P-3: Potentiating Proteasome Inhibitor Activity in non-Hodgkin's Lymphoma (NHL)

蛋白酶体抑制剂（Pis）如硼替佐米（Btzmb）通过以下途径诱导肿瘤细胞的凋亡： 多种机制，包括NF-κ B活化，氧化损伤诱导，ER应激促进， 他人Btzmb在多发性骨髓瘤和几种类型的非霍奇金淋巴瘤中显示出显著的活性 (NHL)，促进了第二代蛋白酶体抑制剂的开发（例如，PR-171）， 与Btzmb相比，具有上级PK/PD特征。然而，需要提高NHL中PI活性， 持续存在。我们实验室的最新证据表明，将Pis与其他临床相关 靶向药物，包括HDAC或小分子Bcl-2抑制剂， NHL细胞系的凋亡。这个项目的目标是阐明，使用弥漫性大B细胞淋巴瘤 在DLBCL模型中，PR-171和这些其他靶向剂之间的协同作用机制，扩展了这些机制。 研究结果在体内模型系统，确定基于实验室的反应决定因素，并使用此 在难治性NHL患者中启动新型联合I期试验的信息。具体目标#1，我们 将确定NHL细胞中PI和HDAC抑制剂（伏立诺他）之间的协同作用是否反映NF-κ B 破坏、诱导氧化损伤、ER应激或这些因素的组合。在具体目标#2中， 将确定PI和小分子Bcl-2抑制剂（例如GX 15 -070）之间的协同作用是否会停止 氧化损伤、应激相关信号通路的活化和/或巴克和Bax活化。我们将 还确定a）这些方法在Btzmb-resistant DLBCL细胞中是否有效;和B） 这些单独的策略可能最适合于特定的DLBCL亚型即，生发中心 与活化B细胞（ABC）相比。在特定目标#3中，我们将这些发现扩展到异种移植DLBCL模型 系统，并确定是否在体外协同作用的决定因素是在体内工作。具体目标#4 我们将从目标1 -3中选择最有希望的方案，作为一个或多个第一阶段的方案来实施 在难治性NHL患者中联合PI与HDAC或小分子Bcl-2抑制剂的试验。我们将 还进行相关的实验室研究，以验证体内协同作用的机制，并确定 疾病反应性的替代标志物。预计这些研究将奠定基础， 新的和潜在的更有效的PI为基础的策略在难治性NHL患者。

Proteasome inhibitors (Pis) such as Bortezomib (Btzmb), induce apoptosis in neoplastic cells through multiple mechanisms, including NF-KB activation, oxidative injury induction, an ER stress promotion, among others. Btzmb displays marked activity in multiple myeloma, and several types of non-Hodgkin's lymphoma (NHL), prompting the development of second generation proteasome inhibitors (e.g., PR-171) which may have superior PK/PD characteristics compared to Btzmb. However, the need to improve PI activity in NHL persists. Recent evidence from our laboratory suggests that combining Pis with other clinically relevant targeted agents, including HDAC or small molecule Bcl-2 inhibitors results in synergistic induction of apoptosis in NHL cell lines. The goal of this project is to elucidate, using a diffuse large B-cell lymphoma (DLBCL) model, mechanisms of synergism between PR-171 and these other targeted agents, extend these findings to an in vivo model system, identify laboratory-based response determinants, and use this information to initiate novel combination Phase I trials in patients with refractory NHL. In Specific Aim #1, we will determine whether synergism between Pis and HDAC inhibitors (vorinostat) in NHL cells reflects NF-KB disruption, induction of oxidative injury, ER stress, or a combination of these factors. In Specific Aim #2, we will determine whether synergism between Pis and small molecule Bcl-2 inhibitors (e.g. GX15-070) stems from oxidative injury, activation of stress-related signaling pathways, and/or Bak and Bax activation. We will also establish a) whether these approaches are effective in Btzmb-resistant DLBCL cells; and b) which of these individual strategies might be most appropriate for specific DLBCL sub-types i.e., germinal center (GC) versus activated B-cell (ABC). In Specific Aim #3, we will extend these findings to a xenograft DLBCL model system, and determine whether in vitro determinants of synergism are operative in vivo . In Specific Aim #4, we will select the most promising of regimens emanating from Aims #1-3 to pursue as one or more Phase I trials combining Pis with HDAC or small molecule Bcl-2 inhibitors in patients with refractory NHL. We will also conduct correlative laboratory studies to validate mechanisms of in vivo synergism, and identify surrogate markers of disease responsiveness. It is anticipated that these studies will lay the foundation for novel and potentially more effective Pi-based strategies in patients with refractory NHL.