Clinical Trial of Ceramide nanoLiposomes in AML

项目总结 急性髓系白血病(AML)是第二种最常见的白血病类型，其五年存活率高 只有27%。虽然剂量密集诱导和巩固化疗导致临床完全 大多数适合治疗的患者缓解，大多数复发，而其他患者则发展为难治性 AML。最近，bc l-2的抑制剂venotclax在联合应用时显示出改善的临床结果。 常规疗法阿糖胞苷(AraC)治疗复发和难治性AML。基于……的功效 临床前模型中，我们假设脂质体递送促凋亡生物活性脂质C6-神经酰胺将 增强这种低剂量AraC/ventoclax标准护理方案的疗效，并有意义的 治疗复发/难治性AML的临床影响。这一假设将从三个具体目标进行检验。在……里面 具体目标1，神经酰胺纳米脂质体1b期(剂量递增)/2a期(剂量扩展)临床试验 小剂量AraC和万乃馨联合治疗复发/难治性AML患者(Pre-IND) 将进行#142902，UVA议定书审查委员会批准#5414，CAV试验)。这样做的前提是 试验得到以下事实的支持：CNL已经达到FDA(IND 109471， NCT02834611)NCI支持(U43 CA186118)实体肿瘤的第一阶段试验，其中CNL一直很好- 耐受多个病人表现出稳定的疾病。在具体目标2中，我们检查潜在的 急性髓系白血病中CNL、AraC和ventoclax的协同作用。我们表明，CNL与AraC的共同管理 和/或万乃馨发挥多种协同增效作用机制。首先，我们证明了这种养生法 增加促凋亡性C16和C18神经酰胺与较少凋亡性C24神经酰胺的比率。利用 分子策略在体外和体内模型中，我们将检验这一假设，即这是由 神经酰胺合成酶，并确定神经酰胺合成酶如何调节AML的生存。第二，我们证明了 CNL可降低万乃馨诱导的促生存蛋白的升高。我们将测试这一效应的假设 在临床前模型中使用分子方法是STAT3依赖的。在具体目标3中，我们证明了 首次应用C18/C24神经酰胺比值预测AML患者的无进展生存期 这一比例作为癌症的生物标记物。我们将扩展并确认鞘脂代谢物或比例为 AML生物学和预后的生物标志物--用大的、特征良好的AML样本作为验证 一群人。同时还从特定目的1调查临床样本，以评估CNL疗效的生物标志物。 已发表和未发表的观察结果表明，酶的高表达会减少 神经酰胺水平(酸性神经酰胺酶、鞘氨酸激酶、葡萄糖神经酰胺合成酶)和减少促凋亡 神经酰胺(如C16/C18)可降低AML患者的存活率。总之，拟议的研究将测试 CNL与AraC/ventoclax协同作用的临床应用及机制探讨 确定急性髓细胞白血病患者鞘磷脂代谢紊乱对预后的影响。

PROJECT SUMMARY Acute Myeloid Leukemia (AML) is the 2nd most common type of leukemia diagnosed with a 5-year survival rate of only 27%. Though dose-intensive induction and consolidation chemotherapy induces clinical complete remission in the majority of patients suitable for treatment, most relapse whereas others develop refractory AML. Recently, the Bcl-2 inhibitor, venetoclax, demonstrated improved clinical outcomes when combined with the conventional therapeutic, cytarabine (AraC), in relapsed and refractory AML. Based upon efficacy in preclinical models, we hypothesize that liposomal delivery of the pro-apoptotic bioactive lipid C6-ceramide will augment the efficacy of this low dose AraC/venetoclax standard-of-care regimen and have a meaningful clinical impact in treating relapsed/refractory AML. This hypothesis will be examined in three Specific Aims. In Specific Aim 1, a Phase 1b (dose escalation)/2a (dose-expansion) clinical trial for ceramide nanoLiposomes (CNL) in relapsed/refractory AML patients treated in combination with low dose AraC and venetoclax (pre-IND #142902, UVA Protocol Review Committee Approval #5414, CAV trial) will be conducted. The premise of this trial is supported by the fact that CNL has already reached its putative MTD in an FDA (IND 109471, NCT02834611) NCI-supported (U43 CA186118) Phase 1 trial for solid tumors, where CNL has been well- tolerated with multiple patients exhibiting stable disease. In Specific Aim 2, we examine the underlying cooperativity between CNL, AraC, and venetoclax in AML. We show that co-administration of CNL with AraC and/or venetoclax exerts multiple synergistic mechanisms of efficacy. First, we demonstrate that this regimen increases the ratio of pro-apoptotic C16- and C18-ceramides over less apoptotic C24 ceramides. Utilizing molecular strategies in both in vitro and in vivo models, we will test the hypothesis that this is mediated by ceramide synthases and determine how ceramide synthases regulate AML survival. Second, we show that CNL reduces venetoclax-induced elevation of pro-survival proteins. We will test the hypothesis that this effect is STAT3-dependent using molecular approaches in preclinical models. In Specific Aim 3, we show that the ratio of C18 to C24 ceramides predicts progression-free survival in AML patients, which is the first application of this ratio as a biomarker for cancer. We will extend and confirm sphingolipid metabolites or ratios as biomarkers of AML biology and prognosis utilizing large, well-characterized AML samples as a validation cohort. while also investigating clinical samples from Specific Aim 1 to assess biomarkers of CNL efficacy. Published and unpublished observations demonstrate that high-expression of enzymes that decrease ceramide levels (acid ceramidase, sphingosine kinase, glucosylceramide synthase) and reduce pro-apoptotic ceramides (e.g. C16/C18) leads to lower survival in AML patients. Together, the proposed studies will test the clinical application and unravel the mechanistic pathways of CNL cooperativity with AraC/venetoclax, while ascertaining the prognostic impact of dysregulated sphingolipid metabolism in AML.