Experimental Therapeutics in Acute Leukemias

描述（由申请人提供）：大多数急性淋巴细胞白血病（ALL）或急性髓细胞白血病（AML）成人最终复发，复发性疾病患者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。该提案描述了两个令人兴奋的I期临床试验，靶向异常信号传导和白血病细胞的生存途径。第一项试验研究了一种新颖的，药代动力学驱动的flavopiridol在ALL或AML中的时间表。鉴于新的实验室数据表明胎牛血清（FBS）与人血浆中药物-蛋白结合之间存在关键差异，基于FBS体外研究的flavopiridol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。基于在人血浆中培养的急性白血病细胞中的体外研究的药代动力学建模表明，通过30分钟静脉内（IV）推注然后4小时连续IV输注（CM）施用夫拉吡醇将实现与体外诱导细胞凋亡所必需的浓度相似的体内血浆药物浓度。一项正在进行的I期临床研究的初步结果表明，使用这种给药策略每周给药一次的难治性慢性淋巴细胞白血病（CLL）患者的临床反应令人印象深刻。此外，观察到急性肿瘤溶解是一种剂量限制性毒性。根据体外和动物研究，拟定的试验以所述方式每三周连续三天给予flavopiridol。其目的是生成初步的药代动力学和药效学数据，以促进ALL和AML的其他疗效研究。然后，研究将进入II期试验，并与其他药物联合进行额外的I期试验。该提案中的第二项试验是热休克蛋白90（HspQO）抑制剂17-烯丙基氨基-去甲氧基格尔德霉素（17-AAG）与蛋白酶体抑制剂PS-341（硼替佐米，万珂）在复发性和难治性AML中的I期联合研究。这两种药物通过改变正常的细胞调节功能起作用，17-AAG通过影响Hsp 90和PS-341的伴侣蛋白功能，通过抑制20 S蛋白酶体。由于17-AAG对Hsp 90的抑制，多种客户蛋白，包括那些在生存途径中重要的蛋白，如Akt被降解。PS-341对20 S蛋白酶体的抑制也具有多种作用，主要是由于NF-κ B活化的丧失（由受抑制的蛋白酶体不能降解NF-κ B抑制剂IkB引起）。单独而言，两种药物均显示出抗白血病疗效。用PS-341治疗白血病细胞导致应激反应，包括上调Hsp 90导致对凋亡的抗性，我们假设用17- AAG和PS-341治疗AML患者将是克服治疗抗性的有效方法。如果该方案耐受良好，将进行II期研究，包括高风险、未经治疗的AML患者。上述两项研究将作为William Blum博士职业发展的基础，William Blum博士是ALL和AML实验治疗领域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州立大学的Clara布卢姆菲尔德博士、John Byrd博士和Guido Marcucci博士。他们将在实验室指导方面得到丹尼斯·古特维尔博士和詹姆斯·道尔顿博士的协助。

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.