Co-targeting BET Bromodomain Proteins and Aberrant Signaling in AML.

共同靶向 BET 溴结构域蛋白和 AML 中的异常信号传导。

• 批准号: 10674738
• 负责人: Benjamin Huang
• 金额: $ 24.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674738
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adolescent and Young Adult; Adult Acute Myeloblastic Leukemia; Alternative Therapies; Apoptosis; Automobile Driving; Biological Models; Bromodomain; Bromodomains and extra-terminal domain inhibitor; CRISPR interference; Cell Line; Chemotherapy-Oncologic Procedure; Child; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Clinical; Combined Modality Therapy; DNMT3a; Data; Dependence; Development; Diagnosis; Drug Combinations; Drug Synergism; Drug resistance; Elderly; Engraftment; Epigenetic Process; Gene Expression Profile; Genes; Genetic; Genetic Heterogeneity; Genetic Transcription; Genomics; Goals; Growth; Human; Immunocompetent; Insertional Mutagenesis; KRAS2 gene; Knowledge; Laboratories; Leukemic Cell; MEK inhibition; MEKs; MLL gene; Malignant Neoplasms; Methodology; Modeling; Molecular; Mus; Mutation; NF1 mutation; Outcome; Pathway interactions; Patients; Play; Proliferating; Proteins; Ras Signaling Pathway; Refractory; Relapse; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Somatic Mutation; System; TP53 gene; Testing; Therapeutic; Translating; Transplantation; Treatment-related toxicity; Work; acute myeloid leukemia cell; candidate validation; cohort; congenic; drug testing; experimental study; genome-wide analysis; hyperactive Ras; improved; in vivo; inhibitor; knock-down; leukemia; leukemia relapse; leukemic transformation; mouse model; mutant; next generation; overexpression; patient derived xenograft model; pediatric patients; permissiveness; programs; resistance mechanism; response; retransplantation; synergism; transcription factor; transcriptome sequencing; validation studies

PROJECT SUMMARY Acute myeloid leukemia (AML) comprises 20% of childhood leukemia cases. In contrast to acute lymphoblastic leukemia (ALL), cure rates for AML remain poor with the majority of patients dying from refractory leukemia or treatment related toxicities. In contrast to AML in older adults, genome-wide studies of AML in children, adolescents, and young adults (AYA) revealed a lower mutational burden and highly prevalent transcription factor fusions and RAS pathway mutations. Additionally, while transcription factor fusions are hypothesized to promote a transcriptional signature that is permissive for AML development, experimental data suggest that signaling mutations play a central role in driving leukemic growth in vivo. Thus, simultaneously targeting the abnormal transcriptional program and aberrant signaling pathways in AML is a rational therapeutic approach that is particularly relevant in children and AYA patients. The overall goals of this proposal are to investigate the efficacy of promising drug combinations that simultaneously target key pathways in pediatric AML and to elucidate molecular mechanisms underlying drug synergy and resistance to these targeted approaches through the following specific aims: (1) to identify and validate mechanisms of drug synergy and resistance to BET + MEK inhibition; and, (2) to investigate the in vivo efficacy of this combination in patient derived xenograft (PDX) models of pediatric AML.

项目总结

项目成果

CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.

• DOI: 10.1172/jci157101
• 发表时间: 2022-11-15
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Le, Quy;Hadland, Brandon;Smith, Jenny L.;Leonti, Amanda;Huang, Benjamin J.;Ries, Rhonda;Hylkema, Tiffany A.;Castro, Sommer;Tang, Thao T.;McKay, Cyd N.;Perkins, LaKeisha;Pardo, Laura;Sarthy, Jay;Beckman, Amy K.;Williams, Robin;Idemmili, Rhonda;Furlan, Scott;Ishida, Takashi;Call, Lindsey;Srivastava, Shivani;Loeb, Anisha M.;Milano, Filippo;Imren, Suzan;Morris, Shelli M.;Pakiam, Fiona;Olson, Jim M.;Loken, Michael R.;Brodersen, Lisa;Riddell, Stanley R.;Tarlock, Katherine;Bernstein, Irwin D.;Loeb, Keith R.;Meshinchi, Soheil
• 通讯作者: Meshinchi, Soheil