Novel Antibody-Drug Conjugate Combination Therapy for Treating Colorectal Cancer

治疗结直肠癌的新型抗体-药物结合物联合疗法

• 批准号: 10551243
• 负责人: Kendra S. Carmon
• 金额: $ 21.44万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551243
• 关键词: Ablation; Adverse effects; Affinity; Aftercare; Antibody-drug conjugates; BRAF gene; Back; Cancer Model; Cell surface; Cells; Cessation of life; Cetuximab; Colitis associated colorectal cancer; Colorectal Cancer; Colorectal Neoplasms; Combined Modality Therapy; Data; Development; Disease Progression; Dose; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epiregulin; Excision; Exhibits; G-Protein-Coupled Receptors; Generations; Genes; Genetic; Goals; Growth; Immunocompetent; In Vitro; Intestines; Knockout Mice; Lead; Leucine-Rich Repeat; Ligands; Link; Measures; Mediating; Metastatic Neoplasm to the Liver; Modeling; Monoclonal Antibodies; Mus; Nature; Neoplasm Metastasis; Normal tissue morphology; Organoids; Pathway interactions; Patients; Primary Neoplasm; Relapse; Reporting; Residual Cancers; Residual Neoplasm; Residual state; Resistance; Safety; Specificity; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Treatment Failure; Tumor Promotion; Up-Regulation; Western Blotting; Xenograft Model; antibody test; cancer cell; cancer stem cell; cell type; colon cancer cell line; colorectal cancer treatment; effective therapy; improved; in vivo; innovation; knock-down; mutational status; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; self-renewal; synergism; targeted treatment; therapeutic target; therapy resistant; transcriptome sequencing; treatment effect; treatment response; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor progression

ABSTRACT: Colorectal cancer stem cells (CSCs) are believed to mediate therapeutic resistance and relapse of residual disease due to their increased capacity for survival and ability to self-renew and differentiate into heterogeneous lineages of tumor cells. Recent therapeutic efforts have been focused on the targeting of CSCs to improve treatment efficacy. However, due to the plastic nature of CSCs and tumor heterogeneity, it is becoming more apparent that in order to successfully eliminate colorectal cancer (CRC), treatment may require a dual- or multi- targeted approach. Several reports have established that LGR5 (Leucine-rich repeat containing, G protein- coupled Receptor 5) is highly upregulated in CRC and marks highly plastic CSCs. The dynamic interconversion of LGR5-positive CSCs to LGR5-negative cancer cells has been shown to be essential during tumor progression and metastasis. We and others generated LGR5-targeted antibody-drug conjugates (ADCs) that were highly effective in eliminating LGR5-positive colorectal tumors without major adverse effects, however a fraction of tumors eventually relapsed. These findings suggest that targeting LGR5-positive CSCs alone may not be sufficient to eliminate colorectal tumors due to their plasticity. Epiregulin (EREG) is a cell surface expressed, EGFR ligand that is upregulated in CRC and highly expressed on both LGR5-postive CSCs and LGR5-negative cancer cells. EREG was also shown to drive colitis-associated CRC and be predictive of CRC-associated liver metastasis. Interesting, EGFR-targeted therapies have been shown to increase LGR5 expression in CRC models and LGR5 knockdown in CRC cells increased EREG levels. Thus, therapeutic targeting of both LGR5 and EREG/EGFR may be a more effective strategy to eliminate LGR5-positive CSCs and overcome plasticity. In Aim 1, we will generate anti-EREG ADCs and evaluate safety and therapeutic efficacy against multiple CRC models. In Aim 2, we will determine if ADC combination treatment can improve therapeutic response and overcome cancer cell plasticity. We will characterize different EREG monoclonal antibodies and screen different linker-payloads to develop an optimal anti-EREG ADC with high specificity, affinity, and potency. Anti-EREG ADCs will be tested as a monotherapy and in combination with anti-LGR5 ADCs linked to the same or different payloads against patient-derived xenograft models of CRC. ADCs will also be evaluated in combination with other EGFR-targeted therapies. This project will lead to the generation of unique ADCs and an innovative ADC combination therapy to potentially overcome CSC plasticity and resistance for the improved treatment of CRC.

抽象的： 据信大肠癌干细胞（CSC）介导治疗性耐药性和残留的复发 疾病由于其生存能力增加以及自我更新和分化为异质的能力而引起的疾病 肿瘤细胞的谱系。最近的治疗工作集中在CSC的靶向上以改进 治疗功效。但是，由于CSC和肿瘤异质性的可塑性，它变得越来越多 显然，为了成功消除大肠癌（CRC），治疗可能需要双重或多重 有针对性的方法。有几份报告表明，LGR5（富含亮氨酸的重复含有G蛋白 耦合受体5）在CRC中高度上调，标记高度塑料CSC。动态互换 LGR5阳性的CSC对LGR5阴性癌细胞已被证明在肿瘤进展中至关重要 和转移。我们和其他人产生的LGR5靶向抗体 - 药物缀合物（ADC）高度高 有效消除没有重大不良反应的LGR5阳性大肠肿瘤，但是 肿瘤最终复发。这些发现表明，仅针对LGR5阳性CSC可能不是 由于其可塑性，足以消除结直肠肿瘤。上环蛋白（EREG）是表达的细胞表面， EGFR配体在CRC中上调，并在LGR5-POSTIVE CSC和LGR5阴性上高度表达 癌细胞。还显示EREG驱动结肠炎相关的CRC，并预测与CRC相关的肝脏 转移。有趣的，靶向EGFR的疗法已显示出增加CRC中LGR5的表达 CRC细胞中的模型和LGR5敲低增加了EREG水平。因此，两个LGR5的治疗靶向 EREG/EGFR可能是消除LGR5阳性CSC并克服可塑性的更有效策略。 在AIM 1中，我们将生成反埃里ADC，并评估针对多个CRC的安全性和治疗功效 型号。在AIM 2中，我们将确定ADC组合治疗是否可以改善治疗反应和 克服癌细胞的可塑性。我们将表征不同的EREG单克隆抗体和屏幕不同 Linker-Pay负载可开发具有高特异性，亲和力和效力的最佳抗极局ADC。反雷 ADC将作为单一疗法进行测试，并与与相同或不同的抗LGR5 ADC结合 CRC的患者衍生异种移植模型的有效载荷。 ADC也将与 其他EGFR靶向疗法。该项目将导致独特的ADC和创新的ADC产生 结合疗法可以克服CSC可塑性和耐药性，以改善CRC的治疗方法。