H-26071 ADVL0916 - A PHASE I STUDY OF VORINOSTAT AND BORTEZOMIB IN CHILDREN WITH

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 伏立诺他（Suberylanilide hydroxamic acid（SAHA），Zolinza <$，IND #71976）是抑制组蛋白脱乙酰酶（HDAC）活性的组蛋白脱乙酰酶抑制剂。HDAC抑制基因转录。在一些癌细胞中，存在HDAC的过表达，或HDAC向致癌转录因子的异常募集。HDAC活性的抑制导致开放的染色质结构和转录激活。在体外，伏立诺他引起乙酰化组蛋白的积累并诱导一些转化细胞的细胞周期停滞和/或凋亡。伏立诺他的抗肿瘤作用机制尚未完全表征。1 硼替佐米（PS-341，万珂，IND #58443）是一种降解泛素化蛋白的26 S蛋白酶体的可逆小分子抑制剂。泛素-蛋白酶体途径在调节细胞内特定蛋白质的浓度，从而维持细胞内的稳态中起重要作用。26 S蛋白酶体的抑制阻止了这种靶向的蛋白水解，这可以影响细胞内的多个信号级联。硼替佐米通过几种不同的机制发挥其抗肿瘤作用，包括抑制细胞生长和存活途径，诱导细胞凋亡，抑制控制细胞粘附、迁移和血管生成的基因表达。正常稳态机制的破坏可导致细胞死亡。 伏立诺他和硼替佐米的组合已显示在多种恶性肿瘤（包括肝癌、多发性骨髓瘤、白血病、淋巴瘤和胃肠癌）中具有体外协同作用。这些研究表明，伏立诺他和硼替佐米之间存在多个水平的潜在相互作用，这可以解释其观察到的协同活性。这些包括NF-B抑制，活性氧产生增加，细胞周期蛋白依赖性激酶抑制剂水平增加，蛋白酶体抑制增加，以及肿瘤抑制基因（如p53，E2 F和Bax）表达增加。此外，伏立诺他可能会破坏硼替佐米诱导的攻击性基因组形成，导致细胞应激和细胞凋亡增加。11伏立诺他联合硼替佐米的成人I期试验表明，这种药物组合通常耐受良好。 这是在21天周期的第1-5天和第8-12天口服施用伏立诺他与在第1、4、8和11天静脉内施用硼替佐米组合的I期研究。它旨在确定这种药物组合在难治性或复发性实体瘤儿童中的安全性。相关研究将评估治疗前后外周血单个核细胞（PBMC）的NF-B抑制和内质网应激反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Vorinostat (Suberylanilide hydroxamic acid (SAHA), Zolinza¿, IND #71976) is a histone deacetylase inhibitor that inhibits the activity of histone deacetylases (HDACs). HDACs repress gene transcription. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors. Inhibition of HDAC activity results in an open chromatin structure and transcriptional activation. In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized.1 Bortezomib (PS-341, Velcade¿, IND #58443) is a reversible small molecule inhibitor of the 26S proteasome that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. Bortezomib exerts its antitumor effect through several distinct mechanisms, including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition of expression of genes that control cellular adhesion, migration, and angiogenesis. The disruption of normal homeostatic mechanisms can lead to cell death.2 The combination of vorinostat and bortezomib has been shown to be synergistic in vitro in a variety of malignancies, including hepatoma,3 multiple myeloma, leukemia, lymphoma and gastrointestinal cancer. These studies showed that there are multiple levels of potential interaction between vorinostat and bortezomib which could explain their observed synergistic activity. These include NF-B inhibition, increased reactive oxygen species production, increased levels of cyclin-dependent kinase inhibitors, increased proteasome inhibition, and increased expression of tumor suppressor genes such as p53, E2F, and Bax. Additionally, vorinostat may disrupt bortezomib-induced aggresome formation resulting in increased cell stress and apoptosis.11 Phase 1 trials in adults of vorinostat in combination of bortezomib demonstrate that this drug combination was generally well-tolerated. This is a phase 1 study of vorinostat administered orally on days 1-5 and 8-12 in combination with bortezomib administered intravenously on days 1, 4, 8, and 11 of a 21 day cycle. It is designed to determine safety of this drug combination in children with refractory or recurrent solid tumors. The correlative studies will assess NF-B inhibition and endoplasmic reticulum stress response in peripheral blood mononuclear cells (PBMC) before and after treatment.