Targeted Sphingolipid Metabolism for Treatment of AML

靶向鞘脂代谢治疗 AML

• 批准号: 10160824
• 负责人: MARK KESTER
• 金额: $ 199.55万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10160824
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adjuvant; Adjuvant Therapy; Adult; Affect; Age; Animals; Apoptosis; Apoptotic; Biochemical; Biochemistry; Biodistribution; Bioinformatics; Biological; Biological Markers; Biophysics; Cell Line; Ceramides; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Cytotoxic Chemotherapy; Data; Development; Diagnosis; Diagnostic; Disease; Disease remission; Dose; Dose-Limiting; Drug Delivery Systems; Drug Kinetics; Drug resistance; Ensure; Enzymes; Funding; Genetically Engineered Mouse; Genomics; Goals; Heterogeneity; Human; Incidence; Institutes; Investigational Drugs; Left; Lipids; Malignant Neoplasms; Memorial Sloan-Kettering Cancer Center; Metabolism; Molecular; Oncologist; Pathogenesis; Patient-Focused Outcomes; Patients; Pharmacological Treatment; Pharmacology; Phase; Phase I Clinical Trials; Population; Pre-Clinical Model; Process; Prognostic Marker; Program Research Project Grants; Progression-Free Survivals; Proteomics; Protocols documentation; Public Health; Publishing; Refractory; Relapse; Resource Sharing; Review Committee; Sampling; Scientist; Solid Neoplasm; Sphingolipids; Stable Disease; System; Systems Biology; Testing; Therapeutic; Toxic effect; Toxicology; Treatment Efficacy; United States; United States National Institutes of Health; Universities; Validation; Virginia; acute myeloid leukemia cell; base; combinatorial; druggable target; efficacious treatment; efficacy evaluation; experience; first-in-human; functional genomics; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; leukemia; lipidomics; metabolomics; molecular targeted therapies; nano; nanoliposome; nanoscale; new therapeutic target; patient derived xenograft model; pre-clinical; preclinical trial; predictive marker; programs; progression marker; small molecule; standard of care; synergism; targeted agent; targeted treatment; therapeutic target; therapy resistant; tumor progression

PROJECT SUMMARY Through three inter-related and inter-dependent Projects and four essential Cores, our team will continue to define the biological basis of dysfunctional sphingolipid metabolism in AML, and in that process, validate new therapeutic targets for pharmacological treatment approaches. The premise of the renewal P01 application is that targeting enzymes responsible for dysfunctional sphingolipid metabolism will lead to new clinical options in AML. The overall hypothesis to be tested by all projects is that increasing endogenous pro-apoptotic ceramide species, while diminishing pro-survival phosphorylated or glycosylated ceramide metabolites, will yield efficacious treatments for AML. The overall premise of this renewal application are the exciting results from the first-in-man clinical trial of ceramide nanoliposomes for solid tumors (NCT02834611), demonstrating the lack of dose-limiting toxicities at doses where stable disease is observed. Exciting preliminary and published in vivo data provide the rationale for nanoscale delivery vehicles for exogenous ceramide as an adjuvant therapy to support standard of care therapy (low-dose AraC and venetoclax) in a phase Ib/IIa clinical trial for relapsed/refractory AML (Project 1, CAV trial, UVA Protocol Review Committee approval #5414, pre-IND 142902). In addition, preliminary and published data are provided demonstrating that selective inhibitors of ceramide metabolism (Projects 2-3) increase the clinical utility of agents that raise levels of pro-apoptotic ceramides. A common scientific theme of all Projects is the mechanistic investigation of drug resistance and programmed cell death, which can be directly altered with sphingolipid-based therapeutics. The major innovation of our P01 is to utilize a bioinformatic and systems biology approach to integrate genomics, sphingolipidomics, and proteomics data from molecularly defined patient samples to reveal susceptible populations for testing innovative sphingolipid-targeted therapeutics in state-of-the-art patient-derived xenografts, genetically engineered murine models, and most importantly, a clinical trial. The major goal of this proposal is to develop new sphingolipid-targeted therapeutics for AML. The interdisciplinary team includes leaders in the fields of leukemia (specifically AML), nanoscale delivery systems for bioactive lipids, programmed cell death, and the biochemistry and biophysics of sphingolipids. This major goal will be accomplished through the following overarching five Specific Aims that are shared by all Projects and Cores: 1) Evaluate the efficacy of therapeutics that elevate exogenous or endogenous levels of pro-apoptotic ceramide species in animal and clinical trials; 2) Obtain preclinical and clinical PK, bio-distribution, and toxicology data to support and/or expand our FDA-IND for sphingolipid-based AML therapeutics; 3) Define the biochemical, biophysical, and molecular mechanisms underlying the synergies obtained with agents that target dysfunctional sphingolipid metabolism; 4) Understand the molecular basis defining variable dysfunctional sphingolipid metabolism for heterogeneous AML; 5) Define and validate lipid-based biomarkers as diagnostic or prognostic indicators.

项目总结 通过三个相互关联和相互依存的项目和四个基本核心，我们的团队将继续 确定急性髓系白血病中鞘磷脂代谢功能障碍的生物学基础，并在此过程中验证新的 药物治疗途径的治疗靶点。续期P01申请的前提是 靶向负责鞘磷脂代谢障碍的酶将导致新的临床选择 AML。所有项目都要检验的总体假设是，增加内源性促凋亡神经酰胺 物种在减少有利于生存的磷酸化或糖基化神经酰胺代谢物的同时，将产生 治疗急性髓系白血病的有效方法。这次续签申请的总体前提是来自 神经酰胺纳米脂质体治疗实体瘤的首例临床试验(NCT02834611)，证明缺乏 在观察到稳定疾病的剂量时的剂量限制毒性。激动人心的初步报告并在体内发表 数据提供了外源性神经酰胺纳米级载体作为辅助治疗的理论基础 支持Ib/IIa期临床试验中的护理标准治疗(小剂量AraC和万乃馨) 复发/难治性AML(项目1，CAV试验，UVA议定书审查委员会批准#5414，Pre-IND 142902)。此外，还提供了初步的和已发表的数据，证明了选择性的抑制剂 神经酰胺代谢(项目2-3)增加了提高促凋亡水平的药物的临床效用 神经酰胺。所有项目的一个共同科学主题是耐药机制调查和 程序性细胞死亡，这可以通过基于鞘磷脂的疗法直接改变。少校 我们P01的创新是利用生物信息学和系统生物学的方法来整合基因组学， 鞘磷脂组学和来自分子定义的患者样本的蛋白质组学数据揭示易感性 在最先进的患者来源中测试创新鞘磷脂靶向疗法的人群 异种移植、基因工程小鼠模型，以及最重要的临床试验。这一行动的主要目标是 提案是为AML开发新的鞘磷脂靶向疗法。跨学科团队包括 白血病(特别是急性髓细胞白血病)领域的领导者，生物活性脂类的纳米级输送系统，编程 细胞死亡，以及鞘脂的生物化学和生物物理。这一主要目标将通过 以下是所有项目和核心共享的五个具体目标：1)评估效果 在动物和动物中提高外源性或内源性促凋亡神经酰胺种类水平的治疗方法 临床试验；2)获得临床前和临床PK、生物分布和毒理学数据，以支持和/或扩展 我们的FDA-IND用于基于鞘磷脂的AML治疗；3)定义生化、生物物理和分子 针对神经鞘脂代谢障碍的药物获得协同作用的潜在机制；4) 了解异质性AML的神经鞘脂脂代谢异常的分子基础； 5)定义和验证基于脂质的生物标记物作为诊断或预后指标。