Architecture and Trajectory of Acquired Resistance to Therapy in AML

AML 获得性治疗耐药的结构和轨迹

• 批准号: 10684101
• 负责人: BRIAN J DRUKER
• 金额: $ 130.9万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684101
• 关键词: Acute Myelocytic Leukemia; Address; Architecture; Atlases; Biological; Biological Assay; Biology; Bone Marrow; CRISPR screen; Cell Communication; Cell Line; Cells; Clinic; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Collaborations; Complement; Complex; Computer Models; Data; Data Set; Data Sources; Deposition; Development; Disease; Disease remission; Drug Combinations; Drug Exposure; Drug Sensitization; Drug resistance; Engineering; Environment; Epigenetic Process; Evaluation; Evolution; Exhibits; Feedback; Funding; Genetic; Goals; Immune; Intrinsic factor; Knowledge; Longitudinal Studies; Maps; Mediating; Modeling; New Drug Approvals; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Primary Neoplasm; Publications; Recurrent disease; Refractory; Refractory Disease; Regimen; Research Personnel; Resistance; Resource Sharing; Sampling; Series; Signal Transduction; Specimen; Standardization; Stress; Stromal Cells; Survival Rate; Testing; Therapeutic; Time; Translating; Translations; Work; acquired drug resistance; acute myeloid leukemia cell; anti-tumor immune response; biobank; catalyst; cohort; data integration; data sharing; deep sequencing; detection method; epigenomics; functional genomics; genome wide screen; genome-wide; genomic data; human model; improved; improved outcome; large datasets; leukemia; monocyte; neoplastic cell; next generation; novel; novel drug combination; novel therapeutic intervention; participant enrollment; pressure; prevent; progenitor; programs; public repository; relapse prevention; resistance mechanism; response; single cell analysis; targeted biomarker; targeted treatment; therapy resistant; translational approach; tumor; tumor-immune system interactions

PROJECT SUMMARY: Overall The long-term goal of this Program is to define mechanisms of acquired drug resistance in acute myeloid leukemia (AML) so that novel drug combinations can be deployed to prevent disease relapse and improve patient outcomes. The overall five-year survival rate for AML remains 20%, an outcome that has not changed for several decades. Although seven new regimens have been approved for AML in recent years, the improved initial remission rates with these therapies do not lead to durable outcomes. Disease relapse is fueled by a complex cross-talk of tumor cells adapting with support from the bone marrow microenvironment. The investigators of this proposed ARTNet Center have collaborated for 15+ years, including as a Center in the DRSN consortium – the predecessor to ARTNet. Our prior work has involved development of the largest-to-date functional genomic dataset on AML patient samples, genome-wide CRISPR screens, broad studies of AML interactions with stromal and immune cells, and testing of diverse drug combinations. These studies have led to >150 collaborative publications, continuous collaborative funding for 15+ years, creation of numerous large datasets deposited into public repositories, and translation of findings into numerous clinical trials. Our overarching hypothesis is that the architecture of acquired drug resistance is governed by temporal extrinsic and intrinsic factors and elucidating this trajectory will allow for the identification of properly timed therapeutic strategies to stave off acquired resistance and stay ahead of tumor evolution and adaptation. This hypothesis will be tested through three well integrated Projects addressing the following questions: 1) How does AML tumor cell intrinsic biology adapt to evade therapeutic pressure? We will use genome-wide CRISPR platforms as well as long-term progenitor expansion of primary AML patient samples to understand feedback pathways and shifting epigenetic and cell state landscapes that can drive acquired drug resistance. 2) How does the stromal and immune microenvironment govern drug resistance? We will use co-culture and advanced bone marrow models to perform genome-wide screens and test the impact of single-agents on AML-microenvironment cross-talk. Through computational modeling, we will nominate targeting strategies to mitigate tumor extrinsic resistance signals and boost immune anti-tumor responses. 3) How can resistance signatures and drug combinations be effectively clinically translated? We will use high-throughput and advanced, engineered models of human bone marrow to test and prioritize drug combinations from targets in Projects 1 and 2. We will also study longitudinal specimens from patients enrolled on ongoing clinical trials. All of these data will inform and refine the work of Projects 1 and 2. Our Center will be supported by an Administrative Core and a Functional Phenotyping Core. Collectively, we will develop a comprehensive understanding of acquired drug resistance in AML and identify new regimens to treat patients at the earliest possible stage, prevent relapse, and achieve durable remissions.

