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
| Autor: | Robert C. Seeger, Francisco M. Vega, Alok R. Singh, Shweta Joshi, Melissa Millard, Hiroyuki Shimada, Donald L. Durden, Susan Groshen, Jingying Xu, Peter W. Laird, Wei Ye, Mihaela Campan, Anat Erdreich-Epstein, Pinzheng Guo, Guillermo A. Morales, Joseph R. Garlich |
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| Přispěvatelé: | National Institutes of Health (US), Concern Foundation, Nautica Malibu Triathlon Fund, Bogart Pediatric Cancer Research Program, T. J. Martell Foundation |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Angiogenesis Integrin 03 medical and health sciences Neuroblastoma 0302 clinical medicine Medicine PTEN Microvessel Protein kinase B neoplasms PI3K/AKT/mTOR pathway biology business.industry medicine.disease PI3-kinase inhibitors 3. Good health 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Immunohistochemistry Integrin αvβ3 BRD4 business |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | 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. This work was supported by grant CA81403 from the National Institutes of Health and a grant from the Concern Foundation. This work was also supported in part by National Institutes of Health grants U01 CA70903, CA60104 and CA02649 to RCS, grant CA14089 to SG, grants CA94233, CA192656 and FD004385 to DLD, the Nautica Malibu Triathlon Fund, the Bogart Pediatric Cancer Research Program and the T.J. Martell Foundation for Leukemia, Cancer, and AIDS Research. |
| Databáze: | OpenAIRE |
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