Experimental Therapeutics in Acute Leukemias

急性白血病的实验治疗

基本信息

批准号：
7479282
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
项目类别：
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/7479282
关键词：
Acute Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Adult Affect Animals Apoptosis Apoptotic Area Area Under Curve Bolus Infusion Bortezomib Bos taurus Cattle Chronic Lymphocytic Leukemia Client Clinical Clinical Investigator Clinical Research Clinical Trials Continuous Intravenous Infusion Cultured Cells Cyclophosphamide/Daunorubicin Cytolysis Data Development Diagnosis Disease Dose Dose-Limiting Drug Kinetics End Point 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 Lymphoblastic Leukemia Maximum Tolerated Dose Mediating Mentors Messenger RNA Methods Minority Molecular Chaperones NF-kappa B New Agents Newly Diagnosed Ohio Outcome PS341 cpd Pathway interactions Patients Personal Satisfaction Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Phosphorylation Plasma Population 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 Risk Schedule Serum Signal Transduction Stem cell transplant Stem cells Therapeutic Therapeutic Agents Toxic effect Transplantation Treatment Failure Treatment Protocols Tumor Lysis Syndrome Universities Up-Regulation Velcade Vertebral column Week asparaginase/prednisone/vincristine protocol base biological adaptation to stress career chemotherapy cytarabine/daunorubicin dalton day fetal flavopiridol improved in vivo inhibitor/antagonist leukemia multicatalytic endopeptidase complex novel novel strategies pharmacokinetic model protein expression response therapeutic target tumor

项目摘要

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）或急性髓样白血病（AML）的成年人最终复发，患有复发性疾病的患者患有当前可用药物的治疗失败可能性很高。需要更有效地治疗这些疾病的新药。该提案描述了在白血病细胞中异常信号传导和生存途径的靶向时进行了两项激动人心的I期临床试验。第一次试验调查了全部或AML的新型药物动力学驱动的时间表。鉴于新的实验室数据表明，在胎儿牛血清（FBS）与人血浆中的药物蛋白质结合之间的关键差异，基于FBS的体外研究的早期负面临床研究可能未能达到（或维持）体内临床活动所需的药物水平。基于在人血浆中培养的急性白血病细胞的体外研究的药代动力学建模表明，通过30分钟的静脉内（IV）推注将黄素寡醇施用，然后进行4小时连续IV输注（CM），将实现与诱导凋亡相似的体内等离子体药物浓度相似。在难治性慢性淋巴细胞性白血病（CLL）的患者中，使用该剂量策略进行的一项I期临床研究的初步结果表现出令人印象深刻的临床反应。另外，将急性肿瘤裂解视为剂量限制毒性。该拟议的试验根据体外和动物研究连续三天以每三周的方式描述了黄虫寡醇。它旨在生成初步的药代动力学和PHAMACODENANIC数据，以促进所有和AML的其他疗效研究。然后，调查将继续进行II阶段试验和其他I期试验，并结合其他代理。该提案中的第二项试验是对热激蛋白90（HSPQO）抑制剂17-乙酰氨基 - 甲氧基甲氧霉素（17-AAG）与蛋白酶体抑制剂PS-341（bortezomib，velcade）中的I期组合研究。两种药物都通过改变正常的细胞调节功能，通过抑制20S蛋白酶体来影响HSP90和PS-341的伴侣功能来改变17-AAG。由于抑制了HSP90乘以17-AAG，多种客户蛋白包括在AKT等生存途径中重要的蛋白质。 PS-341对20S蛋白酶体的抑制也具有多种影响，这主要是由于NF-KB激活的丧失（由抑制蛋白酶体未能降解NF-KB抑制剂IKB）。单独地，两种药物均已证明具有抗白血病功效。用PS-341治疗白血病细胞会导致应力反应，其中包括上调HSP90导致对凋亡的耐药性，我们假设治疗AML 17-AAG和PS-341的AML患者将是一种有效的方法来克服耐药性。如果该方案的耐受性良好，将进行II期研究，包括高风险患者未经治疗的AML。上面描述的两项研究都将成为威廉·布鲁姆（William Blum）博士的职业发展的基础，威廉·布鲁姆（William Blum）是一位有前途的年轻临床研究者，在所有人和AML实验性治疗领域。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。他们将由Denis Guttridge博士和James Dalton博士协助实验室指导。