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）是美国诊断出的第三大癌症，占60万以上每年在全球范围内死亡，主要是由于高度侵略性，耐化学疾病的缓解具有干细胞样性质的分化较差的癌细胞的特征。这些的常见签名化学耐药性肿瘤是Notch受体信号传导的失调，以及其上调。金属蛋白酶激活剂ADAM10。尽管对缺口或ADAM10的小分子抑制已经这些治疗策略证明会产生潜在的抗肿瘤作用，在临床试验中失败了对于全身毒性，尤其是对胃肠道和肌肉骨骼系统的细胞毒性作用，强调需要开发更具针对性的方法。我们以前已经证明了 ADAM10主要存在于正常组织中的抑制状态，但在肿瘤细胞中通过A激活细胞外域中的构象变化，从而为肿瘤特异性调节提供了潜在的靶标 ADAM10活动。在这里，我们要描述一种新型的人类单克隆抗体剂（1H5）有选择地靶向肿瘤细胞上活化的ADAM10的裸露细胞外区域。我们以前证明了用鼠类版本的抗体（8C7）处理，这是针对两者的活化形式的小鼠和人类ADAM10赋予了肿瘤对人CRC细胞系的燃烧显着降低细胞培养和外移模型中的移植，并在8C7与8C7结合时预防继电器化学疗法。该提案的目标将进行深入的临床前“ GO/No-Go”实验提供ADAM10单克隆抗体作为治疗方法的明确评估。在这里，我们看通过通过分子，细胞和物理水平调查我们的鼠和人物mAb剂从生化上，通过体内评估转移性CRC病变来表征其作用机理在合成性免疫功能的小鼠模型（8C7）和使用人肿瘤（1H5）的异种移植模型中。我们假设通过使用遗传工具与体外和体内模型相结合，我们可以获得我们的重要信息可以显着降低基于1H5的治疗剂的临床开发继续进行临床试验，以治疗广泛的CRC患者。我们的研究不仅会帮助我们移动 1H5朝着成功的临床试验进行，它将为全面研究小说的新标准提供先驱治疗剂并尽早确定潜在的失败。该提议的总体目标是完全表征一种独特的治疗剂，可在CRC模型中有选择性损害Notch途径激活以产生有效性但是，毒性较小的疗法只能通过临床试验来推进候选人的成功机会。