Colorectal cancer (CRC) is the third most diagnosed cancer in the USA and accounts for more than 600,000deaths annually worldwide, primarily due to relapse with highly aggressive, chemo-resistant diseasecharacterized by poorly differentiated cancer cells with stem cell-like properties. A common signature of thesechemo-resistant tumors is dysregulation of Notch receptor signaling, as well as upregulation of itsmetalloprotease activator, ADAM10. Although small molecule inhibition of either Notch or ADAM10 has beenshown to produce potent anti-tumor effects, these therapeutic strategies have failed in clinical trials primarily dueto 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 thatADAM10 predominantly exists in an inhibited state in normal tissues but is activated in tumor cells through aconformational change in the extracellular domain, thus providing a potential target for tumor-specific modulationof ADAM10 activity. Here, we look to characterize a novel human monoclonal antibody agent (1H5) thatselectively targets an exposed extracellular region of activated ADAM10 on tumor cells. We previouslydemonstrated that treatment with a murine version of the antibody (8C7), specific for the activated form of bothmouse and human ADAM10, conferred a significant reduction in tumor burden against human CRC cell lines incell culture and transplants in xenograft models, and relapse was prevented when 8C7 was combined withchemotherapy. The goal of this proposal will be perform in-depth preclinical "go/no-go" experimentation that willprovide a definitive evaluation of ADAM10 monoclonal antibodies as a therapeutic approach. Here, we look toinvestigate our murine and human mAb agents at the molecular, cellular, and physiological levels bybiochemically, characterizing their mechanism of action through in vivo assessment of metastatic CRC lesionsin 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 gainimportant information that significantly de-risks the clinical development of 1H5-based therapeutic agents as wemove forward clinical trials to treat a broad population of CRC patients. Our research will not only help us move1H5 toward successful clinical trials, it will also pioneer a new standard to comprehensively study noveltherapeutic agents and identify potential failures early on. The overall goal of this proposal is to fully characterizea unique therapeutic agent to selectively impair Notch pathway activation in models of CRC to produce potentbut less toxic therapies, advancing only candidates with a greater chance of success through clinical trials.
Public Health Relevance Statement: Project Narrative
Many colorectal cancer (CRC) patients present with highly aggressive, poorly differentiated, chemo-resistant
disease often characterized by dysregulation of Notch signaling and upregulation of its regulator, ADAM10. While
ADAM10 is recognized as potential promising therapeutic target, therapeutic agents targeting ADAM10 have
failed in clinical trials due to their nonspecific activity that leads to severe toxicities, leaving no available effective
and tolerable therapies to treat aggressive CRCs. Here, we propose to characterize a newly generated human
monoclonal ADAM10 antibody that binds selectively to the "active" form of the protein found predominantly on
cancer cells, and in parallel, unravel of signaling pathways affected using various modes of ADAM10 modulation
in order to better understand the mechanisms of both disease attenuation and adverse effects.
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