Improving AML Therapy outcome by Cholesterol Modulation

描述（由申请人提供）：耐药性仍然是治疗白血病和其他癌症的主要障碍。我们在急性髓性白血病（AML）中发现了胆固醇介导的耐药性，这可能为新的更有效的治疗提供靶点。我们已经表明，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，并且当胆固醇合成被甲羟戊酸途径抑制剂（他汀类药物）共同治疗抑制时，许多AML会发生化学致敏。当异种移植小鼠暴露于胃肠外化疗时，AML细胞中也发生胆固醇增加。然而，正常的骨髓细胞通常不会产生适应性胆固醇反应，并且对他汀类药物相对不敏感。这些数据和其他发现表明，AML的生存异常依赖于胆固醇，他汀类药物联合给药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毒性。由于普伐他汀产生的不良药物相互作用比其他常用处方他汀类药物少，我们设计了一项I期试验，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给予AML患者普伐他汀的最大耐受剂量（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，与剂量依赖性降低血清胆固醇。在对前3名患者的AML细胞样本的分析中，我们发现4天的常规剂量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1期试验，并使用经过验证的实验室检测来分析来自接受他汀类药物加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与普伐他汀生物有效剂量，从而为临床试验设计提供信息，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不太容易实验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.