Targeted Sphingolipid Metabolism for Treatment of AML

靶向鞘脂代谢治疗 AML

基本信息

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
项目类别：
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

项目摘要

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.

项目概要通过三个相互关联和相互依赖的项目和四个基本核心，我们的团队将继续定义 AML 中鞘脂代谢功能失调的生物学基础，并在此过程中验证新的药物治疗方法的治疗目标。续签P01申请的前提是针对导致鞘脂代谢功能失调的酶将带来新的临床选择反洗钱。所有项目要测试的总体假设是增加内源性促凋亡神经酰胺物种，同时减少促生存磷酸化或糖基化神经酰胺代谢物，将产生有效治疗 AML。此续签申请的总体前提是令人兴奋的结果神经酰胺纳米脂质体治疗实体瘤的首次人体临床试验（NCT02834611），证明缺乏在观察到疾病稳定的剂量下出现剂量限制性毒性。令人兴奋的初步研究并在体内发表数据提供了外源性神经酰胺纳米级递送载体作为辅助疗法的基本原理在 Ib/IIa 期临床试验中支持护理治疗标准（低剂量 AraC 和 Venetoclax）复发/难治性 AML（项目 1，CAV 试验，UVA 方案审查委员会批准 #5414，IND 前 142902）。此外，提供的初步和已发表的数据表明，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效用神经酰胺。所有项目的共同科学主题是耐药性和耐药性的机制研究程序性细胞死亡，可以通过基于鞘脂的疗法直接改变。主要我们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组学和蛋白质组学数据，以揭示易感性在最先进的患者来源中测试创新的鞘脂靶向疗法的人群异种移植、基因工程小鼠模型，最重要的是临床试验。此次活动的主要目标该提案旨在开发新的针对 AML 的鞘脂靶向疗法。跨学科团队包括白血病（特别是 AML）、生物活性脂质纳米级输送系统、程序化领域的领导者细胞死亡，以及鞘脂的生物化学和生物物理学。这一主要目标将通过所有项目和核心共有以下五个总体具体目标： 1) 评估功效提高动物和动物中促凋亡神经酰胺种类的外源性或内源性水平的治疗方法临床试验； 2) 获取临床前和临床 PK、生物分布和毒理学数据以支持和/或扩展我们针对基于鞘脂的 AML 疗法的 FDA-IND 申请； 3) 定义生物化学、生物物理和分子针对功能失调的鞘脂代谢的药物获得协同作用的潜在机制； 4）了解异质性 AML 不同鞘脂代谢功能障碍的分子基础； 5) 定义并验证基于脂质的生物标志物作为诊断或预后指标。