Signature-guided therapy for mismatch repair defective cancers

特征引导治疗错配修复缺陷型癌症

基本信息

批准号：
10215252
负责人：
Shiaw-Yih Lin
金额：
$ 37.33万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10215252
关键词：
Adjuvant Adjuvant Chemotherapy Affect Base Pair Mismatch Biological Models CRISPR/Cas technology Cell Line Cell Survival Cells Clinical Trials Colon Colon Carcinoma Colorectal Cancer Combined Modality Therapy DNA DNA biosynthesis DNA-Directed DNA Polymerase Data Defect Development Disease Effectiveness Endometrial Endometrial Carcinoma Endometrioid Carcinoma Endoplasmic Reticulum Enzymes Gene Expression Goals Hereditary Nonpolyposis Colorectal Neoplasms Human Immunotherapy In Vitro Individual Infiltration Inflammatory Inflammatory Response Inherited Knock-out Knowledge Large Intestine Carcinoma Lead Malignant Epithelial Cell Malignant Neoplasms Microsatellite Instability Microsatellite Repeats Mismatch Repair Mismatch Repair Deficiency Mus Mutation Pathway interactions Patients Pharmaceutical Preparations Phenotype Proteins Refractory Resistance Sampling Stress System Testing Therapeutic Effect Treatment Efficacy Tumor Suppressor Proteins Tumor Tissue Tumor-Infiltrating Lymphocytes Tumorigenicity Ubiquitin Ubiquitination Xenograft procedure anti-PD-1 anti-PD1 antibodies base cancer cell checkpoint therapy chemotherapeutic agent cytokine drug candidate early onset colon cancer endoplasmic reticulum stress genetic signature improved in vivo inhibitor/antagonist insertion/deletion mutation misfolded protein mouse model multicatalytic endopeptidase complex mutant neoplastic cell novel novel therapeutics objective response rate patient derived xenograft model prevent programmed cell death protein 1 protein aggregation proteotoxicity recruit repaired subcutaneous tumor tumor xenograft

项目摘要

Single base pair mismatches, and indels of between 1-4 base pair mismatches, occur during DNA replication when DNA polymerase’s proofreading abilities are compromised. These errors are repaired via an intact mismatch repair (MMR) pathway. Deficiencies in DNA MMR are associated with somatic cancers, including endometrial (30%) and colorectal cancers (15-17%), and in various germline diseases that predispose individuals to cancer development. MMR defect (MMRD) endometrial and colorectal cancers are highly resistant to conventional adjuvant chemotherapy and thus novel therapies are urgently needed for the treatment of MMRD cancers. To this end, we have generated a robust gene signature that can faithfully predict MMRD cancer, and based on this signature, we further identified MLN4924 as an effective drug that diminishes cell viability of MMRD cells in vitro and in vivo. MLN4924 is a NEDD8 Activating Enzyme E1 Subunit 1 (NAE1) inhibitor, which prevents ned-dylation of tumor suppressors. Similar to ubiquitination, the addition of a NEDD8 moiety to protein substrates targets them for degradation via the proteasome. Intriguingly, we found that global neddylation increases in MMRD versus MMR intact endometrioid and colon carcinoma cell lines, which is suppressed with MLN4924 treatment. These data suggest that a high mutational burden in MMRD cancer cells may lead to the excessive aggregation of misfolded mutant proteins and elevated proteotoxic stress levels in MMRD cancers; MLN4924 further increases proteotoxic stress and kills MMRD cancer cells. Moreover, because proteotoxic stress induces pro-inflammatory responses, MLN4924 may enhance the immune checkpoint therapies that have been heavily investigated for the treatment of MMRD colorectal cancer. All of these promising findings strongly support the hypothesis that MLN4924 can specifically target MMRD cancers by increasing proteotoxic stress, thereby potentiating the pro-inflammatory response and enhancing the effects of PD-1 immunotherapy. These hypotheses will be tested via three specific aims: (1) to determine if MLN4924 treatment will inhibit the tumorigenicity of MMRD patient-derived xenografts (PDX) in colon and endometrioid carcinomas. We will establish both subcutaneous and orthotopic endometrioid and colon PDX models to critically evaluate the therapeutic effect of MLN4924 on MMRD cancers; (2) to determine the underlying mechanisms for the therapeutic efficacy of MLN4924 inhibition in MMRD cancers. We will investigate how MLN4924 mechanistically kills MMRD cancer cells; and (3) to determine if MLN4924 will potentiate the effects of PD-1 immunotherapy in MMRD tumors. We will establish syngeneic endometrial and colon mouse models to evaluate the monotherapies and combination therapies using MLN4924 and an anti-mouse PD-1 antibody. All of the proposed studies will lead to the development of novel and effective MLN4924-based mono- and combination therapies to effectively treat MMRD cancers.

DNA 复制过程中，当 DNA 聚合酶的校对能力受到损害时，会发生单碱基对错配和 1-4 个碱基对错配的插入缺失。这些错误可通过完整的错配修复 (MMR) 途径进行修复。DNA MMR 缺陷与体细胞相关。癌症，包括子宫内膜癌 (30%) 和结直肠癌 (15-17%)，以及导致个体易患癌症 MMR 缺陷的各种种系疾病。 (MMRD) 子宫内膜癌和结直肠癌对传统辅助化疗具有高度耐药性，因此迫切需要新的疗法来治疗 MMRD 癌症。为此，我们生成了可以忠实预测 MMRD 癌症的强大基因特征。签名，我们进一步确定 MLN4924 是一种有效的药物，可在体外和体内降低 MMRD 细胞的细胞活力。 MLN4924 是一种 NEDD8 激活酶 E1。亚基 1 (NAE1) 抑制剂，可防止肿瘤抑制因子的 neddy 化，与泛素化类似，在蛋白质底物中添加 NEDD8 部分可靶向它们通过蛋白酶体降解。有趣的是，我们发现 MMRD 与完整 MMR 相比，整体 neddy 化增加。子宫内膜样癌细胞系和结肠癌细胞系，MLN4924 治疗可抑制这些细胞系，这些数据表明 MMRD 癌细胞中存在高突变负荷。可能导致 MMRD 癌症中错误折叠突变蛋白的过度聚集和蛋白毒性应激水平升高；此外，由于蛋白毒性应激会诱导促炎症反应，因此 MLN4924 可能会增强免疫检查点疗法。所有这些有希望的发现都强烈支持这样的假设：MLN4924 可以特异性地通过增加蛋白毒性应激、增强促炎反应和增强 PD-1 免疫疗法的效果来靶向 MMRD 癌症。这些假设将通过三个具体目标进行测试：(1) 确定 MLN4924 治疗是否会抑制 MMRD 患者的致瘤性。结肠癌和子宫内膜样癌中的异种移植物（PDX）我们将建立皮下和原位子宫内膜样癌和结肠 PDX 模型，以严格评估其治疗效果。 MLN4924 对 MMRD 癌症的作用；(2) 确定 MLN4924 抑制 MMRD 癌症的治疗功效的潜在机制；(3) 确定 MLN4924 是否会增强 PD-的作用。 1 MMRD肿瘤的免疫治疗我们将建立同基因子宫内膜和结肠小鼠模型来评估单一疗法和联合疗法。使用 MLN4924 和抗小鼠 PD-1 抗体的疗法将导致开发基于 MLN4924 的新型有效的单一疗法和联合疗法，以有效治疗 MMRD 癌症。