PHASE I TRIAL OF ATRA-IV & DEPAKOTE IN PTS W/ADVANCED SOLID TUMOR MALIGNANCIES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究小组的数据表明，在许多实体肿瘤中，类维生素a耐药性与细胞内视黄醇和视黄醇酯的水平呈负相关，表明增加细胞内视黄酸（RA）水平将改善RA介导的抗肿瘤作用。或者，使RA成为更有效的转录启动器也会导致RA诱导的生长抑制。最近的研究表明，RA受体的转录调控涉及组蛋白去乙酰化酶（hdac）对染色质的修饰，这些酶通过核共抑制因子被募集到RA靶基因上。组蛋白是核小体核心蛋白的一部分。组蛋白的乙酰化和去乙酰化在基因表达调控中发挥作用(4)。组蛋白在去乙酰化状态下导致染色质紧密缠绕在组蛋白核心周围，抑制转录。当组蛋白处于高乙酰化状态时（即当去乙酰化被抑制时），染色质松弛，转录可以进行。组蛋白乙酰化水平由两类酶调节，组蛋白乙酰转移酶（HATs）和hdac。大量研究表明，HDAC抑制剂可以诱导培养的肿瘤细胞发生分化、生长停滞和/或凋亡。hdac可能通过阻止转录进行来阻止ra诱导的转录。基于这些研究和我们自己的前期工作，我们建议研究ATRA-IV与HDAC抑制剂Depakote（丙戊酸）的联合应用。本研究的长期目标是确定这些药物联合使用的II期剂量，以进行II期临床试验，并了解体内RA和HDAC抑制的机制。本研究的具体目的是：1)确定Depakote联合脂质包埋的全反式维甲酸（ATRA-IV）治疗晚期恶性实体瘤患者的最大耐受剂量；2)确定联合治疗的剂量限制和其他毒性；3)确定未来安全性和有效性（II期）试验中应使用的剂量；4)研究维甲酸受体表达和组蛋白乙酰化状态，以确定对肿瘤活检患者外周血单个核细胞和组织的生物学影响；5)评估肿瘤对联合治疗的反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Data from our group indicate that retinoid resistance in many solid tumors inversely correlates with levels of intracellular retinol and retinol esters, and suggest that increasing intracellular levels of retinoic acid (RA) will improve RA mediated anti-tumor effects. Alternatively, enabling RA to become a more potent initiator of transcription would also lead to RA-induced growth inhibition. Recent studies indicate that transcriptional regulation by RA receptors involves modification of chromatin by histone deacetylases (HDACs), which are recruited to RA-target genes by nuclear co-repressors. Histones are part of the core proteins of nucleosomes. Acetylation and deacetylation of histones play a role in regulation of gene expression (4). Histones in their deacetylated state cause chromatin to be tightly wound around the histone cores, inhibiting transcription. When histones are in their hyperacetylated state (i.e. when deacetylation is inhibited), the chromatin relaxes and transcription can proceed. The levels of histone acetylation are regulated by two classes of enzymes, histone acetyl transferases (HATs) and HDACs. Numerous studies show that HDAC inhibitors can induce cultured tumor cells to undergo differentiation, growth arrest and/or apoptosis. HDACs may prevent RA-induced transcription by not allowing transcription to proceed. Based on these studies and our own preliminary work, we propose to study the combination of ATRA-IV and the HDAC inhibitor Depakote (valproic acid). The long-term goal of this study is to determine the Phase II dose of these agents in combination to proceed to Phase II clinical trials, and to understand the mechanisms of RA and HDAC inhibition in vivo. The specific aims of this study are: 1) To determine the maximum tolerated dose of Depakote in combination with liposome encapsulated all-trans retinoic acid (ATRA-IV) in patients with advanced solid tumor malignancies; 2) To define the dose limiting and other toxicities of the combination therapy; 3) To determine the dosing that should be used in future safety and efficacy (Phase II) trials; 4) To study retinoic acid receptor expression and histone acetylation status to ascertain biologic effect on peripheral blood mononuclear cells and tissue obtained from selected patients who undergo tumor biopsies; and 5) To assess for tumor responses to combination therapy.