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

• 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
• 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

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.

背景尽管最近的治疗取得了显著的成功，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和不良反应之间的不一致性 复发性疾病难以挽救是造成这种结果的部分原因。虽然成果有所改善， 在ALL的复发亚型中观察到了令人沮丧的总生存率（低于25%）。 治疗复发性或难治性T-ALL的临床治疗手段必须有新的选择。 战略虽然大多数T-ALL病例在Notch信号传导中表现出功能获得性突变，但针对T-ALL的治疗仍然存在。 Notch尚未实现其临床承诺。为了确定新疗法的替代靶点，我们建议 定义细胞内在致癌事件如何与来自微环境的外部信号整合。最近 研究指出了白血病生物学中“基质”信号的功能影响。然而，一个重要的差距是， 这个知识库是微环境因素如何成为白血病发生和维持的关键。 初步结果。根据我们在原代T-ALL细胞中的结果，Notch中的激活突变未能使 饱和Notch信号传导：当T-ALL细胞遇到Notch配体时，Notch信号强度增加。 微环境-例如白细胞介素7（IL-7）。Notch信号强度的增加与 通过直接转录激活IL-7 R α启动子，使IL-7 R α表面表达，导致T-ALL高表达， 对IL-7的反应。IL-7还诱导细胞周期调节因子SKP 2，激活STAT 5，（令人惊讶的是） STAT3。原代T-ALL细胞表现出持续的STAT 3激活，我们的结果表明STAT 3缺失损害 T-ALL白血病假说.这些数据支持致癌因素之间的重要相互作用， 微环境。根据我们的假设，微环境信号（IL-7），Notch 信号传导、SKP 2和STAT 3形成了T细胞白血病发生所必需的相互正反馈回路; 该轴还补偿了标准疗法在复发性和难治性疾病中的作用。 Approach.为了验证这一点，我们提出：1）为了确定起始时STAT 3缺失的时间要求， 通过使用STAT 3的可诱导基因缺失模型与 Notch诱导的T-ALL模型。2)绘制Notch/IL-7/STAT 3/SKP 2如何影响T-ALL发育 通过使用过表达和基因沉默的方法来定义信号通路的相互调节， Notch、STAT 3和SKP 2。3)确定抑制Notch/STAT/SKP 2回路对复发性T-ALL的影响 通过在临床前PDX中测试STAT信号传导的临床前和临床抑制剂和SKP 2抑制剂， T-ALL模型冲击成功完成这项拟议的工作将：1）确定如何合作， 致癌信号和微环境影响复发和难治性T-ALL的治疗; 2）建立一个 为在复发性和难治性T-ALL中验证新的分子靶点奠定基础; 3）提供原理验证 另一种策略是在开发治疗方法的过程中考虑整个分子回路。