Phase II trial of valproic acid in myelodysplasia

丙戊酸治疗骨髓增生异常的 II 期试验

• 批准号: 7067199
• 负责人: PETER S KLEIN
• 金额: $ 30.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-18 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067199
• 关键词: acetylation; amidohydrolases; biomarker; blood transfusion; bone marrow neoplasms; clinical research; clinical trial phase II; drug screening /evaluation; enzyme inhibitors; flow cytometry; hematopoietic stem cells; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; patient oriented research; polymerase chain reaction; valproate

DESCRIPTION (provided by applicant): The myelodysplastic syndromes (MDS) are a heterogeneous group of neoplastic hematopoietic stem cell disorders characterized by peripheral blood cytopenias and a proclivity for transformation into acute leukemia. Allogeneic bone marrow transplant is the most effective therapy available, but carries high mortality and is a viable option only in younger patients with early disease. The presence of impaired cellular maturation in the setting of marrow hypercellularity has prompted the use of differentiation therapy in MDS. Agents that induce differentiation apparently by altering chromatin structure, such as DMA methyltransferase (Dmt) inhibitors and histone deacetylase (HDAC) inhibitors, are now in clinical trials for MDS as well as acute leukemias and other neoplasias, and recently the Dmt inhibitor 5-azacytidine has been approved by the FDA for MDS. However, many of the novel drugs currently being tested are associated with significant toxicity and in many cases require long term subcutaneous injection or IV infusion. We have found that valproic acid (VPA; depakote), a widely prescribed anticonvulsant, potently inhibits histone deacetylases (HDACs) at concentrations that are within the therapeutic range for treatment of epilepsy. In preclinical studies, we find that a therapeutic concentration of VPA causes robust hyperacetylation of core histones and induces differentiation of leukemic cell lines in culture, as assessed by increased expression of multiple molecular markers of differentiation. We also find that VPA robustly induces the expression of the cell cycle inhibitor p21, similar to other HDAC inhibitors. Furthermore, and in contrast to other HDAC inhibitors, VPA does not inhibit HDAC6, which functions in the cytoplasm to regulate microtubule polymerization, or HDAC10, suggesting a level of specificity in the inhibition of HDACs by VPA. Thus, we plan to administer VPA to patients with MDS to test whether VPA: (1) improves peripheral blood indices and reduces transfusion requirements, (2) inhibits HDACs in vivo, (3) abrogates the hematopoietic defect in the bone marrow or affects other objective markers of the disease, including a change in the size of the MDS clone. VPA offers the significant advantages that it is a clinically well-characterized, relatively safe medication that can be administered orally and can be accurately monitored by well-established methods.

描述（由申请人提供）： 骨髓增生异常综合征（MDS）是一组异质性肿瘤性造血干细胞疾病，其特征是外周血细胞减少和转化为急性白血病的倾向。同种异体骨髓移植是最有效的治疗方法，但死亡率很高，并且仅适用于患有早期疾病的年轻患者。骨髓细胞增多情况下细胞成熟受损的存在促使在MDS中使用分化疗法。通过改变染色质结构明显诱导分化的药物，如 DMA 甲基转移酶 (Dmt) 抑制剂和组蛋白脱乙酰酶 (HDAC) 抑制剂，目前正处于治疗 MDS 以及急性白血病和其他肿瘤的临床试验中，最近 Dmt 抑制剂 5-氮杂胞苷已被 FDA 批准用于治疗 MDS。然而，目前正在测试的许多新药都具有显着的毒性，并且在许多情况下需要长期皮下注射或静脉输注。我们发现丙戊酸（VPA；depakote）是一种广泛使用的抗惊厥药，在治疗癫痫的治疗范围内的浓度下可有效抑制组蛋白脱乙酰酶（HDAC）。在临床前研究中，我们发现治疗浓度的 VPA 会引起核心组蛋白的强烈过度乙酰化，并诱导培养物中白血病细胞系的分化，这是通过多种分化分子标记表达增加来评估的。我们还发现，与其他 HDAC 抑制剂类似，VPA 强烈诱导细胞周期抑制剂 p21 的表达。此外，与其他 HDAC 抑制剂相比，VPA 不会抑制 HDAC6（在细胞质中发挥调节微管聚合作用的功能）或 HDAC10，这表明 VPA 对 HDAC 的抑制具有一定程度的特异性。因此，我们计划对MDS患者施用VPA，以测试VPA是否：（1）改善外周血指数并减少输血需求，（2）抑制体内HDAC，（3）消除骨髓中的造血缺陷或影响疾病的其他客观标志物，包括MDS克隆大小的变化。 VPA 具有显着的优势，即它是一种临床上特征明确、相对安全的药物，可以口服给药，并且可以通过完善的方法进行准确监测。