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

Anat Erdreich-Epstein,Melissa Millard,Mihaela Campan,Susan Groshen,Donald L Durden,Robert C Seeger,Peter W Laird,Wei Ye,Pinzheng Guo,Guillermo Morales,Jingying Xu,Hiroyuki Shimada,Joseph R Garlich,Shweta Joshi,Alok R Singh,Francisco M Vega

doi:10.18632/oncotarget.13386

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.

Highlights

Neuroblastoma (NB) is the most common and deadly extracranial solid tumor in children, arising from the sympathetic nervous system and accounting for 8–10% of all childhood cancers and 15% of deaths from pediatric tumors [1]
The main finding in this analysis is that on average, integrin αvβ3 was expressed on 68% of microvessels in stage 3 MYCN-amplified neuroblastomas, but only on 34% of microvessels in MYCN-non-amplified ones (Table 1; Figure 1B)
In previous work we showed that stage 4 neuroblastoma tumors express the angiogenic integrin, αvβ3 on their endothelial cells in a higher proportion of their microvessels compared to stage 1 and 2 tumors [5]

Summary

Introduction

Neuroblastoma (NB) is the most common and deadly extracranial solid tumor in children, arising from the sympathetic nervous system and accounting for 8–10% of all childhood cancers and 15% of deaths from pediatric tumors [1]. In many cancers, including neuroblastoma, increased angiogenesis is associated with more aggressive tumors and poorer prognosis [3, 4]. Integrin αvβ is preferentially expressed on angiogenic blood vessels in some cancers, where its expression is associated with tumor aggressiveness and worse prognosis [5]. Inhibition of vascular integrins αvβ and αvβ results in apoptosis of angiogenic endothelial cells, inhibition of tumor angiogenesis, and impaired tumor growth [6,7,8], potentially supporting clinical use of integrin-based therapy. Inhibitors of integrin αvβ have not shown much promise in clinical trials [9, 10] suggesting that a different approach is needed to therapeutically exploit the angiogenic expression of integrin αvβ in cancer

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