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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：
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.

项目总结