Association of high microvessel αvβ3 and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126
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Anat Erdreich-Epstein1,2,*, Alok R. Singh3, Shweta Joshi3, Francisco M. Vega3,4, Pinzheng Guo1, Jingying Xu1, Susan Groshen5, Wei Ye5, Melissa Millard1, Mihaela Campan6, Guillermo Morales7, Joseph R. Garlich7, Peter W. Laird6,8,10, Robert C. Seeger1, Hiroyuki Shimada2 and Donald L. Durden3,7,9,*
1Department of Pediatrics, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA
2Department of Pathology, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California, USA
3Department of Pediatrics, Moores Cancer Center, University of California San Diego, California, USA
4Instituto de Biomedicina de Sevilla, IBiS/HUVR/CSIC/Universidad de Sevilla and Department of Medical Physiology and Biophysics, Universidad de Sevilla, Spain
5Department of Preventive Medicine, Keck School of Medicine, Los Angeles, California, USA
6Department of Surgery University of Southern California, Keck School of Medicine, Los Angeles, California, USA
7SignalRx Pharmaceuticals, San Diego, California, USA
8USC Epigenome Center, University of Southern California, Keck School of Medicine, Los Angeles, California, USA
9Department of Pediatrics, UCSD School of Medicine and Rady Children’s Hospital San Diego, California, USA
10Current Address: Van Andel Research Institute, Grand Rapids, Michigan, USA
*These authors contributed equally to this the work
Anat Erdreich-Epstein, email: email@example.com
Donald L. Durden, email: firstname.lastname@example.org
Keywords: angiogenesis, integrin αvβ3, neuroblastoma, PI3-kinase inhibitors, BRD4
Received: March 21, 2016 Accepted: October 26, 2016 Published: November 18, 2016
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.
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