Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/7323
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dc.contributor.authorMaria Milazzo, Ferdinandoen_us
dc.contributor.authorVesci, Loredanaen_us
dc.contributor.authorMaria Anastasi, Annaen_us
dc.contributor.authorChiapparino, Caterinaen_us
dc.contributor.authorRosi, Antonioen_us
dc.contributor.authorGIANNINI, GIUSEPPEen_us
dc.contributor.authorTaddei, Maurizioen_us
dc.contributor.authorCini, Elenaen_us
dc.contributor.authorFALTONI, VALENTINAen_us
dc.contributor.authorPetricci, Elenaen_us
dc.contributor.authorBattistuzzi, Gianfrancoen_us
dc.contributor.authorSALVINI, LAURAen_us
dc.contributor.authorCarollo, Valeriaen_us
dc.contributor.authorDe Santis, Ritaen_us
dc.date.accessioned2021-03-30T16:11:25Z-
dc.date.available2021-03-30T16:11:25Z-
dc.date.issued2020-
dc.identifier.issn2234-943Xen_US
dc.identifier.urihttp://hdl.handle.net/20.500.12779/7323-
dc.description208364en_US
dc.description.abstractTargeted 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.en_US
dc.language.isoenen_US
dc.relationNoneen_US
dc.relation.ispartofFRONTIERS IN ONCOLOGYen_US
dc.titleErbB2 Targeted Epigenetic Modulation: Anti-tumor Efficacy of the ADC Trastuzumab-HDACi ST8176AA1en_US
dc.typeArticleen_US
dc.identifier.doi10.3389/fonc.2019.01534en_US
dc.identifier.urlhttps://www.frontiersin.org/article/10.3389/fonc.2019.01534en_US
dc.relation.volume9en_US
dc.relation.issue2en_US
dc.description.firstpage1534en_US
dc.description.thirdmissionNot applicableen_US
item.cerifentitytypePublications-
item.grantfulltextnone-
item.languageiso639-1en-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.openairetypeArticle-
item.fulltextNo Fulltext-
crisitem.author.orcid0000-0001-8660-7580-
crisitem.author.orcid0000-0002-9685-6342-
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