Preclinical Evaluation of a Novel ADAM10 Modulator to Treat ColorectalCancer

新型 ADAM10 调节剂治疗结直肠癌的临床前评估

基本信息

批准号：
10697653
负责人：
Prem Khovabutr Premsrirut
金额：
$ 39.79万
依托单位：
MIRIMUS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-10 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10697653
关键词：
Address Adverse effects Adverse event Affect Animal Model Antibodies Binding Biochemical Biological Assay Cell Culture Techniques Cell Line Cell Transplantation Cells Cessation of life Chemoresistance Clinical Trials Colorectal Cancer Development Disease Disease Resistance Engineering Environment Evaluation Extracellular Domain Failure Gastrointestinal tract structure Genetic Genetic Models Genotype Goals Human Immune Evasion Immune response Immunocompetent Immunocompromised Host Immunologic Monitoring Immunotherapy Impairment In Vitro Intestines Large Intestine Carcinoma Lesion Memorial Sloan-Kettering Cancer Center Metalloproteases Modeling Molecular Molecular Conformation Monoclonal Antibodies Morbidity - disease rate Morphologic artifacts Mus Musculoskeletal System Mutation Normal tissue morphology Operative Surgical Procedures Organoids Outcome Pathway interactions Patients Phase Physiological Population Pre-Clinical Model Property Proteins Radiation Receptor Signaling Relapse Research Risk Role Scientist Side Signal Pathway Signal Transduction Small Business Technology Transfer Research Therapeutic Therapeutic Agents Toxic effect Treatment Failure Tumor Burden Up-Regulation Xenograft Model Xenograft procedure antitumor effect arm attenuation cancer cell cancer cell differentiation cancer diagnosis chemotherapeutic agent chemotherapy clinical development clinical risk colon cancer cell line colon cancer patients common treatment cytotoxic efficacy evaluation extracellular gastrointestinal system human monoclonal antibodies in vitro Model in vivo in vivo Model inhibitor insight metastatic colorectal mouse model murine monoclonal antibody mutant neoplastic cell notch protein novel novel therapeutic intervention novel therapeutics patient derived xenograft model patient stratification patient subsets pre-clinical preclinical evaluation prevent small molecule stem-like cell success systemic toxicity targeted treatment therapeutic target tool treatment strategy tumor tumor microenvironment

项目摘要

Abstract Colorectal cancer (CRC) is the third most diagnosed cancer in the USA and accounts for more than 600,000 deaths annually worldwide, primarily due to relapse with highly aggressive, chemo-resistant disease characterized by poorly differentiated cancer cells with stem cell-like properties. A common signature of these chemo-resistant tumors is dysregulation of Notch receptor signaling, as well as upregulation of its metalloprotease activator, ADAM10. Although small molecule inhibition of either Notch or ADAM10 has been shown to produce potent anti-tumor effects, these therapeutic strategies have failed in clinical trials primarily due to systemic toxicities, especially cytotoxic effects on the gastrointestinal tract and musculoskeletal system, highlighting the need for development of more targeted approaches. We have previously demonstrated that ADAM10 predominantly exists in an inhibited state in normal tissues but is activated in tumor cells through a conformational change in the extracellular domain, thus providing a potential target for tumor-specific modulation of ADAM10 activity. Here, we look to characterize a novel human monoclonal antibody agent (1H5) that selectively targets an exposed extracellular region of activated ADAM10 on tumor cells. We previously demonstrated that treatment with a murine version of the antibody (8C7), specific for the activated form of both mouse and human ADAM10, conferred a significant reduction in tumor burden against human CRC cell lines in cell culture and transplants in xenograft models, and relapse was prevented when 8C7 was combined with chemotherapy. The goal of this proposal will be perform in-depth preclinical “go/no-go” experimentation that will provide a definitive evaluation of ADAM10 monoclonal antibodies as a therapeutic approach. Here, we look to investigate our murine and human mAb agents at the molecular, cellular, and physiological levels by biochemically, characterizing their mechanism of action through in vivo assessment of metastatic CRC lesions in syngeneic immune-competent mouse models (8C7) and through xenograft models using human tumors (1H5). We hypothesize that through the use of genetic tools combined with in vitro and in vivo models, we can gain important information that significantly de-risks the clinical development of 1H5-based therapeutic agents as we move forward clinical trials to treat a broad population of CRC patients. Our research will not only help us move 1H5 toward successful clinical trials, it will also pioneer a new standard to comprehensively study novel therapeutic agents and identify potential failures early on. The overall goal of this proposal is to fully characterize a unique therapeutic agent to selectively impair Notch pathway activation in models of CRC to produce potent but less toxic therapies, advancing only candidates with a greater chance of success through clinical trials.

抽象的结直肠癌 (CRC) 是美国第三大诊断癌症，占超过 600,000 例全球每年死亡人数，主要是由于高度侵袭性、化疗耐药性疾病的复发其特征是具有干细胞样特性的低分化癌细胞。化疗耐药性肿瘤是由于Notch受体信号传导失调及其上调所致。金属蛋白酶激活剂 ADAM10，尽管 Notch 或 ADAM10 的小分子抑制作用已被证实。这些治疗策略被证明可以产生有效的抗肿瘤作用，但在临床试验中却失败了，主要原因是全身毒性，特别是对胃肠道和肌肉骨骼系统的细胞毒性作用，强调需要制定更有针对性的方法。 ADAM10 在正常组织中主要以抑制状态存在，但在肿瘤细胞中通过细胞外结构域的构象变化，从而为肿瘤特异性调节提供潜在靶点在这里，我们希望表征一种新型人单克隆抗体试剂 (1H5)，该试剂我们之前选择性地靶向肿瘤细胞上激活的 ADAM10 的暴露细胞外区域。用鼠类抗体进行治疗（8C7），对两种抗体的激活形式都有特异性小鼠和人类 ADAM10 显着降低了人类 CRC 细胞系的肿瘤负荷异种移植模型中的细胞培养和移植，当 8C7 与该提案的目标是进行深入的临床前“进行/不进行”实验。在这里，我们希望对 ADAM10 单克隆抗体作为一种治疗方法进行明确的评估。在分子、细胞和生理水平上研究我们的鼠和人单克隆抗体制剂生化方面，通过转移性结直肠癌病变的体内评估来表征其作用机制在同基因免疫活性小鼠模型（8C7）和使用人类肿瘤的异种移植模型（1H5）中。我们培养了通过使用遗传工具结合体外和体内模型，我们可以获得重要信息可显着降低基于 1H5 的治疗药物的临床开发风险，因为我们推进治疗广大结直肠癌患者的临床试验我们的研究不仅有助于我们前进。 1H5迈向成功的临床试验，也将开创全面研究新颖药物的新标准该提案的总体目标是充分表征一种独特的治疗剂，可选择性损害 CRC 模型中的 Notch 通路激活，从而产生有效的效果但毒性较小的疗法，只推进通过临床试验有更大成功机会的候选人。