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

ATRA-IV 的 I 期试验

• 批准号: 7378405
• 负责人: David M. Nanus
• 金额: $ 0.89万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378405
• 关键词: PHASE; TRIAL; ATRA; IV; DEPAKOTE

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。来自我们组的数据表明，许多实体瘤中的类视黄度耐药性与细胞内视黄醇和视黄醇酯的水平成反比，并表明增加细胞内视黄酸（RA）将改善RA介导的抗肿瘤作用。另外，使RA成为更有效的转录发起者也将导致RA诱导的生长抑制作用。最近的研究表明，RA受体的转录调节涉及组蛋白脱乙酰基酶（HDACS）对染色质的修饰，这些乙酰基酶（HDACS）由核共抑制剂募集到RA-TARGET基因。组蛋白是核小体的核心蛋白的一部分。组蛋白的乙酰化和脱乙酰化在基因表达的调节中起作用（4）。其脱乙酰化态中的组蛋白会导致染色质在组蛋白核周围紧紧缠绕，从而抑制转录。当组蛋白处于过度乙酰化态时（即，抑制脱乙酰基化）时，染色质质量会放松和转录。组蛋白乙酰化水平受两类酶，组蛋白乙酰转移酶（HAT）和HDAC的调节。大量研究表明，HDAC抑制剂可以诱导培养的肿瘤细胞进行分化，生长停滞和/或凋亡。 HDAC可以通过不允许转录继续进行RA诱导的转录。基于这些研究和我们自己的初步工作，我们建议研究ATRA-IV和HDAC抑制剂Depakote（丙戊酸）的组合。这项研究的长期目标是确定这些药物组合的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。 这项研究的具体目的是：1）确定晚期实体肿瘤恶性肿瘤患者的脂质体封装全反式视黄酸（ATRA-IV）的最大耐受剂量； 2）定义联合疗法的剂量限制和其他毒性； 3）确定应在将来的安全和功效（II期）试验中使用的剂量； 4）研究视黄酸受体表达和组蛋白乙酰化状态，以确定生物学对从经过肿瘤活检的选定患者获得的外周血单核细胞和组织的生物作用； 5）评估肿瘤对联合疗法的反应。