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Tumor Intrinsic and Microenvironmental Mechanisms Driving Drug Combination Efficacy and Resistance in AML

驱动 AML 药物组合疗效和耐药性的肿瘤内在和微环境机制

基本信息

批准号：
9985229
负责人：
BRIAN J DRUKER
金额：
$ 124.83万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9985229
关键词：
Acute Myelocytic Leukemia Automobile Driving BCL2 gene Back Biological Assay Biology Bone Marrow Cell Line Cells Chemotherapy-Oncologic Procedure Clinic Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Collection Combined Modality Therapy Complex Computer Analysis Data Data Set Development Diagnostic Disease Drug Combinations Drug Kinetics Drug resistance Environment Evaluation Event Exposure to FLT3 gene Future Gene Targeting Genes Genetic Goals Hematologic Neoplasms Immune Immunophenotyping Immunosuppression Inflammatory Knowledge Lesion Light MEKs Malignant Neoplasms Modeling Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Plasma Population Research Personnel Resistance Resolution Sampling Signal Pathway Signal Transduction Stromal Cells T-Lymphocyte Testing Therapeutic Translating Validation Vision Work Xenograft procedure acute myeloid leukemia cell base candidate validation cell growth clinical investigation clinical translation cohort combinatorial cytokine drug candidate drug sensitivity drug testing effective therapy exome experimental study functional genomics genome-wide genomic data genomic profiles immune checkpoint improved improved outcome in vivo in vivo evaluation innovation leukemia mortality mouse model neoplastic cell novel novel drug combination novel strategies personalized medicine pre-clinical programs prospective resistance mechanism response small molecule standard of care targeted agent targeted treatment therapy outcome therapy resistant transcriptome sequencing treatment strategy tumor

项目摘要

PROJECT SUMMARY – Overall Acute myeloid leukemia (AML) is one of the most common hematologic malignancies, representing a diverse collection of complex diseases. Treatment strategies for AML have not changed in 30-40 years. Single-agent targeted therapies based on AML genetics or microenvironmental disease features have been disappointing, at best. The investigators on this DRSC Program, Drug Combinations to Circumvent Resistance (D2CR), have collaborated for over a decade and have developed functional genomic pipelines for evaluation of primary AML patient samples that have collectively led to numerous discoveries with diagnostic and therapeutic implications. For this Program, our long-term goals are to translate effective drug combinations that target tumor- intrinsic and microenvironmental pathways into the clinic for patients with AML. Our immediate goals are to prioritize the most relevant tumor-intrinsic and microenvironmental pathways for each AML disease subset and establish sufficient preclinical data to facilitate immediate clinical investigation of drug combinations. Based on the central hypothesis that drug combinations targeting tumor intrinsic and extrinsic features of AML biology will be essential to the development of more effective and durable therapeutic strategies, we predict that the drug combinations established by this D2CR-DRSC Program will substantially improve outcomes for patients with AML. To accomplish these goals, 3 Projects are proposed: 1) What are the tumor-intrinsic genes and pathways that contribute to drug sensitivity and resistance? Genome-wide CRISPR/Cas screens on parental and drug-resistant AML cells will be integrated with computational analysis of the largest functional genomic AML cohort in the world. The result will nominate genes/pathways for validation on patient samples in gene-edited models and for drug combination studies in Project 3. 2) What are the tumor-extrinsic pathways promoting tumor cell growth, drug resistance, and immune suppression? Inflammatory cytokine profiling of our large bank of AML patient samples will be conducted. Our bank of AML patient bone marrow stromal cells will also be accessed for studies of the reactive signature of these stromal cells when exposed to specific drugs. Finally, high-parameter immunophenotyping and T-cell functional assays will be used to define the immune landscape with candidate drugs tested in an immune-competent, spontaneous mouse model of AML. Candidate targets will be nominated for combination studies with tumor-intrinsic targets. 3) What are the drug combinations that most effectively bridge tumor- intrinsic and microenvironmental biology to eliminate AML cells and circumvent resistance? Drug combinations from targets nominated in Project 1 and 2 will be tested ex vivo on primary AML patient samples and in vivo using AML patient-derived xenografts. Cumulatively, we expect these innovative analyses to have a major impact on our understanding of AML biology, with successful clinical translation of new, more effective drug combination strategies.

项目概述-整体