Experimental Therapeutics in Acute Leukemias

描述(由申请人提供)：大多数患有急性淋巴细胞白血病(ALL)或急性髓系白血病(AML)的成年人最终会复发，而那些复发疾病的人用目前可用的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。这项建议描述了两个令人兴奋的I期临床试验，目标是白血病细胞中的异常信号和生存途径。第一个试验研究了一种新颖的、药代动力学驱动的黄烷醇在ALL或AML中的应用方案。鉴于新的实验室数据显示，胎儿牛血清(FBS)和人血浆中药物-蛋白质结合的关键差异，基于FBS体外研究的早期黄烷醇阴性临床研究可能无法达到(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的体外药代动力学模型表明，静脉滴注30分钟，然后连续静脉滴注4小时，可获得与体外诱导细胞凋亡所需的药物浓度相似的体内药物浓度。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进行的I期临床研究的初步结果显示，临床反应令人印象深刻。此外，急性肿瘤溶解是一种剂量限制性毒性。这项拟议的试验基于体外和动物研究，以每三周连续三天的方式给药。它的目的是产生初步的药代动力学和药效学数据，以促进对ALL和AML的额外疗效研究。然后，调查将进入第二阶段试验和与其他药物联合进行的额外第一阶段试验。这项建议中的第二项试验是热休克蛋白90(HspQO)抑制剂17-烯丙氨基去甲氧基格尔达霉素(17-AAG)与蛋白酶体抑制剂PS-341(Bortezomib，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发挥作用，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，多个客户蛋白，包括那些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种作用，主要是由于失去了核因子-KB的激活(这是由于被抑制的蛋白酶体不能降解核因子-kB抑制剂IKB所致)。单独来看，这两种药物都被证明具有抗白血病的功效。用PS-341处理白血病细胞会产生应激反应，其中包括Hsp90的上调导致对凋亡的抵抗，我们推测17-AAG和PS-341联合治疗AML患者将是克服耐药的有效方法。如果该方案耐受性良好，将进行II期研究，包括高危、未治疗的急性髓细胞白血病患者。上述两项研究将为威廉·布鲁姆博士的职业发展奠定基础，他是一位在所有人和急性髓细胞白血病的实验治疗领域有前途的年轻临床研究员。候选人职业发展的导师是俄亥俄州立大学的克拉拉·布鲁姆菲尔德博士、约翰·伯德博士和吉多·马尔库奇博士。丹尼斯·古特里奇博士和詹姆斯·道尔顿博士将协助他们进行实验室指导。

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.