Targeting the Microenvironment/Oncogene Cooperation to treat poor prognosis T-ALL

靶向微环境/癌基因合作治疗预后不良的 T-ALL

基本信息

批准号：
10659661
负责人：
Nadia Carlesso
金额：
$ 51.23万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-09 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659661
关键词：
Acute Lymphocytic Leukemia Acute T Cell Leukemia Affect Anthracycline Apoptosis BCL2 gene Biological Assay Biology CRISPR/Cas technology Cell Cycle Cell Line Cell Proliferation Cell Survival Cell model Cells Cessation of life Childhood Clinical Compensation Cyclophosphamide Data Development Dexamethasone Disease model EMSA Event Exhibits Feedback Foundations Gene Silencing Genetic Genetic Transcription Growth Factor Human IL7 gene IL7R gene Impairment Interleukin 7 Receptor Interruption Lead Leukemic Cell Ligands Link Maintenance Malignant - descriptor Malignant Childhood Neoplasm Maps Measures Mediating Mediator Methotrexate Modeling Molecular Molecular Analysis Molecular Target Mus Mutation Notch Signaling Pathway Oncogenes Oncogenic Outcome Pathway interactions Patients Phosphorylation Play Pre-Clinical Model Prognosis Proliferating Public Health Recurrent disease Refractory Refractory Disease Regulation Relapse Research Role SKP2 gene STAT3 gene Sampling Signal Transduction Stat5 protein Surface Survival Rate T-Cell Leukemia T-Lymphocyte Testing Therapeutic Therapeutic Intervention Transcriptional Activation Transcriptional Regulation Work asparaginase c-myc Genes cancer type chemotherapy effective therapy effectiveness evaluation gain of function mutation improved inhibitor insight knowledgebase leukemia leukemia initiating cell leukemia relapse leukemia/lymphoma leukemogenesis molecular targeted therapies new therapeutic target notch protein novel therapeutic intervention overexpression patient derived xenograft model pharmacologic pre-clinical promoter success therapy development transcription factor translational impact tumor tumorigenesis

Acute Lymphocytic Leukemia Acute T Cell Leukemia Affect Anthracycline Apoptosis BCL2 gene Biological Assay Biology CRISPR/Cas technology Cell Cycle Cell Line Cell Proliferation Cell Survival Cell model Cells Cessation of life Childhood Clinical Compensation Cyclophosphamide Data Development Dexamethasone Disease model EMSA Event Exhibits Feedback Foundations Gene Silencing Genetic Genetic Transcription Growth Factor Human IL7 gene IL7R gene Impairment Interleukin 7 Receptor Interruption Lead Leukemic Cell Ligands Link Maintenance Malignant - descriptor Malignant Childhood Neoplasm Maps Measures Mediating Mediator Methotrexate Modeling Molecular Molecular Analysis Molecular Target Mus Mutation Notch Signaling Pathway Oncogenes Oncogenic Outcome Pathway interactions Patients Phosphorylation Play Pre-Clinical Model Prognosis Proliferating Public Health Recurrent disease Refractory Refractory Disease Regulation Relapse Research Role SKP2 gene STAT3 gene Sampling Signal Transduction Stat5 protein Surface Survival Rate T-Cell Leukemia T-Lymphocyte Testing Therapeutic Therapeutic Intervention Transcriptional Activation Transcriptional Regulation Work asparaginase c-myc Genes cancer type chemotherapy effective therapy effectiveness evaluation gain of function mutation improved inhibitor insight knowledgebase leukemia leukemia initiating cell leukemia relapse leukemia/lymphoma leukemogenesis molecular targeted therapies new therapeutic target notch protein novel therapeutic intervention overexpression patient derived xenograft model pharmacologic pre-clinical promoter success therapy development transcription factor translational impact tumor tumorigenesis

