Use of BCL-xL Proteolysis targeting chimeras to treat pancreatic cancer

使用 BCL-xL 蛋白水解靶向嵌合体治疗胰腺癌

• 批准号: 10005295
• 负责人: Jose G Trevino
• 金额: $ 52.57万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005295
• 关键词: Adverse effects; BCL1 Oncogene; BCL2 gene; Binding; Blood Platelets; Cancer cell line; Cells; Chemotherapy and/or radiation; Chemotherapy-Oncologic Procedure; Data; Development; Dose-Limiting; Drug resistance; Exhibits; Generations; Granulopoiesis; Hematologic Neoplasms; Human; In Vitro; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Neoplasm Metastasis; Neutropenia; Patients; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Protac; Proteins; Relapse; Role; Solid Neoplasm; Specificity; System; Technology; Thrombocytopenia; Tissues; Toxic effect; Transgenic Mice; Treatment Efficacy; Ubiquitin; Ubiquitination; Xenograft Model; Xenograft procedure; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; clinical translation; cytotoxic; design; differential expression; functional group; gemcitabine; improved; in vivo; inhibitor/antagonist; innovation; mouse model; multicatalytic endopeptidase complex; neoplastic cell; novel; novel strategies; pancreatic cancer cells; prevent; resistance gene; response; senescence; standard of care; tumor xenograft; ubiquitin-protein ligase

PROJECT SUMMARY / ABSTRACT In response to NCI PQ9, we propose to generate platelet-sparing BCL-XL Proteolysis Targeting Chimeras (PROTACs) or BCL-XL-Ps for the treatment of cancer, particularly pancreatic cancer (PC), because BCL-XL is one of the most important and best validated cancer targets and has been identified as the most important drug resistance gene in human PC cells. Potent BCL-XL selective inhibitors and BCL-XL and BCL-2 dual inhibitors such as ABT263 (or navitoclax) have been developed. However, the on-target and dose-limiting thrombocytopenia of these inhibitors has hampered their clinical translation because platelets solely depend on BCL-XL for survival. We hypothesize that we can circumvent BCL-XL inhibition-induced platelet toxicity by converting ABT-263 into BCL-XL-Ps that target BCL-XL to an E3 ligase poorly expressed in platelets for ubiquitination and degradation, because BCL-XL-Ps depend on the E3 ligase to promote BCL-XL ubiquitination and degradation by the ubiquitin proteasome system (UPS). This hypothesis is supported by our preliminary data demonstrating that our newly generated BCL-XL-Ps, which target BCL-XL to the cereblon (CRBN) or von Hippel-Lindau (VHL) E3 ligase, are capable of degrading BCL-XL in various cancer cells examined but have minimal effects on the BCL-XL levels in human platelets, because platelets express significantly lower levels of CRBN and VHL than these cancer cells. As such, these BCL-XL-Ps are more potent against BCL-XL dependent human cancer cell lines but significantly less toxic to platelets than ABT263 in vitro. Compared with ABT-263, one of our lead BCL-XL-Ps exhibited improved antitumor activities in a number of xenograft mouse models without causing thrombocytopenia. In addition, we found that the BCL-XL-Ps converted from ABT263 can specifically degrade BCL-XL but not BCL-2, indicating that the conversion increased the specificity of ABT263. It is well established that inhibition of BCL-XL can sensitize tumor cells to chemotherapy, whereas BCL-2 inhibition exacerbates chemotherapy-induced neutropenia by suppressing granulopoiesis. Thus, this increased specificity of BCL-XL-Ps can potentially reduce another on-target toxicity of ABT263, i.e. neutropenia, which is dose-limiting and prevents the combination of ABT263 with a standard-of-care cytotoxic chemotherapeutic agent to treat cancer. Furthermore, our BCL-XL-Ps are also potent senolytic agents that can selectively kill senescent cells (SnCs) induced by chemotherapy and radiation, because SnCs also rely on BCL-XL for survival. Clearance of chemotherapy-induced SnCs has the potential to improve the therapeutic efficacy of standard-of-care chemotherapy, because SnCs play an important role in mediating the induction of many adverse effects of chemotherapeutic drugs as well as promoting cancer chemoresistance, relapse and metastasis, in part via expression of the senescence-associated secretory phenotype (SASP). Collectively, these findings suggest that BCL-XL-Ps are superior to conventional BCL-2/BCL-XL dual inhibitors and BCL-XL selective inhibitors as novel antitumor and senolytic agents. Based on these promising preliminary data, we plan to pursue the following specific aims: 1) Design and synthesize new BCL-XL-Ps with improved antitumor and senolytic activities but reduced on-target toxicities; 2) Evaluate the antitumor and senolytic activities and on- and off-target toxicities of lead BCL-XL-Ps in vivo; 3) Determine whether lead BCL-XL-Ps can improve the therapeutic efficacy of gemcitabine for PC. Development of platelet-sparing BCL-XL-Ps has the potential to transform the treatment of BCL-XL-dependent solid tumors and hematological malignancies and dramatically improve the treatment of solid tumors such as PC by chemotherapy.

