Targeted Sphingolipid Metabolism for Treatment of AML

靶向鞘脂代谢治疗 AML

• 批准号: 10430087
• 负责人: Myles C. Cabot
• 金额: $ 195.44万
• 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/10430087
• 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; 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; delivery vehicle; druggable target; efficacious treatment; efficacy evaluation; experience; first-in-human; functional genomics; improved; improved outcome; in vivo; inhibitor; innovation; leukemia; lipidomics; metabolomics; molecular targeted therapies; nano; nanoliposome; nanoscale; new therapeutic target; patient derived xenograft model; pre-clinical; preclinical trial; predictive marker; prognostic indicator; 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.

项目摘要 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 定义AML中功能失调的鞘脂代谢的生物学基础，并在此过程中验证新 药理治疗方法的治疗靶标。续订P01申请的前提是 靶向负责功能失调鞘脂代谢的酶将导致新的临床选择 AML。所有项目要检验的总体假设是增加内源性促凋亡神经酰胺 物种虽然降低了生存的磷酸化或糖基化的神经酰胺代谢物，但会产生 有效的AML治疗方法。此更新应用程序的总体前提是来自 神经酰胺纳米型实体瘤的首次临床试验（NCT02834611），证明缺乏 观察到稳定疾病的剂量的剂量限制毒性。令人兴奋的初步并在体内出版 数据为外源神经酰胺作为辅助治疗的纳米级输送车提供了理由 在IB/IIA期临床试验中，支持护理疗法的支持标准（低剂量ARAC和VENETOCLAX） 复发/难治性AML（项目1，CAV审判，UVA协议审查委员会批准＃5414，Pre-Ind 142902）。此外，提供了初步和已发布的数据，表明选择性抑制剂 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实用性 神经酰胺。所有项目的一个普遍科学主题是对耐药性和 程序性细胞死亡，可以通过基于鞘脂的疗法直接改变。专业 我们P01的创新是利用生物信息学和系统生物学方法来整合基因组学， 来自分子定义的患者样本的鞘脂型脂肪组学和蛋白质组学数据显示易感性 用于测试最先进的患者衍生的创新性鞘脂治疗的种群 异种移植物，基因工程的鼠模型，最重要的是临床试验。主要目标 提议是为AML开发新的鞘脂靶性疗法。跨学科团队包括 在白血病领域（特别是AML），生物活性脂质的纳米级输送系统，编程 细胞死亡以及鞘脂的生物化学和生物物理学。这个主要目标将通过 所有项目和核心共享的以下概念五个特定目标：1）评估功效 在动物和 临床试验； 2）获取临床前和临床PK，生物分布和毒理学数据以支持和/或扩展 我们用于基于鞘脂的AML疗法的FDA-IND； 3）定义生化，生物物理和分子 靶向功能障碍鞘脂代谢的药物获得的协同作用的机制； 4） 了解定义可变功能障碍的鞘脂代谢的分子基础； 5）将基于脂质的生物标志物定义并验证为诊断或预后指标。