P- 3: Potentiating Proteasome Inhibitor Activity in NHL

蛋白酶体抑制剂 (Pis)，例如硼替佐米 (Btzmb)，通过以下方式诱导肿瘤细胞凋亡： 多种机制，包括 NF-KB 激活、氧化损伤诱导、内质网应激促进等 其他人。 Btzmb 在多发性骨髓瘤和几种类型的非霍奇金淋巴瘤中表现出显着的活性 （NHL），促进了第二代蛋白酶体抑制剂（例如 PR-171）的开发，这可能 与 Btzmb 相比，具有优越的 PK/PD 特性。然而，需要提高 NHL 中的 PI 活性 持续存在。我们实验室的最新证据表明，将 Pis 与其他临床相关的药物相结合 靶向药物，包括 HDAC 或小分子 Bcl-2 抑制剂，可协同诱导 NHL 细胞系中的细胞凋亡。该项目的目标是利用弥漫性大 B 细胞淋巴瘤来阐明 (DLBCL) 模型，PR-171 和这些其他靶向药物之间的协同机制，扩展了这些 体内模型系统的发现，确定基于实验室的反应决定因素，并使用它 在难治性 NHL 患者中启动新型组合 I 期试验的信息。在具体目标#1 中，我们 将确定 NHL 细胞中 Pis 和 HDAC 抑制剂（伏立诺他）之间的协同作用是否反映了 NF-KB 破坏、诱导氧化损伤、内质网应激或这些因素的组合。在具体目标#2 中，我们 将确定 Pis 和小分子 Bcl-2 抑制剂（例如 GX15-070）之间是否存在协同作用 氧化损伤、应激相关信号通路激活和/或 Bak 和 Bax 激活。我们会 还确定 a) 这些方法是否对 Btzmb 耐药的 DLBCL 细胞有效； b) 哪一个 这些单独的策略可能最适合特定的 DLBCL 亚型，即生发中心 (GC) 与激活的 B 细胞 (ABC) 相比。在具体目标#3中，我们将把这些发现扩展到异种移植 DLBCL 模型 系统，并确定协同作用的体外决定因素在体内是否有效。在具体目标#4中， 我们将选择目标#1-3中最有希望的方案作为一个或多个第一阶段的方案 将 Pis 与 HDAC 或小分子 Bcl-2 抑制剂联合治疗难治性 NHL 患者的试验。我们会 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记。预计这些研究将为 针对难治性 NHL 患者的新颖且可能更有效的基于 Pi 的策略。

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.