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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

基本信息

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
项目类别：
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

项目摘要

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.

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