Experimental Therapeutics in Acute Leukemias

急性白血病的实验治疗

• 批准号: 7659593
• 负责人: WILLIAM G BLUM
• 金额: $ 12.97万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-09 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659593
• 关键词: Acute; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Adult; Affect; Animals; Apoptosis; Apoptotic; Area; Area Under Curve; Bolus Infusion; Bortezomib; Cell Culture Techniques; Chronic Lymphocytic Leukemia; Client; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Continuous Intravenous Infusion; Cyclophosphamide; Cytarabine; Cytolysis; Data; Daunorubicin; Development; Diagnosis; Disease; Dose; Dose-Limiting; Drug Kinetics; Etoposide; FLT3 gene; Failure; Foundations; Frequencies; Genetic Transcription; Heat-Shock Proteins 90; Hour; Human; In Vitro; Infusion procedures; Interruption; Intravenous Bolus; Investigation; Laboratories; Leukemic Cell; Link; Maximum Tolerated Dose; Mediating; Mentors; Messenger RNA; Methods; Minority; Molecular Chaperones; NF-kappa B; New Agents; Newly Diagnosed; Ohio; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphorylation; Plasma; Prednisone; Procedures; Prophylactic treatment; Proteasome Inhibition; Proteasome Inhibitor; Protein Binding; Proteins; Proto-Oncogene Proteins c-akt; RNA Polymerase II; Recurrent disease; Refractory; Relapse; Reporting; Research Personnel; Resistance; Schedule; Signal Transduction; Stem cell transplant; Therapeutic; Therapeutic Agents; Toxic effect; Transplantation; Treatment Failure; Treatment Protocols; Tumor Lysis Syndrome; Universities; Up-Regulation; Velcade; Vertebral column; Vincristine; asparaginase; base; biological adaptation to stress; career development; chemotherapy; dalton; fetal bovine serum; flavopiridol; high risk; improved; in vivo; inhibitor/antagonist; leukemia; multicatalytic endopeptidase complex; novel; novel strategies; pharmacokinetic model; protein expression; response; stem cell population; therapeutic target; tumor

DESCRIPTION (provided by applicant): The majority of adults with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) eventually relapse, and those with relapsed disease have a high likelihood of treatment failure with currently available agents. New drugs that more effectively treat these diseases are needed. This proposal describes two exciting phase I clinical trials in the targeting of aberrant signaling and survival pathways in leukemic cells. The first trial investigates a novel, pharmacokinetically driven schedule of flavopiridol in ALL or AML. Given new laboratory data demonstrating critical differences between drug-protein binding in fetal bovine serum (FBS) vs. human plasma, early negative clinical studies with flavopiridol based on in vitro studies in FBS may have failed to reach (or maintain) drug levels necessary for in vivo clinical activity. Pharmacokinetic modeling based on in vitro studies in acute leukemia cells cultured in human plasma suggested that administering flavopiridol by 30 minute intravenous (IV) bolus followed by 4 hour continuous IV infusion (CM) would achieve an in vivo plasma drug concentration similar to that necessary to induce apoptosis in vitro. Preliminary results of an ongoing phase I clinical study using this dosing strategy administered weekly in patients with refractory chronic lymphocytic leukemia (CLL) demonstrated impressive clinical responses. In addition, acute tumor lysis was observed as a dose limiting toxicity. The proposed trial administers flavopiridol in the manner described for three consecutive days every three weeks based on in vitro and animal studies. It aims to generate preliminary pharmacokinetic and phamacodynamic data to facilitate additional efficacy studies in ALL and AML. Investigations will then proceed to phase II trials and additional phase I trials in combination with other agents. The second trial in this proposal is a phase I combination study of the heat shock protein 90 (HspQO) inhibitor 17-allyamino-demethyoxygeldanamycin (17-AAG) with the proteasome inhibitor PS-341 (bortezomib, Velcade) in relapsed and refractory AML. Both agents act by altering normal cellular regulatory functions, 17-AAG by affecting chaperone function of Hsp90 and PS-341 by inhibiting the 20S proteasome. Due to inhibition of Hsp90 by 17-AAG, multiple client proteins including those important in survival pathways such as Akt are degraded. Inhibition of the 20S proteasome by PS-341 also has multiple effects, mainly due to loss of NF-KB activation (resulting from the inhibited proteasome's failure to degrade the NF-kB inhibitor IkB). Individually, both agents have been shown to have anti-leukemia efficacy. Treatment of leukemic cells with PS-341 results in a stress-response which includes upregulation of Hsp90 leading to resistance to apoptosis, and we hypothesize that treatment of AML patients with both 17- AAG and PS-341 will be an effective method to overcome treatment resistance. If the regimen is well tolerated, a phase II study will be performed, including patients with high risk, untreated AML. Both studies described above will serve as the foundation for the career development of Dr. William Blum, a promising young clinical investigator in the area of experimental therapeutics for ALL and AML. The mentors for the candidate's career development are Dr. Clara Bloomfield, Dr. John Byrd, and Dr. Guido Marcucci at The Ohio State University. They will be assisted in laboratory mentoring by Dr. Denis Guttridge and Dr. James Dalton.

