Functional characterization and rational therapeutic targeting of 18q DNA copy number gains in diffuse large B-cell lymphoma

弥漫性大 B 细胞淋巴瘤 18q DNA 拷贝数增加的功能特征和合理治疗靶向

• 批准号: 10533731
• 负责人: Michael Richard Green
• 金额: $ 43.21万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533731
• 关键词: 18q; Automobile Driving; B-Cell Antigen Receptor; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; BCL2 gene; Biology; Bromodomains and extra-terminal domain inhibitor; Cell Death; Cell Line; Cells; Chromosome 18; Chromosome Arm; Chronic; Clinical; Combination immunotherapy; Complex; DNA copy number; Development; Disease; Down-Regulation; Event; Genes; Genetic; Genus Mentha; Hematopoietic Stem Cell Transplantation; Immunoglobulins; Immunophenotyping; Inhibition of Apoptosis; Investigation; Link; Lymphoma; Lymphomagenesis; MYC gene; Malignant - descriptor; Measures; Mediating; Molecular; Monitor; Mus; Mutation; Non-Hodgkin' s Lymphoma; Oncogenes; Oncogenic; Outcome; Patient-Focused Outcomes; Patients; Phenotype; Play; Population; Pre-Clinical Model; Prognosis; Property; Proteins; Public Health; Receptor Signaling; Recurrence; Refractory; Relapse; Role; Signal Transduction; Structure of germinal center of lymph node; Subgroup; TCF7L2 gene; Testing; Therapeutic; Transgenic Mice; Work; activated B cell like; anergy; clinical heterogeneity; improved outcome; inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; molecular marker; molecular phenotype; molecular subtypes; mouse model; mutant; novel; overexpression; patient derived xenograft model; pre-clinical; precision medicine; prevent; receptor expression; resistance mechanism; risk stratification; rituximab; single-cell RNA sequencing; synergism; therapeutic target; tositumomab; transcription factor; tumor

Project Summary Diffuse large B-cell lymphoma (DLBCL) is the most common form lymphoma and is conventionally treated with a combination of chemotherapeutics with the anti-CD20 antibody, Rituximab. Although more than half of patients can be cured with this approach, the remainder have a dire prognosis with a short survival. Despite the variability in patient outcome, there are currently no routinely utilized molecular biomarkers that can be employed for risk stratification or to direct a specific therapy. That is, precision medicine does not currently exist for DLBCL. We have identified a genetic alteration on the q-arm of chromosome 18 (18q) that is associated with an aggressive subtype of DLBCL, and defined the TCF4 and BCL2 genes as critical targets at this locus. The BCL2 gene encodes an important oncogene that prevents cell death, and can be targeted with the inhibitor Venetoclax. The TCF4 gene encodes a transcription factor protein that we have found to drive key malignant properties of lymphoma, such as promoting the expression of the MYC oncogene and the B-cell receptor. In addition, we have defined a way to eliminate TCF4 expression using a novel type of protein-degrader molecules that are directed towards BET proteins. This therefore provides an exciting rational therapeutic avenue for targeting TCF4. We hypothesize that combining this with an inhibitor of BCL2 will target both genes that are activated by 18q alterations, and provide a precision medicine approach for treating this aggressive subset of DLBCL. Here, we are proposing to investigate the function of 18q alterations in DLBCL and validate the mechanism by which we believe this genetic event leads to lymphoma. We will also perform pre-clinical investigation of combinations of BET and BCL2 inhibitors for the specific therapeutic targeting of 18q alterations. Together, this work will advance our understanding of DLBCL disease biology and may lead to advances in precision medicine for this disease.

项目概要 弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常见的淋巴瘤形式，通常 采用化疗药物与抗 CD20 抗体利妥昔单抗 (Rituximab) 联合治疗。虽然更多 超过一半的患者可以通过这种方法治愈，其余患者的预后很差，且短期内无法治愈。 生存。尽管患者结果存在差异，但目前尚无常规使用的分子治疗方法 可用于风险分层或指导特定治疗的生物标志物。也就是精度 目前尚无治疗 DLBCL 的药物。 我们已经在 18 号染色体 (18q) 的 q 臂上发现了一个基因改变，该改变与 DLBCL 的侵袭性亚型，并将 TCF4 和 BCL2 基因定义为该位点的关键靶点。 BCL2 基因编码一种重要的癌基因，可以防止细胞死亡，并且可以被 抑制剂维奈托克。 TCF4 基因编码一种转录因子蛋白，我们发现它可以驱动 淋巴瘤的关键恶性特性，例如促进 MYC 癌基因的表达和 B 细胞受体。此外，我们还定义了一种使用新型的 TCF4 表达消除方法。 针对 BET 蛋白质的蛋白质降解分子。因此，这提供了令人兴奋的 针对 TCF4 的合理治疗途径。我们假设将其与抑制剂相结合 BCL2将靶向由18q改变激活的两个基因，并提供精准医学 治疗这种侵袭性 DLBCL 亚型的方法。 在这里，我们建议研究 18q 改变在 DLBCL 中的功能并验证 我们相信这种遗传事件导致淋巴瘤的机制。我们还将进行临床前 BET 和 BCL2 抑制剂组合用于 18q 特异性治疗靶向的研究 变更。总之，这项工作将增进我们对 DLBCL 疾病生物学的理解，并可能导致 来推动针对这种疾病的精准医学的进步。