Proteosome Inhibition Therapy for Hematologic Malignancy

血液恶性肿瘤的蛋白酶体抑制疗法

• 批准号: 7030593
• 负责人: Terzah M Horton
• 金额: $ 13.4万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030593
• 关键词: apoptosis; chemosensitizing agent; chemotherapy; clinical research; clinical trial phase I; clinical trials; leukemia; lymphoblast; lymphoma; multiple myeloma; neoplasm /cancer; proteasome

DESCRIPTION (provided by applicant): Bortezomib (PS-341, VELCADE) is a proteasome inhibitor, one of a novel class of chemotherapeutic agents that has been FDA-approved for the treatment of multiple myeloma in adults and is being tested as a chemosensitizer in a variety of adult solid tumor and hematologic malignancies. We have preclinical evidence that bortezomib is a potent inducer of apoptosis in leukemic cells and is synergistic or additive with several standard chemotherapy drugs used in leukemia treatment. Based on this data, I am directing a phase I clinical trial of bortezomib in pediatric patients with relapsed/refractory leukemia. I propose to conduct correlative biology experiments with patient samples obtained from the current phase I and two proposed phase 2 trials to improve our understanding of the mechanism(s) of action of bortezomib in vivo. Specifically, I would like to examine the effects of bortezomib on the NF-KB pathway and explore the use of bortezomib as a chemosensitizing agent in acute lymphoblastic leukemia (ALL) and Hodgkin's lymphoma (HL). Many short-lived regulatory proteins, such the NF-KB inhibitor kB, are ubiquitinated and degraded by proteasome inhibition. There is substantial evidence that NF-KB is deregulated in leukemias and lymphomas. I hypothesize that bortezomib induces tumor cell apoptosis by inhibiting NF-KB activation. I will examine the effects of bortezomib on tumor cell apoptosis, NF-KB activation, and pretreatment protein expression profiles. Since there is evidence that bortezomib-induced apoptosis may occur through NF-KB-independent mechanisms, I will also examine other key regulatory proteins that are degraded by ubiquitination. The phase I studies will be used to further refine correlative biology studies for the proposed phase 2 clinical trials that will examine the effectiveness of bortezomib as a chemosensitizing agent in relapsed ALL and HL.

描述（由申请人提供）：bortezomib（PS-341，Velcade）是一种蛋白酶体抑制剂，是一种新型的化学治疗剂之一，已通过FDA批准了用于治疗成人多发性骨髓瘤的多发性骨髓瘤，并且正在作为各种成人固体固体肿瘤和血液的化学效应进行测试，并正在接受化学效应。我们有临床前证明硼替佐米是白血病细胞凋亡的有效诱导剂，并且与白血病治疗中使用的几种标准化学疗法药物具有协同作用或添加剂。基于这些数据，我指挥了对复发/难治性白血病的儿科患者的硼替佐米的I期临床试验。我建议与从当前I期和两项拟议的2期试验获得的患者样品进行相关生物学实验，以提高我们对硼替佐米在体内作用机制的理解。具体而言，我想检查硼替佐米对NF-KB途径的影响，并探讨硼替佐米作为急性淋巴细胞白血病（ALL）和Hodggkin的淋巴瘤（HL）中的化学敏化剂的使用。许多短寿命的调节蛋白，例如NF-KB抑制剂KB，都被蛋白酶体抑制剂泛素化和降解。有大量证据表明，NF-KB在白血病和淋巴瘤中受到管制。 我假设硼替佐米通过抑制NF-KB激活来诱导肿瘤细胞凋亡。我将研究硼替佐米对肿瘤细胞凋亡，NF-KB激活和预处理蛋白表达谱的影响。由于有证据表明硼替佐米诱导的凋亡可能通过NF-KB独立的机制发生，因此我还将检查其他因泛素化降解的关键调节蛋白。第一阶段的研究将用于进一步完善拟议的2期临床试验的相关生物学研究，该研究将研究硼替佐米作为复发和HL的化学敏化剂的有效性。