Proteasome/HDAC Inhibition in Leukemia/MDS; Phase I Trial and Correlative Studies

白血病/MDS 中的蛋白酶体/HDAC 抑制；

• 批准号: 7944168
• 负责人: Steven Grant
• 金额: $ 58.98万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944168
• 关键词: Academia; Accounting; Acetylation; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Address; Aftercare; Apoptosis; Apoptotic; BIRC4 gene; Biochemical; Biological Assay; Blast Cell; Blast Phase; Bortezomib; Cancer Center; Cell Death; Cells; Chronic Myeloid Leukemia; Clinical; Combined Modality Therapy; Correlative Study; Development; Disease; Dose; Dose-Limiting; Down-Regulation; Drug Industry; Event; Fluorescence Microscopy; Functional disorder; Future; Goals; Hematologic Neoplasms; Hematopoietic; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; In Vitro; Individual; Indolent; Institution; Laboratories; Laboratory Study; Lead; Malignant - descriptor; Malignant lymphoid neoplasm; Mediating; Methods; Monitor; Morbidity - disease rate; Multiple Myeloma; Nuclear; Patients; Performance; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Refractory; Regimen; Reproduction spores; Resources; Safety; Schedule; Surrogate Markers; Syndrome; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Up-Regulation; Western Blotting; X-linked IAP; anti-cancer therapeutic; base; cell transformation; cell type; effective therapy; high risk; in vivo; insight; leukemia; mortality; multicatalytic endopeptidase complex; novel; p65; pre-clinical; preclinical study; pro-apoptotic protein; prototype; public health relevance; resistance mechanism; response; synergism; treatment strategy

DESCRIPTION (provided by applicant): The central goal of this GO RC2 application is to leverage the collective resources of three institutions (VCU/Massey Cancer Center, MD Anderson Cancer Center, H. Lee Moffitt Cancer Center) and various associated support mechanisms (i.e., R01, P01, N01, and SPORE) to conduct a mechanism-based Phase I trial of the histone deacetylase inhibitor (HDACI) belinostat (PXD-101) and the proteasome inhibitor (PI) bortezomib in patients with refractory AML, high-risk MDS, CML-blast crisis, and ALL. The second goal is to perform correlative laboratory studies to test the adequacy of methods for monitoring candidate surrogate markers that may predict for disease responsiveness and help to define mechanisms of resistance to this regimen in future efficacy-based trials (e.g., Phase II). Previous studies from our laboratories documented pronounced synergism between HDACIs and PIs in malignant hematopoietic cells, including human leukemia cells. Mechanisms responsible for synergistic interactions are likely to be multi-factorial, including PI-mediated inhibition of HDACI-induced NF-:B activation, down-regulation of NF-:B-dependent anti-apoptotic proteins (Bcl-xL, XIAP), HDACI-mediated up-regulation of Bim, and disruption of aggresome function. In addition, evidence suggests that HDACIs disrupt proteasome function, raising the possibility that combined treatment with these agents may result in enhanced proteasome inhibition. Notably, recent preclinical evidence from our laboratories indicates that very low (e.g., nM) concentrations of belinostat and bortezomib interact in a highly synergistic manner in cultured and primary AML blasts to induce apoptosis in association with diminished nuclear p65/RelA localization, down-regulation of NF-:B-dependent proteins (Bcl-xL and XIAP), and up- regulation of Bim. Despite this preclinical evidence, a strategy combining HDACIs with PIs has not yet been evaluated in AML, MDS, and related acute leukemias. Specific Aim #1 of this proposal is to conduct a Phase I trial of belinostat given IVP days 1-5 and 8-12 of a 3-wk schedule in conjunction with bortezomib given IVP twice weekly x two weeks and to identify the RPTD (recommended Phase II doses) for future Phase II trials. Secondary aims are to identify the dose-limiting toxicities of this regimen, and to gain preliminary insights into the potential therapeutic efficacy of this strategy. Specific Aim #2 of this proposal is to test the adequacy of methods for monitoring candidate correlative pharmacodynamic determinants in leukemic blast cells prior to and 24 hr after treatment with belinostat/bortezomib, focusing on events observed in vitro in preclinical studies e.g., diminished p65/RelA nuclear localization by digitized fluorescence microscopy; Bcl-xL/XIAP down- regulation and Bim up-regulation by Western blot analysis; and inhibition of 20S proteasome activity. The successful conduct of this trial and performance of correlative laboratory studies could serve as a prototype for future partnerships between the NCI, academia, and the pharmaceutical industry in the development of novel, mechanism-based anti-cancer therapeutic strategies involving two or more investigational agents. PUBLIC HEALTH RELEVANCE: Acute myelogenous leukemia and related diseases (myelodysplasic syndrome, acute lymphocytic leukemia, chronic myelogenous leukemia in blast crisis) are responsible for significant morbidity and mortality. If successful, the current proposal could lead to the development of a new and potentially more effective treatment strategy for these diseases, and could also help to identify laboratory correlates that might predict for disease responsiveness in individual patients.

