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Targeted Sphingolipid Metabolism for Treatment of AML

靶向鞘脂代谢治疗 AML

基本信息

批准号：
10661015
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/10661015
关键词：
Acute Myelocytic Leukemia Acute leukemia Adjuvant Adjuvant Therapy Adult Affect Age 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 Investigation Investigational Drugs Left Lipids Malignant Neoplasms Memorial Sloan-Kettering Cancer Center Metabolism Molecular Oncologist Pathogenesis Patient-Focused Outcomes Patients Pharmacological Treatment Phase Phase I Clinical Trials Phosphorylation Population Pre-Clinical Model Predisposition 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 clinical trials in animals combinatorial delivery vehicle druggable target efficacious treatment efficacy evaluation experience first-in-human functional genomics glycosylation improved improved outcome in vivo inhibitor innovation leukemia lipidomics metabolomics molecular targeted therapies nano nanoliposome nanoscale new therapeutic target patient derived xenograft model pharmacologic 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.

项目摘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中鞘脂代谢功能障碍的生物学基础，并在此过程中，验证新的药理学治疗方法的治疗靶点。续期P01申请的前提是靶向负责功能失调的鞘脂代谢的酶将导致新的临床选择，急性髓细胞白血病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，而减少促生存磷酸化或糖基化神经酰胺代谢产物，将产生有效治疗AML。这一更新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（NCT 02834611），证明缺乏在观察到稳定疾病的剂量下的剂量限制性毒性。令人兴奋的初步和发表的体内数据提供了外源性神经酰胺的纳米级递送载体作为辅助治疗的基本原理，在Ib/IIa期临床试验中支持标准治疗（低剂量AraC和维奈托克），复发性/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，提供了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一个共同科学主题是耐药性的机制研究，程序性细胞死亡，这可以用基于鞘脂的治疗剂直接改变。主要我们P01的创新是利用生物信息学和系统生物学方法整合基因组学，神经鞘脂组学和蛋白质组学数据，从分子定义的患者样本，以揭示易感用于在最先进的患者源性异种移植，基因工程小鼠模型，最重要的是，临床试验。这个项目的主要目标是该提案旨在开发针对AML的新鞘脂靶向疗法。跨学科团队包括白血病（特别是AML）领域的领导者，生物活性脂质的纳米级递送系统，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都有以下五个总体目标：1）评估有效性提高动物中促凋亡神经酰胺种类的外源或内源水平的治疗剂，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用于基于鞘脂的AML治疗; 3）定义生物化学，生物物理和分子生物学，与靶向功能失调的鞘脂代谢的药剂获得协同作用的潜在机制; 4）了解异质性AML中定义可变的功能障碍性鞘脂代谢的分子基础; 5)定义和验证脂质生物标志物作为诊断或预后指标。

项目成果

期刊论文数量（39）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

On the nature of ceramide-mitochondria interactions - Dissection using comprehensive mitochondrial phenotyping.

DOI：
10.1016/j.cellsig.2020.109838
发表时间：
2021-03
期刊：
Cellular signalling
影响因子：
4.8
作者：
Fisher-Wellman KH;Hagen JT;Neufer PD;Kassai M;Cabot MC
通讯作者：
Cabot MC

Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells.

DOI：
10.1016/j.celrep.2023.112794
发表时间：
2023-07-25
期刊：
Cell reports
影响因子：
8.8
作者：
通讯作者：

Targeting glucosylceramide synthase synergizes with C6-ceramide nanoliposomes to induce apoptosis in natural killer cell leukemia.

DOI：
10.3109/10428194.2012.752485
发表时间：
2013-06
期刊：
Leukemia & lymphoma
影响因子：
2.6
作者：
Watters RJ;Fox TE;Tan SF;Shanmugavelandy S;Choby JE;Broeg K;Liao J;Kester M;Cabot MC;Loughran TP;Liu X
通讯作者：
Liu X

Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia.

鞘脂组成和线粒体生物能的改变代表与白血病中多药耐药性相关的协同治疗脆弱性。