Co-regulation of p53 and PD-L1 by the VPRBP-USP2 axis in transcription and ubiquitylation

VPRBP-USP2 轴在转录和泛素化中共同调控 p53 和 PD-L1

• 批准号: 10439098
• 负责人: Wei Gu
• 金额: $ 46.84万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-08 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439098
• 关键词: Acetylation; Animal Model; Antibodies; Antibody Therapy; Attenuated; C-terminal; Cancer Patient; Cell Survival; Cell-Mediated Cytolysis; Clinical Data; Clinical Research; Cytotoxic T-Lymphocytes; Data; Development; Dose-Limiting; Event; Genes; Genetic Transcription; Human; Immune; Immunologic Surveillance; In Vitro; Knock-out; Ligands; MDM2 gene; Malignant Neoplasms; Mediating; Molecular; Mus; Mutate; Normal tissue morphology; Nude Mice; Pathway interactions; Patients; Peptides; Regulation; Role; Signal Transduction; T-Lymphocyte; TP53 gene; Therapeutic; Thinking; Toxic effect; Tumor Immunity; Tumor Suppression; Up-Regulation; Yang; anti-PD-1; anti-PD1 antibodies; antitumor effect; attenuation; cancer cell; cancer therapy; dosage; gene repression; immune checkpoint; improved; in vivo; inhibitor; insight; knock-down; mouse model; neoplastic cell; novel; overexpression; patient stratification; prevent; programmed cell death ligand 1; programmed cell death protein 1; receptor; side effect; small molecular inhibitor; small molecule inhibitor; success; therapeutic target; therapeutically effective; tissue culture; tumor; tumor growth; tumorigenesis; ubiquitin-protein ligase

Although p53 is frequently mutated in almost 50% of human cancers, many human tumors retain wild-type p53 but its activities are downregulated through multiple mechanisms. For example, Mdm2 is a key repressor of p53 by acting as a major E3 ligase for ubiquitylation-mediated degradation. Inhibition of Mdm2 is well accepted as a validated approach for the treatment of human cancers retaining wild-type p53 by reactivating the p53 tumor suppressor function. Nevertheless, despite of intense efforts in developing highly potent Mdm2 inhibitors, none of them has been approved therapeutically very effective because of the toxicity of these inhibitors in vivo. To overcoming this major issue, it is necessary to search for a candidate by thinking about a ‘out of box’ strategy. In this application, we identify the VPRBP-USP2 axis as such a candidate. Like Mdm2, VPRBP can suppress p53 function by both transcriptional repression and ubiquitylation-mediated degradation. Interestingly, unlike Mdm2, VPRBP acts as a master regulator of PD-L1.Moreover, the stability of VPRBP is tightly control by USP2. Blocking the PD-L1/PD-1 pathway has been shown remarkable anti-tumor effects in cancer patients. Interestingly, clinical studies demonstrated that the success of PD1–PD-L1 blockade by either anti-PD1 or anti-PD-L1 antibody has a positive correlation with PD-L1 expression levels in tumor cells. Thus, although high levels of PD-L1 prevents cytotoxic T cells from effectively targeting tumor cells, it apparently also serves as a potential selective marker for patient stratification for PD1–PD-L1 blockade therapy. Strikingly, our preliminary studies showed that combining VPRBP knockdown/or USP2 inhibitors with an anti-PD-1 antibody treatment dramatically enhanced tumor growth suppression in the immune-proficient mice bearing the tumors expressing wild type p53. Notably, unlike Mdm2, knockout of the USP2 gene has no obvious effect on normal development or cell viability in normal tissues. These data suggest that USP2 is a promising therapeutic target for activating p53-mediated tumor suppressive effects in human cancers without causing severe toxicity to normal tissues. Thus, it is very important to dissect the precise mechanism of the VPRBP-USP2 axis in regulating both p53 and PD-L1 in human cancers and provide critical insights into potential cancer treatment. In Aim1, we will elucidate the molecular mechanism of the VPRBP/USP2 axis in regulating p53 and PD-L1 through transcription repression and the ubiquitylation pathway. In Aim 2, will examine whether the combination of USP2 inhibitors (or VPRBP knockdown) with the anti-PD-1 treatment is able to significantly improve the efficacy in p53-mediated tumor growth suppression in vivo by triggering anti-tumor immunity without cause severe toxicity.

尽管 p53 在近 50% 的人类癌症中经常发生突变，但许多人类肿瘤 保留野生型 p53，但其活性通过多种机制下调。例如， Mdm2 是 p53 的关键抑制因子，可作为泛素化介导的主要 E3 连接酶 降解。 Mdm2 的抑制作为治疗人类疾病的有效方法被广泛接受 通过重新激活 p53 肿瘤抑制功能来保留野生型 p53 的癌症。尽管如此， 尽管人们在开发高效 Mdm2 抑制剂方面付出了巨大的努力，但它们都还没有被开发出来。 由于这些抑制剂在体内的毒性，被批准在治疗上非常有效。到 为了克服这个重大问题，有必要通过“开箱即用”的方式来寻找候选人 战略。在此应用中，我们将 VPRBP-USP2 轴确定为此类候选轴。像Mdm2一样， VPRBP 可以通过转录抑制和泛素化介导抑制 p53 功能 降解。有趣的是，与 Mdm2 不同，VPRBP 充当 PD-L1 的主调节因子。 VPRBP 的稳定性受到 USP2 的严格控制。已显示阻断 PD-L1/PD-1 通路 对癌症患者有显着的抗肿瘤作用。有趣的是，临床研究表明， 抗 PD1 或抗 PD-L1 抗体成功阻断 PD1–PD-L1 呈正相关 与肿瘤细胞中 PD-L1 的表达水平相关。因此，尽管高水平的 PD-L1 可以防止细胞毒性 来自有效靶向肿瘤细胞的 T 细胞，它显然也可以作为潜在的选择标记 用于 PD1-PD-L1 阻断治疗的患者分层。引人注目的是，我们的初步研究表明 将 VPRBP 敲低/或 USP2 抑制剂与抗 PD-1 抗体治疗相结合 显着增强免疫功能强大的携带肿瘤小鼠的肿瘤生长抑制 表达野生型p53。值得注意的是，与Mdm2不同的是，敲除USP2基因并没有明显的影响 正常组织中的正常发育或细胞活力。这些数据表明 USP2 是 激活 p53 介导的人类肿瘤抑制作用的有前景的治疗靶点 癌症而不会对正常组织造成严重毒性。因此，剖析非常重要 VPRBP-USP2轴在人类癌症中调节p53和PD-L1的精确机制 并为潜在的癌症治疗提供重要见解。在Aim1中，我们将阐明分子 VPRBP/USP2轴通过转录抑制调节p53和PD-L1的机制 和泛素化途径。在目标 2 中，将检查 USP2 抑制剂的组合是否 （或 VPRBP 敲低）联合抗 PD-1 治疗能够显着提高疗效 p53 通过无故触发抗肿瘤免疫来抑制体内肿瘤生长 严重毒性。