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Adeno-associated virus-mediated trastuzumab delivery to the central nervous system for human epidermal growth factor receptor 2+ brain metastasis

ABSTRACT: Trastuzumab improves overall survival for HER2+ breast cancer, but its short half-life in the cerebral spinal fluid (~2-4 days) and delivery limitations restrict the ability to target HER2+ central nervous system (CNS) disease.We developed an adeno-associated virus (AAV) vector expressing a codon-optimized, ubiquitin C (UbC)-promoter-driven trastuzumab sequence (AAV9.UbC.trastuzumab) for intrathecal administration. Transgene expression was evaluated in adult Rag1 knockout mice and rhesus nonhuman primates (NHPs) after a single intracerebroventricular (ICV) or intra-cisterna magna (ICM) AAV9.UbC.trastuzumab injection, respectively, using real-time PCR, ELISA, Western blot, in situ hybridization, single-nucleus RNA sequencing, and liquid chromatography-mass spectrometry; antitumor efficacy was evaluated in brain xenografts using HER2+ breast cancer cell lines (BT-474, MDA-MB-453).Transgene expression was detected in brain homogenates of Rag1 knockout mice following a single ICV injection of AAV9.UbC.trastuzumab (1×1011 vector genome copies [GC]/mouse) and tumor progression was inhibited in xenograft models of breast-to-brain metastasis. In NHPs, ICM delivery of AAV9.UbC.trastuzumab (3×1013 GC/animal) was well tolerated (36–37 days in-life) and resulted in transgene expression in CNS tissues and cerebrospinal fluid at levels sufficient to induce complete tumor remission in MDA-MB-453 brain xenografts. With AAV9’s proven clinical safety record, this gene therapy may represent a viable approach for targeting HER2+ CNS malignancies.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE255027 | GEO | 2024/02/05

REPOSITORIES: GEO

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Treatment effects of trastuzumab and TDM-1 in a murine model of breast cancer brain metastasis

Project description:Background: Central nervous system (CNS) metastases represent a major problem in the treatment of HER2-positive breast cancer due to the disappointing efficacy of HER2-targeted therapies in the brain microenvironment. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in preclinical models of brain metastases. Methods: We treated mice bearing BT474 or MDA-MB-361 tumors in the CNS (N=9-11 per group), or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. All statistical tests were two-sided. Results: T-DM1 significantly delayed the growth of HER2-positive breast cancer brain metastases compared to trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a striking survival benefit (median survival for BT474 tumors: 28d for trastuzumab vs 112d for T-DM1, HR=6.2, 95% CI=6.1 to 85.84; P<.001). No difference in drug distribution and HER2-signaling was revealed between the two groups. However, T-DM1 led to a significant increase in tumor cell apoptosis (One-way ANOVA for ApopTag, p<.001), which was associated with mitotic catastrophe. Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven and PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted. Comparison of trastuzumab (n=4) and TDM-1 (n=4) treated BT-474 human breast carcinoma cells growing in murine brain

2015-11-09 | E-GEOD-69042 | biostudies-arrayexpress

Treatment effects of trastuzumab and TDM-1 in a murine model of breast cancer brain metastasis

2015-11-09 | GSE69042 | GEO

Identification of resistance mechanisms to anti-HER2 antibody in breast cancer cell line BT-474

Project description:Background: The addition of the anti-HER2 antibody pertuzumab to trastuzumab/chemotherapy treatment in HER2+ breast cancer significantly improves clinical outcome. Concomitantly, the drug-antibody conjugate T-DM1 (trastuzumab-emantasine) has demonstrated efficacy, at least equal, to the combination of trastuzumab/chemotherapy. Scientific, economic and health challenges emerge from the clinical use of these novel anti-HER2 antibodies, aimed to identify new resistance mechanisms and to select the target breast cancer population. Objectives: (1) To identify primary resistance mechanisms to anti-HER2 antibodies trastuzumab, pertuzumab, and to the combined trastuzumab/pertuzumab or pertuzumab/T-DM1 therapy, (2) To identify acquired resistance mechanisms to anti-HER2 antibodies trastuzumab, pertuzumab, and to the combined trastuzumab/pertuzumab or pertuzumab/T-DM1 therapy, (3) To develop new combinations of anti-HER2 antibodies with other targeted therapies.

