CDK/histone deacetylase inhibition in acute leukemia

描述（由申请人提供）：本申请的目标是进行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）抑制剂黄吡醇（NSC 649890）与组蛋白去乙酰化酶抑制剂（HDACI） SAHA （NSC 701852）联合用于治疗难治性急性白血病。这一概念是基于该实验室和其他实验室的临床前结果，这些结果表明，黄吡醇尽管诱导细胞周期阻滞，但不会促进hdac介导的白血病细胞成熟；相反，它会导致线粒体损伤和细胞凋亡的显著增加。这种现象可能源于黄烷醇介导的PTEF-b转录复合物和其他激酶的抑制，导致多种抗凋亡蛋白下调/失活，包括p21CIP1、XIAP、Mcl-1、NF-kappa B，以及RNA pol II羧基末端结构域（CTD）磷酸化减少。此外，黄吡醇和SAHA在早期I期试验中都显示出对急性白血病有活性的良好证据。这些考虑促使cep批准了一项I期试验（NCI #P6637）的开展，该试验针对难治性白血病患者，将SAHA与黄酮吡醇（1小时输注1-5天）联合应用于TID x 14 d。本应用的目的是：1)确定以这种方式给药的SAHA和黄吡醇的最大耐受剂量（MTD）；2)确定该方案的推荐II期剂量（RPTD）；3)表征这些药物的剂量限制性毒性（dlt）；4)获得该方案有效的初步证据；5)表征黄吡醇和SAHA的药动学。相关的实验室研究也将进行，以验证以下假设：1)在临床前研究中观察到，黄酮类吡醇和SAHA体内给药会导致原发性患者来源的母细胞中p21CIP1、XIAP、Mcl-1、NF-kappa B的下调/失活，以及CTD RNA pol II磷酸化降低；2)在体外暴露于这些制剂的细胞也会发生类似的事件；3)血浆黄吡醇水平将达到足以阻断培养白血病细胞系中saha介导的p21CIP1诱导。从该试验中获得的信息将为后续合理设计的II期试验奠定基础，该试验采用一种新的策略，包括同时抑制CDK和HDAC来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.