Improving AML Therapy outcome by Cholesterol Modulation

描述(申请人提供)：化疗耐药性仍然是治愈白血病和其他癌症的主要障碍。我们发现，在急性髓细胞白血病(AML)中，胆固醇介导的耐药性可能为新的、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急性心肌梗死细胞中，胆固醇水平通常会增加，当甲氧戊酸途径抑制剂(他汀类药物)联合治疗阻止胆固醇合成时，许多AML是化学敏感的。当异种移植的小鼠接受肠外化疗时，AML细胞中也会出现胆固醇增加。然而，正常的骨髓细胞通常不会做出适应性的胆固醇反应，而且对他汀类药物相对不敏感。这些数据和其他发现表明，AML的生存异常依赖胆固醇，联合应用他汀类药物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为高胆固醇血症的适应症，我们的回顾性分析表明，在接受标准化疗的AML患者中，联合使用这些常规剂量的他汀类药物并不会增加与治疗相关的毒性。由于普伐他汀产生的不良药物-药物相互作用比其他常用的他汀类药物少，我们设计了一项第一阶段试验，以估计在伊达比星加阿糖胞苷诱导(IDA/HDAC)方案之前和期间联合应用于AML患者时的最大耐受量(MTD)。我们以常规剂量的普伐他汀开始了这项试验，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，与剂量依赖的血清胆固醇降低有关。在对前3名患者的AML细胞样本进行分析时，我们发现常规剂量的4天普伐他汀治疗可以有效地降低AML细胞中的胆固醇水平。我们现在正在申请资金，以使我们能够完成这项第一阶段试验，并使用经过验证的实验室测试来分析接受他汀类药物加LDA/HDAC治疗的患者和仅接受化疗的患者的样本。这些研究将比较普伐他汀MTD与生物有效剂量的普伐他汀，从而为临床试验的设计提供信息，以测试普伐他汀改善急性髓细胞白血病化疗结果的能力。我们的数据可能对其他实验上不太容易治疗的、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.