CDK/histone deacetylase inhibition in acute leukemia

描述（由申请人提供）：本申请的目的是进行I期试验和相关实验室研究，其中细胞周期蛋白依赖性激酶（CDK）抑制剂flavopiridol（NSC 649890）与组蛋白脱乙酰酶抑制剂（HDACI）SAHA（NSC 701852）联合治疗难治性急性白血病。这个概念是基于临床前的结果，从这个和其他实验室表明，flavopiridol，尽管诱导细胞周期停滞，不促进HDACI介导的成熟白血病细胞，相反，它会导致线粒体损伤和细胞凋亡的显着增加。这种现象可能源于flavopiridol介导的PTEF-B转录复合物和其他激酶的抑制，导致各种抗凋亡蛋白的下调/失活，包括p21 CIP 1、XIAP、Mcl-1、NF-κ B，以及RNA pol II羧基末端结构域（CTD）的磷酸化减少。此外，flavopiridol和SAHA都在早期I期试验中显示出对急性白血病有活性的有希望的证据。这些考虑促使开发了CTEP批准的I期试验（NCI #P6637），其在难治性白血病患者中经口给予SAHA，TID × 14天，结合flavopiridol，作为1小时输注，第1-5天给药。本申请的目的是：1）确定以这种方式给药的SAHA和Flavopiridol的最大耐受剂量（MTD）; 2）定义该方案的推荐II期剂量（RPTD）; 3）表征这些药物的剂量限制性毒性（DLT）; 4）获得方案活性的初步证据; 5）表征Flavopiridol和SAHA的药代动力学。还将进行相关的实验室研究以检验以下假设：1）如在临床前研究中所观察到的，体内施用夫拉匹醇和SAHA将导致原发性患者来源的母细胞中p21 CIP 1、XIAP、Mcl-1、NF-κ B的下调/失活以及CTD RNA pol II的磷酸化减少; 2）在离体暴露于这些药剂的母细胞中将发生类似的事件;和3）血浆flavopiridol水平将达到足以阻断培养的白血病细胞系中SAHA介导的p21 CIP 1诱导。从这项试验中获得的信息将为随后合理设计的II期试验奠定基础，该试验采用一种新的策略，涉及同时抑制CDK和HDAC治疗难治性急性白血病。

DESCRIPTION (provided by applicant): The goal of this application is to conduct a Phase I trial and correlative laboratory studies in which the cyclin-dependent kinase (CDK) inhibitor flavopiridol (NSC 649890) is combined with the histone deacetylase inhibitor (HDACI) SAHA (NSC 701852) for the treatment of refractory acute leukemia. This concept is based on preclinical results from this and other laboratories indicating that flavopiridol, despite inducing cell cycle arrest, does not promote HDACI-mediated maturation in leukemic cells; instead, it results in a pronounced increase in mitochondrial injury and apoptosis. This phenomenon may stem from flavopiridol-mediated inhibition of the PTEF-b transcription complex and other kinases, leading to down-regulation/inactivation of various anti-apoptotic proteins, including p21CIP1, XIAP, Mcl-1, NF-kappa B, and diminished phosphorylation of RNA pol II carboxy-terminal domain (CTD). Furthermore, both flavopiridol and SAHA have shown promising evidence of activity in acute leukemia in early Phase I trials. These considerations have prompted the development of a CTEP-approved Phase I trial (NCI #P6637) of SAHA administered po TID x 14 d in conjunction with flavopiridol administered as a 1-hr infusion d 1-5 for patients with refractory leukemia. The goals of this application are 1) to establish the maximally tolerated dose (MTD) of SAHA and Flavopiridol administered in this manner; 2) define the recommended Phase II dose (RPTD) for this regimen; 3) characterize the dose-limiting toxicities (DLTs) of these agents; 4) obtain preliminary evidence of activity of the regimen; 5) characterize the pharmacokinetics of flavopiridol and SAHA. Correlative laboratory studies will also be carried out to test the hypotheses that 1) in vivo administration of flavopiridol and SAHA will result in down-regulation/inactivation of p21CIP1, XIAP, Mcl-1, NF-kappa B, and diminished phosphorylation of CTD RNA pol II in primary patient-derived blasts, as observed in preclinical studies; 2) similar events will occur in blasts exposed to these agents ex vivo; and 3) plasma flavopiridol levels will be achieved sufficient to block SAHA-mediated p21CIP1 induction in cultured leukemia cell lines. Information derived from this trial will lay the groundwork for subsequent rationally designed Phase II trials employing a novel strategy involving simultaneous CDK and HDAC inhibition in the treatment of refractory acute leukemia.