Phase II trial of valproic acid in myelodysplasia

描述（由申请人提供）： 骨髓增生异常综合征（MDS）是一组异质性的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。异基因骨髓移植是最有效的治疗方法，但死亡率高，仅适用于早期疾病的年轻患者。在骨髓细胞过多的情况下，细胞成熟受损的存在促使在MDS中使用分化治疗。明显通过改变染色质结构诱导分化的药物，如DMA甲基转移酶（Dmt）抑制剂和组蛋白脱乙酰酶（HDAC）抑制剂，目前正在进行MDS以及急性白血病和其他肿瘤形成的临床试验，最近Dmt抑制剂5-氮杂胞苷已被FDA批准用于MDS。然而，目前正在测试的许多新型药物与显著的毒性相关，并且在许多情况下需要长期皮下注射或IV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导致核心组蛋白的强烈超乙酰化，并诱导培养物中白血病细胞系的分化，如通过多种分化分子标志物的表达增加所评估的。我们还发现，VPA强烈诱导细胞周期抑制剂p21的表达，类似于其他HDAC抑制剂。此外，与其他HDAC抑制剂相反，VPA不抑制HDAC 6（其在细胞质中发挥调节微管聚合的功能）或HDAC 10，表明VPA抑制HDAC的特异性水平。因此，我们计划对MDS患者给予VPA，以测试VPA是否：（1）改善外周血指标并减少输血需求，（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具有显著的优势，即它是一种临床特征良好、相对安全的药物，可口服给药，并可通过成熟的方法进行准确监测。

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.