Improving AML Therapy outcome by Cholesterol Modulation

描述（由申请人提供）：化疗耐药性仍然是治疗白血病和其他癌症的主要障碍。我们发现在急性髓性白血病（AML）中胆固醇介导的耐药可能为新的、更有效的治疗提供靶点。我们已经证明，在体外暴露于标准化疗药物的AMI细胞中，胆固醇水平通常会增加，并且当与甲羟戊酸途径抑制剂（他汀类药物）联合治疗禁止胆固醇合成时，许多AMI会发生化学致敏。当异种移植小鼠暴露于肠外化疗时，AML细胞也会出现胆固醇增加。然而，正常骨髓细胞通常不会产生适应性胆固醇反应，并且相对而言对他汀不敏感。这些数据和其他研究结果表明，aml的生存异常依赖胆固醇，他汀类药物联合使用将提高标准抗白血病方案的疗效。安全有效的他汀类药物剂量已被确定用于高胆固醇血症适应症，我们的回顾性分析显示，在接受标准化疗的AML患者中，以这些常规剂量联合使用他汀类药物不会增加治疗相关的毒性。由于普伐他汀比其他常用的他汀类药物产生更少的不良药物相互作用，我们设计了一项1期试验，以估计在伊达柔比星加阿糖胞苷诱导（Ida/HDAC）方案之前和期间，AML患者共同使用普伐他汀时的最大耐受剂量（MTD）。我们以常规剂量的普伐他汀开始这项试验，并且已经安全地治疗了4个患者队列。我们已经看到了令人鼓舞的临床反应，与血清胆固醇的剂量依赖性降低有关。在对前3例患者的AML细胞样本的分析中，我们发现常规剂量的普伐他汀治疗4天可以有效降低AML细胞中的胆固醇水平。我们现在正在申请资金，以允许我们完成这项1期试验，并使用经过验证的实验室测试来分析来自他汀类药物加lda/HDAC治疗的患者和仅接受化疗治疗的患者的样本。这些研究将比较普伐他汀MTD和普伐他汀生物有效剂量，从而为设计临床试验提供信息，以测试普伐他汀改善AML化疗结果的能力。我们的数据可能对其他实验上不易处理的、他汀类药物敏感的癌症具有广泛的意义。

DESCRIPTION (provided by applicant): Chemoresistance remains a major impediment to curing leukemias and other cancers. We have discovered in acute myeloid leukemia (AML) cholesterol-mediated drug resistance that may provide targets for new, more effective therapies. We have shown that cholesterol levels commonly increase in AMI cells exposed in vitro to standard chemotherapeutics, and that many AMLs are chemosensitized when cholesterol synthesis is prohibited by co-treatments with mevalonate pathway inhibitors (statins). Cholesterol increments also occur in AML cells when xenografted mice are exposed to parenteral chemotherapy. However, normal bone marrow cells do not typically make adaptive cholesterol responses, and are relatively statin-insensitive. These data and other findings suggest that AMLs are abnormally dependent on cholesterol for their survival, and that statin co-administration will improve the efficacy of standard anti-leukemia regimens. Safe and effective statin doses have been identified for hypercholesterolemia indications, and our retrospective analyses showed that co-administration of statins at these conventional doses does not increase therapy-related toxicities in AML patients treated with standard chemotherapies. Since pravastatin produces fewer adverse drug-drug interactions than other commonly-prescribed statins, we designed a Phase 1 trial to estimate the maximally-tolerated pravastatin dose (MTD) when it is co-administered to AML patients before and during an idarubicin-plus-cytarabine induction (Ida/HDAC) regimen. We began this trial with pravastatin at conventional doses, and have already safely treated 4 patient cohorts. We have seen encouraging clinical responses, in association with dose-dependent reductions in serum cholesterol. In assays of AML cell samples from the first 3 patients, we found that 4-day, conventional dose pravastatin treatments can effectively reduce cholesterol levels in AML cells. We are now requesting funding that will allow us to complete this Phase 1 trial and to use validated, laboratory tests to analyze samples from patients treated with statin-plus-lda/HDAC and from patients treated with chemotherapy only. These studies will compare the pravastatin MTD with bioeffective pravastatin doses and thereby inform the design of clinical trials testing pravastatin's ability to improve chemotherapy outcomes in AML. Our data could have broad significance for other less experimentally tractable, statin-sensitive cancers.