项目概述：

项目成果

Automated decision tree to evaluate genetic abnormalities when determining prognostic risk in acute myeloid leukemia.

在确定急性髓系白血病的预后风险时评估遗传异常的自动决策树。

• DOI: 10.3324/haematol.2018.190926
• 发表时间: 2018
• 期刊: Haematologica
• 影响因子: 10.1
• 作者: Watanabe-Smith,Kevin;Druker,BrianJ;Tyner,JeffreyW;Edwards5th,DavidK
• 通讯作者: Edwards5th,DavidK

Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy.

• DOI: 10.1182/blood.2022015752
• 发表时间: 2023-12-21
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Frank, Daria;Patnana, Pradeep Kumar;Vorwerk, Jan;Mao, Lianghao;Gopal, Lavanya Mokada;Jung, Noelle;Hennig, Thorben;Ruhnke, Leo;Frenz, Joris Maximillian;Kuppusamy, Maithreyan;Autry, Robert;Wei, Lanying;Sun, Kaiyan;Mohammed Ahmed, Helal Mohammed;Kunstner, Axel;Busch, Hauke;Muller, Heiko;Hutter, Stephan;Hoermann, Gregor;Liu, Longlong;Xie, Xiaoqing;Al-Matary, Yahya;Nimmagadda, Subbaiah Chary;Cano, Fiorella Charles;Heuser, Michael;Thol, Felicitas;Gohring, Gudrun;Steinemann, Doris;Thomale, Jurgen;Leitner, Theo;Fischer, Anja;Rad, Roland;Rollig, Christoph;Altmann, Heidi;Kunadt, Desiree;Berdel, Wolfgang E;Huve, Jana;Neumann, Felix;Klingauf, Jurgen;Calderon, Virginie;Opalka, Bertram;Duhrsen, Ulrich;Rosenbauer, Frank;Dugas, Martin;Varghese, Julian;Reinhardt, Hans Christian;von Bubnoff, Nikolas;Moroy, Tarik;Lenz, Georg;Batcha, Aarif M N;Giorgi, Marianna;Selvam, Murugan;Wang, Eunice;McWeeney, Shannon K;Tyner, Jeffrey W;Stolzel, Friedrich;Mann, Matthias;Jayavelu, Ashok Kumar;Khandanpour, Cyrus
• 通讯作者: Khandanpour, Cyrus

GoPeaks: histone modification peak calling for CUT&Tag.

• DOI: 10.1186/s13059-022-02707-w
• 发表时间: 2022-07-04
• 期刊: Genome biology
• 影响因子: 12.3

Two myeloid leukemia cases with rare FLT3 fusions.

两例罕见 FLT3 融合的骨髓性白血病病例。

• DOI: 10.1101/mcs.a003079
• 发表时间: 2018
• 期刊: Cold Spring Harbor molecular case studies
• 影响因子: 1.8
• 作者: Zhang,Haijiao;Paliga,Aleksandra;Hobbs,Evie;Moore,Stephen;Olson,Susan;Long,Nicola;Dao,Kim-HienT;Tyner,JeffreyW
• 通讯作者: Tyner,JeffreyW

Immune cell proportions correlate with clinicogenomic features and ex vivo drug responses in acute myeloid leukemia.

• DOI: 10.3389/fonc.2023.1192829
• 发表时间: 2023
• 期刊: FRONTIERS IN ONCOLOGY
• 影响因子: 4.7
• 作者: Romine, Kyle A.;Bottomly, Daniel;Yashar, William;Long, Nicola;Viehdorfer, Matthew;McWeeney, Shannon K.;Tyner, Jeffrey W.
• 通讯作者: Tyner, Jeffrey W.