描述（由申请人提供）：大多数患有急性淋巴细胞白血病（ALL）或急性髓性白血病（AML）的成年人最终会复发，而那些复发的疾病使用现有药物治疗失败的可能性很高。需要更有效地治疗这些疾病的新药。本提案描述了两个令人兴奋的I期临床试验，针对白血病细胞中的异常信号传导和生存途径。第一项试验研究了一种新的、药代动力学驱动的黄匹吡醇治疗ALL或AML的方案。鉴于新的实验室数据显示胎牛血清（FBS）与人血浆中药物-蛋白结合的关键差异，基于胎牛血清体外研究的黄吡醇早期阴性临床研究可能未能达到（或维持）体内临床活性所需的药物水平。基于人血浆培养的急性白血病细胞体外研究的药代动力学模型表明，黄匹吡醇通过30分钟静脉注射（IV），然后连续静脉输注（CM） 4小时，可以达到与体外诱导细胞凋亡所需的体内血浆药物浓度相似的浓度。一项正在进行的I期临床研究的初步结果显示，在难治性慢性淋巴细胞白血病（CLL）患者中，使用这种剂量策略每周给药，显示出令人印象深刻的临床反应。此外，急性肿瘤溶解被观察为剂量限制性毒性。根据体外和动物研究，拟议的试验以上述方式每三周连续三天给药黄匹吡醇。它旨在产生初步的药代动力学和药效学数据，以促进对ALL和AML的其他疗效研究。随后将进行II期试验和与其他药物联合的额外I期试验。该提案的第二项试验是热休克蛋白90 （HspQO）抑制剂17-allyamino-demethyoxygeldanamycin （17-AAG）与蛋白酶体抑制剂PS-341（硼替佐米，Velcade）在复发和难治性AML中的I期联合研究。这两种药物都通过改变正常的细胞调节功能起作用，17-AAG通过抑制20S蛋白酶体影响Hsp90和PS-341的伴侣功能。由于17-AAG对Hsp90的抑制作用，多种客户蛋白（包括在生存途径中重要的蛋白，如Akt）被降解。PS-341对20S蛋白酶体的抑制也有多重作用，主要是由于NF-KB活化的丧失（由于被抑制的蛋白酶体无法降解NF-KB抑制剂IkB）。单独来看，这两种药物都显示出抗白血病的功效。用PS-341治疗白血病细胞会导致应激反应，包括Hsp90上调导致细胞凋亡抵抗，我们假设同时使用17- AAG和PS-341治疗AML患者将是克服治疗抵抗的有效方法。如果该方案耐受性良好，将进行II期研究，包括高风险，未经治疗的AML患者。上述两项研究将为William Blum博士的职业发展奠定基础，他是ALL和AML实验治疗领域的一位有前途的年轻临床研究者。候选人职业发展的导师是俄亥俄州立大学的Clara Bloomfield博士、John Byrd博士和Guido Marcucci博士。他们将得到丹尼斯·古特里奇博士和詹姆斯·道尔顿博士的实验室指导。