Association of high microvessel αβ and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126.

Oncotarget 2017 Aug 18;8(32):52193-52210. Epub 2016 Nov 18.

Department of Pediatrics, Moores Cancer Center, University of California San Diego, California, USA.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Our previous studies showed that the angiogenic integrin αβ was increased in high-risk metastatic (stage 4) NB compared with localized neuroblastomas. Herein, we show that integrin αβ was expressed on 68% of microvessels in MYCN-amplified stage 3 neuroblastomas, but only on 34% (means) in MYCN-non-amplified tumors ( < 0.001; = 54). PTEN, a tumor suppressor involved in αβ signaling, was expressed in neuroblastomas either diffusely, focally or not at all (immunohistochemistry). Integrin αβ 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 ( < 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 . These data suggest integrin αβ, MYCN/BRD4 and PTEN/PI3K/AKT signaling as biomarkers and hence therapeutic targets in neuroblastoma and support testing of the RGD integrin αβ-targeted PI-3K/BRD4 inhibitor, SF1126 as a therapeutic strategy in this specific subgroup of high risk neuroblastoma.

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http://dx.doi.org/10.18632/oncotarget.13386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581022PMC
August 2017
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