BCLW in lymphoma survival and resistance to targeted BCL2 family therapies

BCLW 在淋巴瘤生存和对靶向 BCL2 家族疗法的耐药性中的作用

• 批准号: 10056214
• 负责人: CHRISTINE M. EISCHEN
• 金额: $ 42.98万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056214
• 关键词: Apoptosis; Apoptotic; B-Cell Leukemia; B-Cell Lymphomas; B-Lymphocytes; BCL2 gene; BCL2L1 gene; Biological Markers; Burkitt Lymphoma; Cancer Etiology; Cell Line; Cell Survival; Clinic; Clinical Trials; Development; Diagnostic; FDA approved; Family; Family member; Family psychotherapy; Follicular Lymphoma; Foundations; Genomic approach; Genomics; Hematologic Neoplasms; Human; Human Cell Line; Investigation; Knowledge; Lead; Link; Lymphoid; Lymphoma; Lymphoma cell; Lymphomagenesis; MCL1 gene; Malignant Neoplasms; Molecular; Monitor; Mus; Pathway interactions; Patients; Population; Prognostic Marker; Protein Family; Proteins; Resistance; Role; Sampling; Scientist; Spermatogenesis; System; Testing; Therapeutic; Therapeutic Intervention; biomarker identification; cancer cell; cancer therapy; experimental study; improved; inhibitor/antagonist; innovation; knowledge base; large cell Diffuse non-Hodgkin' s lymphoma; leukemia; mouse model; non-genomic; novel; overexpression; patient derived xenograft model; pressure; prognostic; resistance mechanism; response; single cell analysis; targeted treatment; therapeutic target; therapy resistant; tumor; tumorigenesis

Summary A prerequisite for tumor development is acquiring resistance to apoptosis. This can be accomplished through multiple mechanisms, but a frequent alteration in human cancers that protects from apoptosis is the overexpression of one or more of the anti-apoptotic BCL2 family members. BCL2 itself is frequently overexpressed in multiple types of B cell lymphomas and many other lymphoid and non-lymphoid malignancies. Because of the perceived reliance of cancer cells on BCL2 for survival, a targeted specific BCL2 inhibitor was developed, ABT-199 (venetoclax). Although, venetoclax has been FDA approved for the treatment of specific leukemias, clinical trials with venetoclax have not been successful for B cell lymphomas with high levels of BCL2, such as follicular lymphomas and diffuse large B cell lymphomas (DLBCL) that have translocated or amplified BCL2. The results indicate these lymphomas do not require BCL2 for their continued survival, revealing a significant gap in knowledge of what lymphomas use to protect themselves from apoptosis. Recently, we made the unexpected discovery that BCLW, an unexplored anti-apoptotic BCL2 family member that was only thought to be important in spermatogenesis, was overexpressed in six different types of B cell lymphomas, including follicular lymphoma and DLBCL. We determined patients with DLBCL containing higher levels of BCLW had reduced survival, and BCLW was more highly expressed than BCL2 in higher grade follicular lymphoma. We also showed BCLW was necessary for the survival of Burkitt lymphoma cells, and increased levels of BCLW provided resistance to Burkitt lymphoma cells to an inhibitor that targets three anti-apoptotic BCL2 family members. Therefore, we hypothesize BCLW overexpression is necessary for the survival of multiple types of B cell lymphomas and confers resistance to lymphoma cells to venetoclax and other BCL2 family inhibitors. We propose two Aims to test this hypothesis. In Aim 1, we propose to evaluate the requirements of BCLW in multiple different B cell lymphomas in relationship to other BCL2 family members and mechanisms for its overexpression. In Aim 2, we propose to determine the contribution of BCLW to resistance to inhibitors of anti-apoptotic BCL2 family members and ways to overcome this resistance. Completion of these Aims will significantly increase knowledge into the BCL2 family of proteins and the contribution of BCLW to B cell lymphomas and resistance to targeted inhibitors of BCL2 family members. Results are also likely to lead to improved lymphoma clinical trials, diagnostics, prognostics, and therapeutic interventions with knowledge based treatment combinations.

概括 肿瘤发育的先决条件是获得对凋亡的抗性。这可以通过 多种机制，但是保护凋亡的人类癌症经常改变是 一个或多个抗凋亡BCL2家庭成员的过表达。 Bcl2本身经常 在多种类型的B细胞淋巴瘤以及许多其他淋巴和非淋巴恶性肿瘤中过表达。 由于癌细胞对BCL2的生存依赖的依赖，因此，有针对性的特异性BCL2抑制剂是 开发，ABT-199（Venetoclax）。虽然，已批准Venetoclax用于治疗特定 Venetoclax的临床试验白血病尚未成功用于BCl2水平高的B细胞淋巴瘤， 例如易位或扩增的卵泡淋巴瘤和扩散的大B细胞淋巴瘤（DLBCL） bcl2。结果表明，这些淋巴瘤不需要Bcl2才能继续生存，揭示了 关于淋巴瘤用来保护自己免受凋亡的知识的显着差距。最近，我们做了 意想不到的发现是一个未经探索的抗凋亡BCL2家庭成员BCLW的发现 在精子发生中很重要，在六种不同类型的B细胞淋巴瘤中过表达 卵泡淋巴瘤和DLBCL。我们确定含有较高水平BCLW的DLBCL患者的患者 降低的存活率，在高级卵泡淋巴瘤中，BCLW比BCL2高度表达。我们 还表明BCLW对于Burkitt淋巴瘤细胞的存活是必要的，并且BCLW水平升高 提供了对靶向三个抗凋亡BCL2家族的抑制剂的抗伯基特淋巴瘤细胞的抗性 成员。因此，我们假设BCLW过表达对于多种类型B的存活是必要的 细胞淋巴瘤并赋予对淋巴瘤细胞对Venetoclax和其他BCL2家族抑制剂的抗性。我们 提出了两个旨在检验这一假设的目标。在AIM 1中，我们建议评估BCLW的要求 与其他BCL2家族成员的关系以及其过表达的机制的不同B细胞淋巴瘤。 在AIM 2中，我们建议确定BCLW对抗凋亡BCL2抑制剂的抗性的贡献 家庭成员和克服这种抵抗的方法。这些目标的完成将大大增加 对BCL2蛋白质家族的知识以及BCLW对B细胞淋巴瘤的贡献以及对 BCL2家族成员的靶向抑制剂。结果也可能导致改善淋巴瘤临床试验， 具有基于知识的治疗组合的诊断，预后和治疗干预措施。