项目概要/摘要 为了响应 NCI PQ9，我们建议生成保留血小板的 BCL-XL 蛋白水解靶向嵌合体 (PROTAC) 或 BCL-XL-P 用于治疗癌症，特别是胰腺癌 (PC)，因为 BCL-XL 是 最重要和最有效的癌症靶点之一，并已被确定为最重要的药物 人类 PC 细胞中的抗性基因。强效 BCL-XL 选择性抑制剂以及 BCL-XL 和 BCL-2 双重抑制剂 例如ABT263（或navitoclax）已经被开发出来。然而，目标和剂量限制 这些抑制剂的血小板减少症阻碍了它们的临床转化，因为血小板仅依赖于 BCL-XL 用于生存。我们假设我们可以通过以下方式规避 BCL-XL 抑制引起的血小板毒性： 将 ABT-263 转化为 BCL-XL-P，将 BCL-XL 靶向血小板中表达不佳的 E3 连接酶 泛素化和降解，因为 BCL-XL-Ps 依赖 E3 连接酶来促进 BCL-XL 泛素化 以及泛素蛋白酶体系统 (UPS) 的降解。这个假设得到了我们初步的支持 数据表明我们新生成的 BCL-XL-P，其将 BCL-XL 靶向 cereblon (CRBN) 或 von Hippel-Lindau (VHL) E3 连接酶能够在所检查的各种癌细胞中降解 BCL-XL，但 对人类血小板中 BCL-XL 水平的影响最小，因为血小板表达的 BCL-XL 水平显着降低 CRBN和VHL比这些癌细胞更重要。因此，这些 BCL-XL-P 对抗 BCL-XL 依赖性的药物更有效。 人类癌细胞系，但在体外对血小板的毒性明显低于 ABT263。与ABT-263相比， 我们的一种领先 BCL-XL-P 在许多异种移植小鼠模型中表现出改善的抗肿瘤活性 而不引起血小板减少症。此外，我们发现从 ABT263 转化而来的 BCL-XL-P 可以 特异性降解 BCL-XL 但不降解 BCL-2，表明该转化增加了 ABT263 的特异性。它 众所周知，抑制 BCL-XL 可以使肿瘤细胞对化疗敏感，而抑制 BCL-2 通过抑制粒细胞生成加剧化疗引起的中性粒细胞减少症。因此，这种增加的特异性 BCL-XL-P 可能会降低 ABT263 的另一种靶向毒性，即中性粒细胞减少症，这是剂量限制性的 并防止 ABT263 与标准护理细胞毒性化疗药物联合治疗 癌症。此外，我们的 BCL-XL-P 也是有效的衰老剂，可以选择性杀死衰老细胞 (SnCs) 由化疗和放疗诱导，因为 SnCs 也依赖 BCL-XL 生存。清关 化疗诱导的 SnCs 有潜力提高标准护理的治疗效果 化疗，因为 SnCs 在介导化疗的许多不良反应中发挥着重要作用 化疗药物以及促进癌症化疗耐药、复发和转移，部分是通过 衰老相关分泌表型（SASP）的表达。总的来说，这些发现表明 BCL-XL-Ps 优于传统的 BCL-2/BCL-XL 双重抑制剂和 BCL-XL 选择性抑制剂，是一种新型抑制剂 抗肿瘤剂和抗衰老剂。基于这些有希望的初步数据，我们计划采取以下措施 具体目标： 1) 设计和合成具有改进的抗肿瘤和抗衰老活性的新 BCL-XL-P，但 降低目标毒性； 2) 评估抗肿瘤和衰老活性以及靶向和脱靶毒性 体内先导 BCL-XL-P； 3) 确定先导BCL-XL-Ps是否可以提高治疗效果 吉西他滨 PC 版。血小板保留 BCL-XL-P 的开发有可能改变以下疾病的治疗 BCL-XL依赖性实体瘤和血液系统恶性肿瘤，并显着改善实体瘤的治疗 肿瘤如PC通过化疗。