2019-12-31 | GSE89216 | GEO

Trastuzumab produces therapeutic actions by upregulating miR-26a and miR-30b in breast cancer cells

Project description:Objective: Trastuzumab has been used for the treatment of HER2-positive breast cancer (BC). However, a subset of BC patients exhibited resistance to trastuzumab therapy. Thus, clarifying the molecular mechanism of trastuzumab treatment will be beneficial to improve the treatment of HER2-positive BC patients. In this study, we identified trastuzumab-responsive microRNAs that are involved in the therapeutic effects of trastuzumab. Methods and results: RNA samples were obtained from HER2-positive (SKBR3 and BT474) and HER2-negetive (MCF7 and MDA-MB-231) cells with and without trastuzumab treatment for 6 days. Next, we conducted a microRNA profiling analysis using these samples to screen those microRNAs that were up- or downregulated only in HER2-positive cells. This analysis identified miR-26a and miR-30b as trastuzumab-inducible microRNAs. Transfecting miR-26a and miR-30b induced cell growth suppression in the BC cells by 40% and 32%, respectively. A cell cycle analysis showed that these microRNAs induced G1 arrest in HER2-positive BC cells as trastuzumab did. An Annexin-V assay revealed that miR-26a but not miR-30b induced apoptosis in HER2-positive BC cells. Using the prediction algorithms for microRNA targets, we identified cyclin E2 (CCNE2) as a target gene of miR-30b. A luciferase-based reporter assay demonstrated that miR-30b post-transcriptionally reduced 27% (p=0.005) of the gene expression by interacting with two binding sites in the 3’-UTR of CCNE2. Conclusion: In BC cells, trastuzumab modulated the expression of a subset of microRNAs, including miR-26a and miR-30b. The upregulation of miR-30b by trastuzumab may play a biological role in trastuzumab-induced cell growth inhibition by targeting CCNE2. We obtained microRNA expression profiles of breast cancer cell lines, MCF7, MDA-MB-231, SKBR3, and BT474, with or without trastuzumab (4microgram/mL) treatment.

2012-06-02 | E-GEOD-38415 | biostudies-arrayexpress

Gene expression profiling of primary HER2-positive breast cancers treated with neoadjuvant trastuzumab

2016-03-31 | E-GEOD-62327 | biostudies-arrayexpress

Gene expression profiling of primary HER2-positive breast cancers treated with adjuvant trastuzumab

Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients relapse after treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. To search for genes predictive of relapse in HER2-positive breast carcinoma patients treated with adjuvant trastuzumab, we conducted gene expression profiling analysis in 53 cases treated in the clinic with doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF) and trastuzumab. Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded tissues from 53 patients with primary HER2-positive (HER2+) tumors. The series consists in 23 relapsed and 30 non-relapsed cases with similar clinical-pathological characteristics (size, pathological lymph node involvement and estrogen receptor positivity) (3-year median follow up).

2015-10-19 | E-GEOD-55348 | biostudies-arrayexpress

Trastuzumab produces therapeutic actions by upregulating miR-26a and miR-30b in breast cancer cells

2012-06-03 | GSE38415 | GEO

Human HER2-breast cancer cell line, trastuzumab-resistant, LC-MSMS

Project description:We established an acquired trastuzumab-resistant model in vitro from a trastuzumab-sensitive, HER2-amplified breast-cancer cell line. A multi-omic strategy was implemented to obtain gene, proteome, and phosphoproteome signatures associated with acquired resistance to trastuzumab in HER2-positive breast cancer, followed by validation in human clinical samples.

2020-06-01 | PXD010574 | Pride

HER2-enriched tumor initiating cell (HTIC) genomic predictor of response following neoadjuvant trastuzumab-based chemotherapy in HER2+ breast cancer

Project description:We identified a 17-gene Her2-enriched tumor initiating cell (HTIC) signature in MMTV-Her2/Neu mouse mammary TICs. Here, we show that patients with HTICS+ HER2+:ERα− tumors are more likely to achieve a pathologic complete response to trastuzumab-based neoadjuvant chemotherapy compared with HER2+:ER+ tumors. Neoadjuvant study of 50 HER2-positive breast cancer cases treated with trastuzumab-based chemotherapy pre-operatively. Pre-treatment FNA from primary tumors were obtained and RNA extracted and hybridized to Affymetrix microarrays according to manufacturer protocol. Pathologic response was assessed at the end of neoadjuvant treatment.

2012-05-11 | E-GEOD-37946 | biostudies-arrayexpress

Gene expression profiling of primary HER2-positive breast cancers treated with adjuvant trastuzumab

2015-10-19 | GSE55348 | GEO

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