase II Randomized Trial of Neoadjuvant Trastuzumab or Lapatinib or the Combination of Trastuzumab and Lapatinib, Followed by Docetaxel and Carboplatin with Trastuzumab and/or Lapatinib in Patients with HER2+ Breast Cancer [treatments]

Project description:Adjuvant docetaxel, carboplatin, and trastuzumab (TCH) is a standard regimen for HER2+ breast cancer. Dual HER2-blockade with lapatinib (L) and trastuzumab demonstrated significant activity in the metastatic and neoadjuvant settings. This study evaluates neoadjuvant TC plus trastuzumab (H) and/or lapatinib (L). This study demonstrated a similar pCR rate with TCH and TCHL and a lower rate of pCR with TCL. Treatment-related toxicity limited the ability for participants to receive protocol-specified chemotherapy and HER2-targeted therapy in the TCHL Arm.

2019-05-08 | GSE130787 | GEO

2019-05-08 | GSE130786 | GEO

Defining the molecular response to trastuzumab, pertuzumab and combination therapy in ovarian cancer

Project description:The purpose of this study was to characterise the effects of trastuzumab and pertuzumab, either as single agents or as combination therapy on gene and protein expression in human ovarian cancer in vivo. Illumina BeadChips were used to profile the transcriptome after four days treatment of SKOV3 tumor xenografts. Although genes involved with HER2, MAP-kinase and p53 signaling pathways were commonly induced by all treatments, a greater number and variety of genes were differentially expressed by the complementary combination therapies compared to either drug on its own. The protein level of the CDK-inhibitors p21 and p27 were increased in response to both agents alone and further by the combination; pERK signaling was inhibited by all treatments; but only pertuzumab alone inhibited pAkt signaling. The expression of proliferation, apoptosis, cell division and cell cycle markers was distinct in a panel of primary ovarian cancer xenografts, suggesting heterogeneity of response in ovarian cancer and the need to establish biomarkers of response. This first comprehensive study of the molecular response to trastuzumab, pertuzumab and combination therapy in vivo highlights that there are both common and distinct downstream effects to different HER2 antibodies and that pathways may be invoked more strongly or in a different manner by a combination of agents. Some of the in vivo results for ovarian tumors differ from previous in vitro studies in breast cancer cells, emphasizing that the molecular response to anti-cancer agents involves variable and complex disease-specific interactions of signaling mechanisms. SCOV3 Ovarian cell line xenografts treated with Trastuzumab, pertuzumab or combination after 4 days

2012-05-02 | E-GEOD-31432 | biostudies-arrayexpress

Transcriptomic Signatures of Auger Electron Radioimmunotherapy Using Nuclear Targeting (111)In-Trastuzumab for Potential Combination Therapies.

Project description:(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-?B target genes in cells treated with (111)In-trastuzumab-NLS-L. Interestingly, bortezomib, a drug known as a NF-?B 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.

| S-EPMC4601633 | biostudies-literature

Gene expression data from trastuzumab-hypersensitive clones

Project description:Genes involved in trastuzumab response were identified using transcriptomic data from cells hypersensitive to trastuzumab derived from BT474.

2021-09-24 | GSE184655 | GEO

RNA sequencing of BT474 cells treated with trastuzumab or trastuzumab + pertuzumab and BT474-derived cells resistant to trastuzumab or trastuzumab + pertuzumab

Project description:RNA sequencing of BT474 cells treated with trastuzumab or trastuzumab + pertuzumab and BT474-derived cells resistant to trastuzumab or trastuzumab + pertuzumab

| PRJNA495653 | ENA

Human breast cancer SKBr-3 cells: trastuzumab-resistant vs. parental

Project description:Human breast cancer SKBr-3 cells selected with trastuzumab for 6 month compared with parental SKBr-3 cells; Goal was to screen for microRNAs involved in development of trastuzumab resistance. Human breast cancer SKBr-3 cells were continuously cultured in the presence ofM-BM- 5M-BM-5g/ml trastuzumab for 6 months, and the resulting alive cells were regarded as trastuzumab-resistant. Total RNAs were prepared from these cells and cells cultured in parallel in control media, and were subjected to hybridization on the miRCURY LNA Array (Exiqon, version 11.0).

2013-05-25 | E-GEOD-47011 | biostudies-arrayexpress

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