dc.creator | Erdreich-Epstein, A. | es |
dc.creator | Singh, AR | es |
dc.creator | Joshi, S. | es |
dc.creator | Vega Moreno, Francisco Manuel | es |
dc.creator | Guo, PZ | es |
dc.creator | Xu, JY | es |
dc.creator | Groshen, S | es |
dc.creator | Durden, DL | es |
dc.date.accessioned | 2023-10-23T13:01:27Z | |
dc.date.available | 2023-10-23T13:01:27Z | |
dc.date.issued | 2016-10-26 | |
dc.identifier.citation | Erdreich-Epstein, A., Singh, A., Joshi, S., Vega Moreno, F.M., Guo, P., Xu, J.,...,Durden, D. (2016). Association of high microvessel alpha(v)beta(3) and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126. ONCOTARGET, 8 (32), 52193-52210. | |
dc.identifier.issn | 1949-2553 | es |
dc.identifier.uri | https://hdl.handle.net/11441/149844 | |
dc.description.abstract | Neuroblastoma (NB) is the most common extracranial solid tumor in children. Our previous studies showed that the angiogenic integrin αvβ3 was increased in high-risk metastatic (stage 4) NB compared with localized neuroblastomas. Herein, we show that integrin αvβ3 was expressed on 68% of microvessels in MYCN-amplified stage 3 neuroblastomas, but only on 34% (means) in MYCN-non-amplified tumors (p < 0.001; n = 54). PTEN, a tumor suppressor involved in αvβ3 signaling, was expressed in neuroblastomas either diffusely, focally or not at all (immunohistochemistry). Integrin αvβ3 was expressed on 60% of tumor microvessels when PTEN was negative or focal, as compared to 32% of microvessels in tumors with diffuse PTEN expression (p < 0.001). In a MYCN transgenic mouse model, loss of one allele of PTEN promoted tumor growth, illustrating the potential role of PTEN in neuroblastoma pathogenesis. Interestingly, we report the novel dual PI-3K/BRD4 activity of SF1126 (originally developed as an RGD-conjugated pan PI3K inhibitor). SF1126 inhibits BRD4 bromodomain binding to acetylated lysine residues with histone H3 as well as PI3K activity in the MYCN amplified neuroblastoma cell line IMR-32. Moreover, SF1126 suppressed MYCN expression and MYCN associated transcriptional activity in IMR-32 and CHLA136, resulting in overall decrease in neuroblastoma cell viability. Finally, treatment of neuroblastoma tumors with SF1126 inhibited neuroblastoma growth in vivo. These data suggest integrin αvβ3, MYCN/BRD4 and PTEN/PI3K/AKT signaling as biomarkers and hence therapeutic targets in neuroblastoma and support testing of the RGD integrin αvβ3-targeted PI-3K/BRD4 inhibitor, SF1126 as a therapeutic strategy in this specific subgroup of high risk neuroblastoma. | es |
dc.format | application/pdf | es |
dc.format.extent | 18 p. | es |
dc.language.iso | eng | es |
dc.relation.ispartof | ONCOTARGET, 8 (32), 52193-52210. | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Angiogenesis | es |
dc.subject | Integrin αvβ3 | es |
dc.subject | Neuroblastoma | es |
dc.subject | PI3-kinase inhibitors | es |
dc.subject | BRD4 | es |
dc.title | Association of high microvessel alpha(v)beta(3) and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126 | es |
dc.type | info:eu-repo/semantics/article | es |
dcterms.identifier | https://ror.org/03yxnpp24 | |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica | es |
dc.journaltitle | ONCOTARGET | es |
dc.publication.volumen | 8 | es |
dc.publication.issue | 32 | es |
dc.publication.initialPage | 52193 | es |
dc.publication.endPage | 52210 | es |