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Ref Type Journal Article
PMID (32039017)
Authors Milazzo FM, Vesci L, Anastasi AM, Chiapparino C, Rosi A, Giannini G, Taddei M, Cini E, Faltoni V, Petricci E, Battistuzzi G, Salvini L, Carollo V, De Santis R
Title ErbB2 Targeted Epigenetic Modulation: Anti-tumor Efficacy of the ADC Trastuzumab-HDACi ST8176AA1.
Journal Frontiers in oncology
Vol 9
Date 2019
Abstract Text Targeted therapy using monoclonal antibodies conjugated to toxins is gaining space in the treatment of cancer. Here, we report the anti-tumor effect of a new antibody drug conjugate (ADC) delivering a HDAC inhibitor to ErbB2+ solid tumors. Trastuzumab was partially reduced with tris [2-carboxyethyl] phosphine (TCEP) and conjugated to ST7464AA1, the active form of the prodrug HDAC inhibitor ST7612AA1, through a maleimide-thiol linker to obtain the Antibody Drug Conjugate (ADC) ST8176AA1. The average drug/antibody ratio (DAR) was 4.5 as measured by hydrophobic interaction chromatography (HIC). Binding of ST8176AA1 to ErbB2 receptor and internalization in tumor cells were investigated by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), cytofluorimetry, and High Content Screening (HCS) Imaging. The biological activity of the ADC was evaluated in vitro and in vivo by measuring cell proliferation/cell cycle, apoptosis/DNA damage, tubulin, and histone acetylation and modulation of Epithelial/Mesenchymal Transition (EMT) markers. Receptor binding and internalization of ST8176AA1 were confirmed to be similar to trastuzumab. Higher anti-tumor activity of ST8176AA1 compared to trastuzumab was observed in vitro in tumor cell lines. Such higher activity correlated with increased acetylation of histones and alfa-tubulin as a consequence of HDAC inhibitor-mediated epigenetic modulation that also induced increased expression of ErbB2 and estrogen receptor in triple negative breast cancer cells. Consistently with in vitro data, ST8176AA1 exhibited higher tumor growth inhibition than trastuzumab in xenograft models of ovary and colon carcinoma and in two patient-derived xenograft (PDX) models of pancreatic carcinoma. Immunohistochemistry analysis of tumor masses showed lower expression of the proliferation marker Ki67 and higher expression of cleaved caspase-3 in mice treated with the ADC compared to those treated with trastuzumab and results correlated with increased acetylation of both histones and tubulin. Collectively, present data indicate that ADC ST8176AA1 can target epigenetic modulation to ErbB2+ tumors. Interestingly, the amount of HDACi estimated to be delivered at the ST8176AA1 effective dose would correspond to ~1/1,000 of ST7612AA1 effective dose. Therefore, ST8176AA1 is an attractive new therapeutic candidate because it exhibits increased anti-tumor potency compared to trastuzumab by exerting epigenetic modulation at a much safer dose compared to standard HDACi-based therapeutic protocols.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
ADC ST8176AA1 Trastuzumab-HDACi ST8176AA1|ST8176AA1 ADC|ST8176AA1-ADC HER2 (ERBB2) Antibody 47 ADC ST8176AA1 is an antibody-drug conjugate comprising Herceptin (trastuzumab), an ERBB2 (HER2) antibody, linked to ST7464AA1, which delivers the HDAC inhibitor to tumor cells expressing ERBB2 (HER2), potentially inhibiting Erbb2 signaling, and resulting in increased DNA damage and apoptosis, and reduced cell proliferation and tumor growth (PMID: 32039017).
ST7612AA1 HDAC Inhibitor 38 ST7612AA1 is a second-generation pan-HDAC inhibitor, which leads to decreased proliferation and increased apoptosis of tumor cells (PMID: 25671299, PMID: 32039017).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 over exp pancreatic carcinoma sensitive ADC ST8176AA1 Preclinical - Pdx Actionable In a preclinical study, ADC ST8176AA1 treatment inhibited tumor growth in patient-derived xenograft (PDX) models of pancreatic carcinoma overexpressing ERBB2 (HER2) (PMID: 32039017). 32039017
ERBB2 positive colon carcinoma sensitive ADC ST8176AA1 Preclinical - Cell line xenograft Actionable In a preclinical study, ADC ST8176AA1 treatment reversed epithelial to mesenchymal (EMT) transition, induced DNA damage, increased apoptosis, and inhibited Erbb2 (Her2) signaling and proliferation of ERBB2 (HER2) expressing colon carcinoma cells in culture, and increased median survival in a cell line xenograft model (PMID: 32039017). 32039017
ERBB2 positive ovarian carcinoma sensitive ADC ST8176AA1 Preclinical - Cell line xenograft Actionable In a preclinical study, ADC ST8176AA1 treatment induced apoptosis and inhibited proliferation of ERBB2 (HER2) expressing ovary carcinoma cells in culture, and inhibited tumor growth, and increased median survival in cell line xenograft models (PMID: 32039017). 32039017