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项目摘要

Background. Despite the significant success of recent therapies, Acute Lymphoblastic Leukemia (ALL) remains the second leading cause of childhood death. The discordance between therapeutic improvements and poor outcomes is partially caused by the difficulty of salvaging relapsed disease. While outcomes have improved in de novo treatment, dismal rates of overall survival (less than 25%) were observed in relapsed subtypes of ALL. The clinical armamentarium for treating relapsed or refractory T-ALL must be supported with new options. Strategy. While most of T-ALL cases exhibit gain-of-function mutations in Notch signaling, therapies against Notch have not fulfilled their clinical promise. To identify alternative targets for new therapies, we propose to define how cell-intrinsic oncogenic events integrate with external signals from the microenvironment. Recent studies point to the functional impact of “stromal” signals in leukemia biology. However, one significant gap in this knowledgebase is how microenvironmental factors become essential for leukemogenesis and maintenance. Preliminary results. According to our results in primary T-ALL cells, activating mutations in Notch failed to saturate Notch signaling: Notch signal strength increased when T-ALL cells encounter Notch ligands within the microenvironment – e.g. interleukin 7 (IL-7). The increased strength of Notch signaling correlated with increased surface expression of IL-7Rα by direct transcriptional activation of the IL-7Rα promoter, resulting in T-ALL hyper- responsiveness to IL-7. IL-7 also induced the cell cycle regulator SKP2, activated STAT5, and (surprisingly) STAT3. Primary T-ALL cells showed persistent STAT3 activation and our results suggest STAT3 deletion impairs T-ALL leukemogenesis. Hypothesis. These data support significant interplay between oncogenic factors and the microenvironment. According to our hypothesis, interplay between microenvironmental signals (IL-7), Notch signaling, SKP2, and STAT3 form a reciprocal positive feedback loop that is essential for T-cell leukemogenesis; this axis also compensates for the action of standard therapies in relapsed and refractory disease. Approach. To test this, we propose: 1) To determine the temporal requirement for STAT3 deletion in initiation, progression, and relapse in T-ALL by using a model of inducible genetic deletion of STAT3 in combination with a model of Notch-induced T-ALL. 2) To map how T-ALL development is affected by Notch/IL-7/STAT3/SKP2 signaling circuitry by using overexpression and gene silencing approaches to define the reciprocal regulation of Notch, STAT3, and SKP2. 3) To identify the impact of inhibiting Notch/STAT/SKP2 circuitry in relapsed T-ALL by testing both pre-clinical and clinical inhibitors of STAT signaling and SKP2 inhibitors in pre-clinical PDX models of T-ALL. Impact. Successful completion of this proposed work will: 1) define how cooperation between oncogenic signaling and the microenvironment affects therapy of relapsed and refractory T-ALL; 2) build a foundation for validating new molecular targets in relapsed and refractory T-ALL; 3) provide a proof-of-principle for an alternative strategy in which entire molecular circuits are considered during the development of therapies.

背景。尽管最近的疗法取得了显着成功，但急性淋巴细胞白血病（ALL）仍然存在儿童死亡的第二大原因。治疗改善与差的不一致结果部分是由于挽救继电器疾病的困难引起的。虽然结果有所改善从头处理，在所有人的继电器亚型中观察到了整体生存率（少于25％）。必须支持新选择的临床手臂治疗接力或难治性T-ALL。战略。虽然大多数T-All病例在Notch信号传导中表现出功能收益突变，但针对的疗法 Notch尚未实现他们的临床承诺。为了确定新疗法的替代目标，我们建议定义细胞中的致癌事件如何与微环境的外部信号集成。最近的研究指出了“基质”信号在白血病生物学中的功能影响。但是，一个重大差距这个知识基础是微环境因素如何成为白血病和维持至关重要的。初步结果。根据我们在主要T-ALL细胞中的结果，Notch中的激活突变未能饱和凹口信号传导：当T-All细胞遇到Notch配体时，Notch信号强度会增加微环境 - 例如白介素7（IL-7）。 Notch信号的强度与增加相关 IL-7Rα通过直接转录激活的IL-7Rα启动子的表面表达，导致T-All超级对IL-7的响应能力。 IL-7还诱导细胞周期调节剂SKP2，激活的STAT5和（令人惊讶的是） Stat3。原代T-ALL细胞显示持续的STAT3激活，我们的结果表明STAT3缺失会损害 T-ALL白血病。假设。这些数据支持致癌因素和微环境。根据我们的假设，微环境信号（IL-7）之间的相互作用，Notch 信号传导，SKP2和STAT3形成了对T细胞白血病生成至关重要的相互反馈回路。该轴还弥补了继电器和难治性疾病中标准疗法的作用。方法。要测试这一点，我们建议：1）确定启动中STAT3缺失的临时要求，通过使用STAT3的诱导遗传缺失模型与T-All中继和中继 Notch引起的T-ALL的模型。 2）映射T-ALL开发如何受Notch/IL-7/STAT3/SKP2的影响通过使用过表达和基因沉默方法来定义信号传导电路 Notch，STAT3和SKP2。 3）确定在继电器中抑制缺口/stat/skp2电路的影响通过测试临床前PDX中Stat信号传导和SKP2抑制剂的临床前和临床抑制剂 T-all模型。影响。成功完成这项拟议的工作将：1）定义如何合作致癌信号传导和微环境会影响传递和难治性T-ALL的治疗； 2）建造一个验证继电器和难治性T-ALL中的新分子靶标的基础； 3）提供原理证明对于在疗法开发过程中考虑整个分子回路的替代策略。