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: 9813626
• 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/9813626
• 关键词: Adverse effects; BCL1 Oncogene; BCL2 gene; Binding; Blood Platelets; Cancer cell line; Cells; Chemotherapy-Oncologic Procedure; Chimera organism; 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; Proteins; Proteolysis; Radiation; 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.

项目摘要/摘要 作为对NCI PQ9的响应，我们建议产生针对嵌合体的血小板保留的bclxl蛋白水解酶 (PROTAC)或BCL-XL-Ps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，已被确定为最重要的药物 人PC细胞中的耐药基因。强效bclxl选择性抑制物及bclxl和bcl2双重抑制物 例如ABT263(或Navitoclax)。然而，靶向和剂量限制 这些抑制物的血小板减少症阻碍了它们的临床翻译，因为血小板仅依赖于 BCL-XL代表生存。我们假设，我们可以通过以下方式绕过bclxl抑制引起的血小板毒性 将ABT-263转化为靶向BCL-XL的BCL-XL-Ps为在血小板中低表达的E3连接酶 泛素化和降解，因为BCL-XL-Ps依赖E3连接酶促进BCL-XL泛素化 以及泛素蛋白酶体系统(UPS)的降解。这一假设得到了我们初步的支持 数据表明，我们新生成的针对BCL-XL的BCL-XL-Ps针对Cereblon(CRBN)或von Hippel-Lindau(VHL)E3连接酶，能够在被检测的各种癌细胞中降解bclxl，但 对人血小板bcl-xl水平的影响很小，因为血小板表达显著较低水平的 CRBN和VHL比这些癌细胞强。因此，这些BCL-XL-P对依赖BCL-XL的作用更强 但在体外对血小板的毒性明显低于ABT263。与ABT-263相比， 我们的一种主要的bcl-xl-Ps在许多异种小鼠模型中显示出更好的抗肿瘤活性。 而不会导致血小板减少。此外，我们还发现，从ABT263转化而来的BCL-XL-Ps可以 特异性地降解bclxl，但不能降解bcl2，表明该转换增强了ABT263的特异性。它 BCL-XL的抑制可以使肿瘤细胞对化疗敏感，而BCL-2的抑制 通过抑制粒细胞生成而加重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-Ps可以潜在地降低ABT263的另一种靶向毒性，即中性粒细胞减少，这是剂量限制的 并阻止ABT263与标准护理细胞毒化疗药物的联合治疗 癌症。此外，我们的BCL-XL-Ps也是有效的感光剂，可以选择性地杀死衰老细胞 化疗和放疗诱导的小细胞肺癌(SNCs)，因为SNCs也依赖bclxl生存。净空 化疗诱导的SNCs有可能提高标准护理的治疗效果 化疗，因为SNCs在介导许多不良反应的诱导中发挥重要作用 化疗药物以及促进癌症化疗耐药、复发和转移，部分通过 衰老相关分泌表型(SASP)的表达。总而言之，这些发现表明 BCL-XL-Ps作为一种新型抑制剂，优于传统的BCL-2/BCL-XL双重抑制剂和BCL-XL选择性抑制剂 抗肿瘤和抗衰老药物。基于这些有希望的初步数据，我们计划进行以下工作 具体目标：1)设计和合成新的bcl-xL-Ps，其抗肿瘤和感光活性增强，但 降低靶上毒性；2)评价其抗肿瘤和抗衰老活性以及靶上和靶外毒性 3)检测bcl-xL-Ps铅能否提高小鼠卵巢癌的治疗效果。 PC用吉西他滨。抗血小板bc1-xL-Ps的开发有可能改变治疗方法 BCL-XL依赖实体瘤和血液系统恶性肿瘤并显著提高实体瘤的治疗水平 PC等肿瘤经化疗。