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.

摘要： 结肠直肠癌干细胞（CSC）被认为介导了治疗抗性和残余肿瘤复发。 疾病，由于他们的生存能力和自我更新能力的增加，并分化成异质 肿瘤细胞的谱系。最近的治疗努力已经集中在靶向CSC以改善肿瘤的生长。 治疗效果然而，由于CSCs的可塑性和肿瘤的异质性， 显然，为了成功消除结肠直肠癌（CRC），治疗可能需要双重或多重治疗， 有针对性的方法。几份报告已经确定LGR 5（富含亮氨酸的重复序列，G蛋白- 偶联受体5）在CRC中高度上调并标记高度可塑性CSC。动态相互转换 LGR 5阳性CSC与LGR 5阴性癌细胞的比例在肿瘤进展过程中至关重要 和转移。我们和其他人产生了LGR 5靶向的抗体-药物缀合物（ADC），其高度依赖于LGR 5。 有效消除LGR 5阳性结直肠肿瘤，无主要副作用，然而， 肿瘤最终复发。这些发现表明，单独靶向LGR 5阳性CSC可能不适合治疗肿瘤。 由于其可塑性，足以消除结肠直肠肿瘤。上皮调节蛋白（EREG）是细胞表面表达的， EGFR配体在CRC中上调，并在LGR 5阳性CSC和LGR 5阴性CSC中高度表达 癌细胞EREG也被证明可以驱动结肠炎相关的CRC，并预测CRC相关的肝脏 转移有趣的是，EGFR靶向治疗已显示增加CRC中的LGR 5表达 模型和CRC细胞中的LGR 5敲低增加了EREG水平。因此，LGR 5和LGR 5的治疗靶向都是有效的。 EREG/EGFR可能是清除LGR 5阳性CSC和克服可塑性的更有效策略。 在目标1中，我们将产生抗EREG ADC并评估针对多种CRC的安全性和治疗功效 模型在目标2中，我们将确定ADC联合治疗是否可以改善治疗反应， 克服癌细胞的可塑性。我们将表征不同的EREG单克隆抗体，并筛选不同的 因此，本发明提供了用于开发具有高特异性、亲和力和效力的最佳抗EREG ADC的方法。抗EREG ADC将作为单一疗法以及与连接至相同或不同的抗LGR 5 ADC的组合进行测试。 有效载荷针对患者来源的CRC异种移植模型。ADC还将结合以下指标进行评估： 其他EGFR靶向治疗。该项目将导致产生独特的ADC和创新的ADC 联合治疗以潜在地克服CSC的可塑性和抗性，从而改善CRC的治疗。