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

大约30%的弥漫性大B细胞淋巴瘤共表达高水平的Myc和Bcl2 蛋白质(Myc+/Bcl2+DLBCL)，在接受标准化疗时预后较差 养生法。因此，Myc+/Bcl2+表达定义了DLBCL患者的一个子集，其明显的未满足 医疗需要。这个项目的目标是开发新的基于机制的治疗方法来提高治愈率。 Myc+/Bcl2+DLBCL患者。为了做到这一点，我们将利用我们的 Myc和Bcl2，Myc和激活的PI3K之间的致癌合作的小组和其他人 可以通过新的有针对性的方法来利用的途径。随着药物的发展，可以直接 抑制Myc蛋白仍然具有挑战性，我们将研究替代方法，包括针对Myc 使用HDAC抑制剂和溴域抑制剂转录，或使用抑制剂Myc翻译 MTORC1和eIF4A RNA解旋酶。在目标1中，我们将研究蛋白质翻译对 MYC/Bcl2在DLBCL中的表达在目标2中，我们将进行临床前实验，以开发新的 Myc+/Bcl2+DLBCL的机制治疗策略在目标3中，我们会进行第一阶段/第二阶段的研究 根据AIMS 1和2开发的新疗法用于评估Myc+/Bcl2+患者的安全性和有效性 DLBCL。

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.