Development of Mechanism-Based Therapy For Myc+/Bcl2+ Diffuse Large B Cell Lymphoma

Myc/Bcl2 弥漫性大 B 细胞淋巴瘤基于机制的治疗方法的开发

• 批准号: 9754070
• 负责人: ANAS YOUNES
• 金额: $ 26.76万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9754070
• 关键词: Adult Non-Hodgkin' s Lymphoma; B-Cell Lymphomas; BCL-2 Protein; Behavior; Biological Markers; Bromodomain; Cell Line; Cell Proliferation; Cell Survival; Cells; Chemotherapy-Oncologic Procedure; Chromosomal translocation; Clinical; Complex; Data; Development; FRAP1 gene; Genetic; Genetic Transcription; Goals; Histologic; Histone Deacetylase; Histone Deacetylase Inhibitor; In Vitro; Incidence; Knowledge; Lymphoma; Lymphomagenesis; MYC Family Protein; Medical; Metabolism; Mutation; Natural Products; Oncogenic; Outcome; PI3K/AKT; Pathway interactions; Patients; Pharmacology; Phase; Play; Prognostic Factor; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; RNA Helicase; Relapse; Reporting; Risk; Role; Safety; Translation Initiation; Translations; Treatment Efficacy; United States; base; cell growth; chemotherapy; drug development; experimental study; first-in-human; improved; inhibitor/antagonist; large cell Diffuse non-Hodgkin' s lymphoma; mTOR Signaling Pathway; new therapeutic target; novel; novel therapeutics; outcome forecast; patient subsets; phase 1 study; phase 2 study; pre-clinical; predictive modeling; protein expression; silvestrol; synergism; therapy development; treatment strategy

Approximately 30% of diffuse large B cell lymphomas (DLBCLs) co-express high levels of Myc and Bcl2 proteins (Myc+/Bcl2+ DLBCL), which confers a poor prognosis when treated with standard chemotherapy regimens. Accordingly, Myc+/Bcl2+ expression defines a subset of patients with DLBCL with a clear unmet medical need. The goal of this project is to develop novel mechanism-based therapy to improve the cure rate of patients with Myc+/Bcl2+ DLBCL. To do that, we will capitalize on the recent knowledge reported by our group and others demonstrating oncogenic cooperation between Myc and Bcl2, and Myc and activated PI3K pathway that can be exploited by novel targeted approaches. As the development of drugs that can directly inhibit Myc protein remains challenging, we will examine alternative approaches, including targeting Myc transcription using HDAC inhibitors and bromodomain inhibitors, or Myc translation using inhibitors of mTORC1 and the eIF4A RNA helicase. In Aim 1, we will investigate the contribution of protein translation to Myc/Bcl2 expression In DLBCL. In Aim 2, we will perform preclinical experiments to develop novel mechanism-based treatment strategies for Myc+/Bcl2+ DLBCL. In Aim 3, we will conduct phase I/II studies of novel therapies developed from Aims 1 and 2 to evaluate their safety and efficacy in patients with Myc+/Bcl2+ DLBCL.

大约30％的扩散大B细胞淋巴瘤（DLBCLS）共表达高水平的MYC和BCL2 蛋白质（MYC+/BCL2+ DLBCL），用标准化疗治疗后，预后不良 方案。因此，myc+/bcl2+表达表达式定义了DLBCL患者的子集 医疗需求。该项目的目的是开发基于机制的新型治疗以提高治愈率 MYC+/BCL2+ DLBCL的患者。为此，我们将利用我们的最新知识 小组和其他人在MYC和BCL2之间以及MYC和激活的PI3K之间表现出致癌合作 可以通过新颖的目标方法利用的途径。作为可以直接的药物的开发 抑制MYC蛋白仍然具有挑战性，我们将检查替代方法，包括针对MYC 使用HDAC抑制剂和溴结构域抑制剂或使用抑制剂的MYC翻译转录 MTORC1和EIF4A RNA解旋酶。在AIM 1中，我们将研究蛋白质翻译对 DLBCL中的MYC/BCL2表达。在AIM 2中，我们将执行临床前实验以发展新颖 MYC+/BCL2+ DLBCL的基于机制的治疗策略。在AIM 3中，我们将进行I/II期研究 从目标1和2开发出新的疗法，以评估其在MYC+/BCL2+患者中的安全性和功效 DLBCL。