Preclinical Evaluation of a Novel ADAM10 Modulator to Treat ColorectalCancer

点击翻译按钮获取中文摘要

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.