权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting the Unfolded Protein Response in Leukemia Biology and Chemotherapy Resistance

靶向白血病生物学和化疗耐药中未折叠的蛋白质反应

基本信息

批准号：
10395497
负责人：
Stephen Matthew Sykes
金额：
$ 30.35万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-07 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395497
关键词：
Acute Myelocytic Leukemia Address Affect American Ara-C Automobile Driving Autophagocytosis Binding Biology Cell Death Cell Differentiation process Cell Survival Cellular Stress Chemicals Chemoresistance Cholesterol Cholesterol Homeostasis Complex Cytarabine DNA Damage Data Dependence Development Disease Disease Progression Doxorubicin Effectiveness Experimental Models Functional disorder Gene Expression Gene Order Genes Genetic Transcription Genetically Engineered Mouse Goals Hematopoietic Neoplasms Hematopoietic stem cells Human Human Cell Line In Vitro Karyotype Length Malignant Neoplasms Mediating Mediator of activation protein Molecular Newly Diagnosed Onset of illness Outcome Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Pharmacology Phenocopy Positioning Attribute Process Proteins Public Health Recurrent disease Regulatory Element Resistance Role Safety Sampling Signal Transduction Sterols Survival Rate Therapeutic Toxic effect Transcript Treatment Efficacy Xenograft Model activating transcription factor acute myeloid leukemia cell attenuation cancer diagnosis cell behavior chemotherapy effective therapy improved in vivo in vivo Model inhibitor insight knock-down leukemia mutant novel novel therapeutic intervention patient derived xenograft model response small hairpin RNA small molecule small molecule inhibitor standard of care stem cell function therapeutic target therapeutically effective therapy resistant transcription factor tumor uptake young adult

项目摘要

Project Summary/Abstract Acute myeloid leukemia (AML) is an aggressive blood cancer that encompasses a variety of genetically distinct sub-types. AML patients overall, display one of the lowest overall 5-year survival rates (<25%) of all cancer diagnoses and currently ranks as the deadliest form of leukemia. These unsatisfactory outcomes are largely the result of the ineffectiveness and toxicities of existing chemotherapies and highlight the urgent need for more-effective therapies that either replace or improve the effectiveness these chemotherapies. The development of more-effective therapies begins by identifying the molecular mechanisms that underpin AML pathogenesis and chemotherapy ineffectiveness. We recently discovered that the two transcription factors (TFs) TFs, ATF4 and XBP1s, which are components of the signal transduction network, the unfolded protein response (UPR), are key mediators of AML cell survival and disease progression. Specifically, we have found that inhibition of ATF4 or XBP1s antagonizes AML cell survival and disease progression in multiple in vitro and in vivo models of AML. We also found that small-molecule inhibitors of PERK and IRE1, which are upstream activators of ATF4 and XBP1s, respectively, antagonizes AML cell survival and enhances the effectiveness of first-line chemotherapies. The collective goals of this proposal aim to address two key unanswered questions: 1. What are the downstream transcriptional targets of ATF4 and XBP1s that support AML biology and 2. What are the molecular nodes of the UPR that can be targeted with chemical strategies? With respect to the first question, we have identified two candidates, DDIT4 and SREBF1, which are known regulators of autophagy and cholesterol biology, respectively. We will use a combination of established genetically engineered mouse models of AML and patient-derived AML samples to assess the functional roles of DDIT4 and SREBF1 in AML as well as their relationship to the UPR. Additionally, we will assess the contribution of DDIT4 and SREBF1 – as well as the downstream-regulated processes contribute to the pro-leukemia functions of ATF4 and XBP1s. Second, we will assess therapeutic strategies for targeting the UPR, autophagy and cholesterol biology either alone or simultaneously in experimental models of AML. The results of these studies will provide new insight on the molecular mechanisms that support the pathogenesis and chemotherapy responses of AML and establish a platform for developing novel therapeutic strategies. Moreover, components of the UPR support the pathophysiology of many other tumor settings and thus results from our proposed studies will likely have implications for other forms of human cancers.

项目总结/文摘