Targeting GSK3B in refractory B-cell malignancies

靶向 GSK3B 治疗难治性 B 细胞恶性肿瘤

基本信息

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
项目类别：
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

项目摘要

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 是 E-catenin 的重要负调节因子，而 E-catenin 的积累则代表着 E-catenin 的中心作用。癌症的致癌驱动因素。在实体瘤中，E-catenin 与 TCF7 转录因子形成复合物 MYC1-5 的激活。与实体瘤形成鲜明对比的是，我们发现 B 细胞白血病和淋巴瘤不是仅免于激活 E-catenin 损伤，但对 E-catenin 积累高度敏感，并且严重依赖 GSK3E 介导的降解对其负向调节：与其他癌症类型不同，E-的诱导激活 B 细胞恶性肿瘤中的连环蛋白抑制 MYC 表达并迅速诱导细胞死亡。而不是转录激活因子 TCF7，我们在 B 细胞恶性肿瘤中的相互作用组研究表明，E-catenin 形成了具有淋巴特异性 Ikaros 锌指 (IKZF)6-8 因子的抑制复合体。 E- 代替 MYC 激活连环蛋白组装淋巴特异性 Ikaros 因子和抑制性核小体的多个成员用于 MYC 转录抑制的重塑和脱乙酰化 (NuRD)9-10 复合物。 GSK3E 磷酸化 E-连环蛋白外显子 3 中的 S/T 残基，以启动 E-连环蛋白降解。发挥杠杆作用淋巴特异性抑制性 E-连环蛋白复合物作为以前未被认识到的治疗脆弱性，我们检查了 GSK3E 小分子抑制剂。引人注目的是，已建立的 GSK3E 抑制剂目前正处于临床阶段针对神经系统疾病和实体瘤的试验在 B 细胞中低纳摩尔浓度下有效恶性肿瘤，诱导 E-catenin 大量积累，抑制 MYC 和急性细胞死亡。临床前基于患者来源的异种移植物的实验验证了小分子 GSK3E 抑制剂的靶向作用淋巴特异性抑制性E-连环蛋白复合物的参与克服难治性B-的耐药性体内细胞恶性肿瘤。基于这一发现，该提案的中心目标是将 GSK3E 抑制剂重新用于靶向治疗抑制性E-连环蛋白复合物在难治性B细胞恶性肿瘤中的参与。鉴于四个 GSK3E- 抑制剂已经进行了全面的临床开发，并在以下领域表现出良好的安全性：十八项临床试验，我们预计这种强大的新方法可以迅速开发出来造福患者难治性 B 细胞恶性肿瘤，未来将进一步扩展到 T 细胞恶性肿瘤。我们建议两个旨在 (1) 阐明 E-连环蛋白介导的肿瘤抑制的机制基础并 (2) 发展概念利用 E-catenin-Ikaros 复合物的靶向激活对难治性 B 细胞进行治疗干预恶性肿瘤。