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Targeting GSK3 in AML

AML 中的靶向 GSK3

基本信息

批准号：
9908247
负责人：
Nethrie Idippily-Singh
金额：
$ 26.87万
依托单位：
CURONBIOTECH, INC.
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：
2019-09-11 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908247
关键词：
Acute Myelocytic Leukemia Acute Promyelocytic Leukemia Adult Age Animal Model Awareness Biological Biological Assay Bone Marrow Bone Marrow Cells Cell model Cells Chronic Clinical Clinical Trials Colonic Neoplasms Cyclin-Dependent Kinases Development Differentiation Inducer Differentiation Therapy Differentiation and Growth Disease Dose Drug Targeting Drug resistance Elderly Exhibits FDA approved FLT3 gene FLT3 inhibitor Genetic Glycogen Growth Hematopoietic Hematopoietic stem cells Human Immunodeficient Mouse Impairment In Vitro Incidence Lead Leukemic Cell Metabolic Modeling Morbidity - disease rate Mus Myeloid Cells Nuclear Outcome Patients Pharmacology Pharmacology Study Phosphotransferases Property Proteins Public Health Refractory Regimen Relapse Reporting Retinoic Acid Receptor Retinoids Safety Sampling Therapeutic Therapeutic Index Toxic effect Tretinoin Work acute myeloid leukemia cell animal efficacy arm chemotherapy efficacy study improved in vivo inhibitor/antagonist kinase inhibitor leukemia mortality mouse model nanomolar novel novel strategies novel therapeutic intervention novel therapeutics outcome forecast overexpression patient subsets retinoic acid receptor alpha stem success synergism transcription factor

项目摘要

Acute myeloid leukemia (AML) is one of the most common forms of leukemia in adults and despite advances in treatment the 5 year survival is less than 20-50% in adults and significantly lower in the elderly. The remarkable success in treating one relatively uncommon subset of AML, acute promyelocytic leukemia, with all trans-retinoic acid (ATRA) illustrates the great promise for agents with greater efficacy and less toxicity. Utilizing ATRA, the presumed cure of 75-85% of patients is possible. ATRA’s remarkable success stems from the fact that AML is a disease characterized by the arrest of differentiation of immature myeloid cells. ATRA overcomes this block in differentiation by forcing leukemic cells to mature. Unfortunately, ATRA does not work clinically for 90-95% of AML patients. Recently we identified that targeting the kinase GSK3 is a promising strategy to induce AML differentiation, particularly in combination with ATRA. Unfortunately, there are no FDA approved specific GSK3 inhibitors. We have identified a highly potent and specific GSK3 inhibitor that exhibits promise against AML in cell and animal models. In this proposal, we will assess the pharmacologic properties of this GSK3 inhibitor, perform animal efficacy studies, and determine its effects on primary patient samples. It is hoped that this work will lead to a new differentiation therapy that can improve the prognosis of patients with non-APL leukemia.

急性髓性白血病（AML）是成人和儿童最常见的白血病之一