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ABERRANT SIGNALING IN ACUTE MYELOID LEUKEMIA

急性髓系白血病中的异常信号传导

基本信息

批准号：
10480910
负责人：
Alex Kentsis
金额：
$ 46.92万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-22 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10480910
关键词：
Acetylation Acute Myelocytic Leukemia Acute leukemia Adult Apoptosis Benchmarking Binding Biological Markers Biology Cell Differentiation process Cell Survival Cell physiology Cells Chemoresistance Child Combination Drug Therapy Communication Complex Dependence Development Disease Engineering Epigenetic Process Exhibits Functional disorder Fusion Oncogene Proteins Gene Expression Gene Expression Regulation Gene Mutation Genes Genetic Genetic Transcription Genomics Goals Human Knowledge Lead Leukemic Cell Link MLL gene Malignant Neoplasms Mission Molecular Nature Oncogenes Oncogenic Outcome Patient Care Patients Peptides Pharmacology Proteomics Public Health Refractory Research Research Project Grants Resistance Signal Transduction Stem cell transplant Techniques Technology Testing Therapeutic Transcription Factor 3 Translating Treatment Efficacy United States National Institutes of Health Xenograft procedure base cell growth chemotherapy clinical care clinically relevant cohort design effective therapy functional genomics high risk improved in vivo inhibitor innovation insight leukemia leukemia relapse loss of function mutation molecular subtypes molecular targeted therapies mouse model novel peptidomimetics pre-clinical preclinical study prospective refractory cancer restoration small molecule inhibitor therapeutic target therapeutically effective transcription factor treatment strategy

项目摘要

Project Summary Despite intense efforts, the long-term cure rates of patients with acute myeloid leukemia are inadequate. Resistance to chemotherapy is prevalent, and targets for molecular therapies are only beginning to be defined. For example, mutation of genes encoding transcription factors and epigenetic regulators cause most subtypes of AML, but their molecular pathophysiology and pharmacologic accessibility remain poorly defined. We have now found that leukemogenic gene expression in AML requires distinct molecular interactions between the pioneer transcription factor MYB and its coactivator CBP. Remarkably, peptidomimetic inhibitors of MYB transcriptional coactivation exhibit potent anti-leukemia activity in most molecular subtypes of AML while sparing healthy cells. The central hypothesis of this proposal is that defining and blocking the molecular mechanisms of aberrant transcriptional coactivation in AML will lead directly to improved therapies for patients. Aim 1 will define the molecular mechanisms of aberrant activation of leukemic MYB transcription factor complexes that control oncogenic gene expression. Aim 2 will pursue the preliminary evidence that peptidomimetic and targeted small molecule inhibitors can be used to dismantle leukemic transcriptional complexes in vivo and develop effective therapeutic strategies using accurate genetic and patient-derived preclinical mouse models. Successful completion of this project is expected to yield essential molecular mechanisms and effective therapies of aberrant transcription factors and gene control in AML, thus providing essential insights into a fundamental problem that remains poorly understood. This should have broad and lasting significance for understanding and treating refractory leukemias in particular and human cancer generally.

项目摘要尽管付出了巨大的努力，但急性髓细胞白血病患者的长期治愈率仍然不足。对化疗的耐药性很普遍，分子治疗的靶点才刚刚开始确定。例如，编码转录因子和表观遗传调节因子的基因突变引起大多数亚型但其分子病理生理学和药理学可及性仍不清楚。我们有现在发现，AML中的致白血病基因表达需要不同的分子相互作用，先锋转录因子MYB及其辅激活因子CBP。值得注意的是，MYB的拟肽抑制剂转录共激活在大多数AML分子亚型中表现出有效的抗白血病活性，健康的细胞这一建议的中心假设是，定义和阻断的分子机制， AML中的异常转录共激活将直接导致患者治疗的改善。目标1将定义白血病MYB转录因子复合物异常激活的分子机制，致癌基因表达目标2将寻求初步证据，肽模拟物和靶向小分子抑制剂可用于在体内拆除白血病转录复合物，使用精确的遗传和患者来源的临床前小鼠模型的治疗策略。成功该项目的完成有望产生异常的重要分子机制和有效的治疗方法。转录因子和基因控制的AML，从而提供了一个基本的问题，仍然知之甚少。这对于认识和对待特别是难治性白血病和一般的人类癌症。