Targeting GSK3B in refractory B-cell malignancies

靶向 GSK3B 治疗难治性 B 细胞恶性肿瘤

• 批准号: 10720232
• 负责人: Markus Müschen
• 金额: $ 61.01万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720232
• 关键词: Acute; Adhesions; Alleles; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; B-Cell Leukemia; B-Cell Neoplasm; B-Lymphocytes; Cell Adhesion; Cell Death; Cell Death Induction; Cell Nucleus; Cell membrane; Clinical Trials; Complex; Data; Deacetylation; Disease; Drug Combinations; Drug resistance; E-Cadherin; Elements; Engineering; Enhancers; Epithelial Cells; Exclusion Criteria; Exons; Future; Gene Expression; Genes; Genetic; Glucocorticoids; Goals; Human; In Vitro; Knock-in; Label; Lesion; Lymphoid; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Mantle Cell Lymphoma; Mediating; Mutation; Nuclear; Nucleosomes; Oncogenic; Patients; Phosphorylation; Refractory; Regulation; Repression; Repressor Proteins; Resistance; Role; Safety; Signal Transduction; Solid Neoplasm; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; Treatment Protocols; Tumor Suppression; Zinc Fingers; cancer type; cell transformation; clinical development; experimental study; gene repression; genome editing; humanized mouse; in vivo; inhibitor; leukemia/lymphoma; loss of function mutation; lymphoid neoplasm; member; mouse model; nanomolar; nervous system disorder; new therapeutic target; novel strategies; patient derived xenograft model; patient subsets; pre-clinical; response; small molecule; small molecule inhibitor; stem cells; transcription factor

Abstract GSK3E functions as essential negative regulator of E-catenin, while E-catenin accumulation represents a central oncogenic driver in cancer. In solid tumors, E-catenin forms complexes with TCF7-factors for transcriptional activation of MYC1-5. In striking contrast to solid tumors, we found that B-cell leukemias and lymphomas are not only exempt from activating E-catenin lesions but highly sensitive to E-catenin accumulation and critically depend on its negative regulation by GSK3E-mediated degradation: Unlike other cancer types, inducible activation of E- catenin in B-cell malignancies suppressed MYC-expression and rapidly induced cell death. Instead of the transcriptional activator TCF7, our interactome studies in B-cell malignancies revealed that E-catenin formed a repressive complex with lymphoid-specific Ikaros zinc finger (IKZF)6-8 factors. Instead of MYC-activation, E- catenin assembled lymphoid-specific Ikaros factors and multiple members of the repressive nucleosome remodeling and deacetylation (NuRD)9-10 complex for transcriptional repression of MYC. GSK3E phosphorylates S/T-residues in E-catenin exon 3, to initiate E-catenin- degradation. To leverage lymphoid-specific repressive E-catenin-complexes as previously unrecognized therapeutic vulnerability, we examined GSK3E small molecule inhibitors. Strikingly, established GSK3E-inhibitors that are currently in clinical trials for the neurological disorders and solid tumors, were effective at low nanomolar concentrations in B-cell malignancies, induced massive accumulation of E-catenin, repression of MYC and acute cell death. Preclinical experiments based on patient-derived xenografts validated small molecule GSK3E-inhibitors for targeted engagement of lymphoid-specific repressive E-catenin-complexes to overcome drug-resistance in refractory B- cell malignancies in vivo. Based on this discovery, the central goal of this proposal is to repurpose GSK3E-inhibitors for targeted engagement of repressive E-catenin-complexes in refractory B-cell malignancies. Given that four GSK3E- inhibitors have already undergone full clinical development and demonstrated favorable safety profiles in eighteen clinical trials, we anticipate that this powerful new approach can rapidly be developed to benefit patients with refractory B-cell malignancies and be further extended to T-cell malignancies in the future. We propose two Aims to (1) elucidate the mechanistic basis of E-catenin-mediated tumor suppression and to (2) develop concepts to leverage targeted activation of E-catenin-Ikaros complexes for therapeutic intervention in refractory B-cell malignancies.

抽象的 GSK3E充当E-catenin的基本负调节剂，而E-catenin积累代表中心 癌症中的致癌驱动力。在实体瘤中，e-catenin与TCF7因子形成复合物，用于转录 Myc1-5的激活。与实体瘤形成对比的是，我们发现B细胞白血病和淋巴瘤不是 仅免除激活电子蛋白病变，但对e-catenin的积累高度敏感，并且非常依赖 关于GSK3E介导的降解的阴性调节：与其他癌症类型不同，E-的诱导激活 B细胞恶性肿瘤中的Catenin抑制了MYC表达，并迅速诱导细胞死亡。而不是 转录激活剂TCF7，我们在B细胞恶性肿瘤中的相互作用组研究表明，e-catenin形成了A 具有淋巴特异性Ikaros锌指（IKZF）6-8因子的抑制性复合物。而不是Myc激活，E- Catenin组装的淋巴特异性Ikaros因子和抑制性核小体的多个成员 重塑和脱乙酰化（NURD）9-10复合物，用于转录抑制MYC。 GSK3E磷酸化E-Catenin Exon 3中的S/T-沉积物，以启动E-Catenin-降解。利用 淋巴特异性的抑制E-catenin-复合物作为以前无法​​识别的治疗脆弱性，我们 检查了GSK3E小分子抑制剂。令人惊讶的是，目前处于临床中的已建立的GSK3E抑制剂 神经系统疾病和实体瘤的试验在B细胞的低纳摩尔浓度下有效 恶性肿瘤，诱导的e-catenin大量积累，抑制MYC和急性细胞死亡。临床前 基于患者衍生异种移植的实验验证了针对目标的小分子GSK3E抑制剂 淋巴特异性的抑制E-Catenin-复合物的参与以克服难治性b-的药物抗药性 体内细胞恶性肿瘤。 基于这一发现，该提案的核心目标是重新利用gsk3e抑制剂的目标 在难治性B细胞恶性肿瘤中参与抑制性e-Catenin-复合物。鉴于四个GSK3E- 抑制剂已经进行了完整的临床发展，并在 十八次临床试验，我们预计可以迅速开发这种强大的新方法以使患者受益 使用难治性B细胞恶性肿瘤，将来进一步扩展到T细胞恶性肿瘤。我们提出了两个 旨在（1）阐明e-catenin介导的肿瘤抑制的机理基础，并发展概念 利用E-Catenin-Ikaros复合物的靶向激活进行难治性B细胞的治疗干预 恶性肿瘤。