Association of high microvessel α(v)β(3) and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126.
Association of high microvessel α(v)β(3) and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126.
复制标题
DOI：
10.18632/oncotarget.13386
复制
发表时间：
2017-08-08
期刊：
影响因子：
--
通讯作者：
Durden DL
中科院分区：
文献类型：
--
作者：
Erdreich-Epstein A;Singh AR;Joshi S;Vega FM;Guo P;Xu J;Groshen S;Ye W;Millard M;Campan M;Morales G;Garlich JR;Laird PW;Seeger RC;Shimada H;Durden DL
神经母细胞瘤（NB）是儿童颅外最常见的实体瘤。我们以前的研究表明，与局限性神经母细胞瘤相比，血管生成整合素αvβ3在高危转移性（4期）NB中增加。在此，我们发现整合素αvβ3在MYCN扩增的3期神经母细胞瘤中68%的微血管上表达，而在MYCN非扩增的肿瘤中仅34%（平均值）表达（p < 0.001; n = 54）。PTEN是一种参与αvβ3信号传导的肿瘤抑制因子，在神经母细胞瘤中呈弥漫性、局灶性或完全不表达（免疫组织化学）。当PTEN阴性或局灶性表达时，60%的肿瘤微血管表达整合素αvβ3，而在弥漫性表达的肿瘤中，32%的微血管表达整合素αvβ3（p < 0.001）。在MYCN转基因小鼠模型中，PTEN的一个等位基因的缺失促进了肿瘤生长，说明了PTEN在神经母细胞瘤发病机制中的潜在作用。有趣的是，我们报告了SF 1126（最初开发为RGD缀合的泛PI 3 K抑制剂）的新型PI-3 K/BRD 4双重活性。SF 1126抑制BRD 4布罗莫结构域与组蛋白H3的乙酰化赖氨酸残基结合以及MYCN扩增的神经母细胞瘤细胞系IMR-32中的PI 3 K活性。此外，SF 1126抑制MYCN表达和MYCN相关的转录活性在IMR-32和CHLA 136，导致神经母细胞瘤细胞活力的整体下降。最后，用SF 1126治疗神经母细胞瘤肿瘤抑制了体内神经母细胞瘤的生长。这些数据表明，整合素αvβ3、MYCN/BRD 4和PTEN/PI 3 K/AKT信号传导是神经母细胞瘤的生物标志物，因此是治疗靶点，并支持将RGD整合素αvβ3靶向PI-3 K/BRD 4抑制剂SF 1126作为该特定高危神经母细胞瘤亚组的治疗策略进行测试。
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.
登录
查看更多内容
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
BROOKS, PC;MONTGOMERY, AMP;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
56.9
作者：
BROOKS, PC;CLARK, RAF;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS
DOI：
10.1158/1078-0432.ccr-12-1243
发表时间：
2013-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Liu Y;Wu HW;Sheard MA;Sposto R;Somanchi SS;Cooper LJ;Lee DA;Seeger RC
通讯作者：
Seeger RC