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: 10588175
• 负责人: Wei Gu
• 金额: $ 45.9万
• 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/10588175
• 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; Probability; Repression; Role; Signal Transduction; T-Cell Activation; T-Lymphocyte; TP53 gene; Therapeutic; Thinking; Toxic effect; Tumor Immunity; Tumor Suppression; Up-Regulation; 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 isopeptidase; 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.

尽管在几乎50%的人类癌症中，p53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是泛素化介导的主要E3连接酶，是P53的关键抑制因子 退化。抑制MDM2被广泛接受为治疗人类癌症的有效方法 通过重新激活P53肿瘤抑制功能而保留野生型P53的癌症。不过， 尽管在开发高度有效的MDM2抑制剂方面付出了巨大的努力，但没有一种是成功的 批准的治疗非常有效，因为这些抑制剂在体内的毒性。至 要克服这一重大问题，有必要通过考虑“开箱即用”来寻找候选人 策略。在本应用程序中，我们将VPRBP-USP2轴确定为这样的候选轴。就像MDM2一样， VPRBP通过转录抑制和泛素化介导抑制P53功能 退化。有趣的是，与MDM2不同，VPRBP充当PD-L1的主调节器。此外， VPRBP的稳定性受到USP2的严格控制。阻断PD-L1/PD-1通路已被证明 对癌症患者有显著的抗肿瘤作用。有趣的是，临床研究表明， 抗PD1和抗PD-L1抗体阻断PD1-PD-L1的成功与否呈正相关 肿瘤细胞中PD-L1的表达水平。因此，尽管高水平的PD-L1阻止了细胞毒性 T细胞有效地靶向肿瘤细胞，显然它也是一个潜在的选择性标记 对患者进行PD1-PD-L1分层阻断治疗。令人惊讶的是，我们的初步研究表明 将VPRBP基因敲除/或USP2抑制剂与抗PD-1抗体治疗相结合 显著增强免疫熟练荷瘤小鼠的肿瘤生长抑制 野生型P53的表达。值得注意的是，与MDM2不同，敲除USP2基因没有明显的影响 在正常组织中的正常发育或细胞活力。这些数据表明，USP2是一个 激活p53介导的人肿瘤抑制作用的有希望的治疗靶点 不会对正常组织造成严重毒性的癌症。因此，剖析 VPRBP-USP2轴在人类肿瘤中同时调节P53和PD-L1的精确机制 并为潜在的癌症治疗提供关键的见解。在Aim1中，我们将阐明分子 VPRBP/USP2轴通过转录抑制调控P53和PD-L1的机制 泛素化途径。在目标2中，将检查USP2抑制剂的组合是否 (或VPRBP基因敲除)与抗PD-1治疗能够显著提高疗效 无缘无故激发抗肿瘤免疫抑制P53体内肿瘤生长 严重的毒性。