描述（由申请人提供）：此 GO RC2 申请的中心目标是利用三个机构（VCU/梅西癌症中心、MD 安德森癌症中心、H. Lee Moffitt 癌症中心）的集体资源和各种相关支持机制（即、R01、P01、N01 和 SPORE）对组蛋白脱乙酰酶抑制剂 (HDACI) belinostat (PXD-101) 和蛋白酶体抑制剂 (PI) 硼替佐米治疗难治性 AML、高危 MDS、CML 急变和 ALL 患者。第二个目标是进行相关的实验室研究，以测试监测候选替代标志物的方法是否充分，这些标志物可以预测疾病反应性，并有助于在未来基于疗效的试验（例如 II 期）中确定对该方案的耐药机制。我们实验室之前的研究记录了 HDACIs 和 PI 在恶性造血细胞（包括人类白血病细胞）中存在明显的协同作用。负责协同相互作用的机制可能是多因素的，包括 PI 介导的 HDACI 诱导的 NF-:B 激活抑制、NF-:B 依赖性抗凋亡蛋白（Bcl-xL、XIAP）的下调， HDACI 介导的 Bim 上调和攻击体功能的破坏。此外，有证据表明 HDACIs 会破坏蛋白酶体功能，这增加了与这些药物联合治疗可能导致蛋白酶体抑制增强的可能性。值得注意的是，我们实验室最近的临床前证据表明，极低（例如，nM）浓度的贝利司他和硼替佐米在培养和原发性 AML 母细胞中以高度协同的方式相互作用，诱导与核 p65/RelA 定位减少、下调相关的细胞凋亡。 NF-:B 依赖性蛋白（Bcl-xL 和 XIAP）的表达以及 Bim 的上调。尽管有这些临床前证据，HDACIs 与 PI 相结合的策略尚未在 AML、MDS 和相关急性白血病中进行评估。该提案的具体目标 #1 是进行贝利诺他的 I 期试验，在 3 周计划的第 1-5 天和第 8-12 天进行 IVP，与硼替佐米联合每周两次×两周进行 IVP，并确定 RPTD（推荐） II 期剂量）用于未来的 II 期试验。次要目标是确定该方案的剂量限制毒性，并初步了解该策略的潜在治疗效果。该提案的具体目标#2是测试在用贝利司他/硼替佐米治疗之前和之后24小时监测白血病母细胞中候选相关药效决定因素的方法的充分性，重点关注临床前研究中体外观察到的事件，例如p65/p65/通过数字化荧光显微镜进行 RelA 核定位；通过蛋白质印迹分析发现 Bcl-xL/XIAP 下调和 Bim 上调；并抑制20S蛋白酶体活性。这项试验的成功进行以及相关实验室研究的进行可以作为 NCI、学术界和制药行业之间未来合作伙伴关系的原型，以开发涉及两种或多种研究药物的新型、基于机制的抗癌治疗策略。 公众健康相关性：急性髓性白血病及相关疾病（骨髓增生异常综合征、急性淋巴细胞白血病、急变期慢性髓性白血病）是造成显着发病率和死亡率的原因。如果成功，当前的提议可能会导致针对这些疾病开发一种新的、可能更有效的治疗策略，并且还可能有助于确定可能预测个体患者疾病反应的实验室相关因素。