Cancers of the digestive system, including colorectal, liver, and stomach cancer, represent major types of cancer with high morbidity and mortality in Texas and the rest of the world. In particular, liver cancer is becoming increasingly more common in this state with few treatment options available. This project is aimed at creating a novel class of therapeutics that targets a group of receptors with increased levels in cancers of the digestive system. LGR4, 5, and 6 (leucine-rich repeat containing, G protein-coupled receptor 4, 5, 6) are three related proteins with critical roles in tumor formation and metastasis. Aberrant activation of the three receptors has been shown to drive canc...

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Cancers of the digestive system, including colorectal, liver, and stomach cancer, represent major types of cancer with high morbidity and mortality in Texas and the rest of the world. In particular, liver cancer is becoming increasingly more common in this state with few treatment options available. This project is aimed at creating a novel class of therapeutics that targets a group of receptors with increased levels in cancers of the digestive system. LGR4, 5, and 6 (leucine-rich repeat containing, G protein-coupled receptor 4, 5, 6) are three related proteins with critical roles in tumor formation and metastasis. Aberrant activation of the three receptors has been shown to drive cancer cell growth and migration of colon, stomach, and liver cancers. We have identified a small protein that can specifically bind to all three receptors and block their function. Fusion of this protein with part of a human antibody creates a chimeric protein called a peptibody. Attaching a cytotoxic payload to the peptibody generates a peptibody-drug conjugate (PDC) that can deliver the payload to and kill cancer cells with high levels of LGR4-6. This strategy is similar to that of antibody-drug conjugate (ADC) which has been successfully used for cancer treatment. We have created a prototype PDC that binds LGR4-6 and kill tumor cells expressing high levels of these receptors in vitro and in vivo. This approach combines the specificity and efficacy of ADCs with the broad targeting ability of the peptibody. The specific goals of this project are to create drug candidates that are highly potent and efficacious in killing genetically engineered and patient-derived tumors in mice. The candidates will also be assessed for safety and pharmacokinetics in animal models in preparation for pre-clinical development. Success of this project may lead to the development of novel therapeutics for a broad category of cancers.

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