Lung cancer is the leading cause of cancer deaths worldwide and is caused by mutations that promote uncontrolled cell growth or inappropriate cell survival. Despite the recent successes in the development of targeted therapies and immunotherapies, disease progression is inevitable, underscoring the need for the identification of new approaches to treat this disease. Our lab is one of the first to investigate the role of the cell surface protein PCDH7 in lung cancer development. PCDH7 represents an attractive target for treating lung cancer for several reasons. PCDH7 is present at higher levels in lung cancer cells compared to normal lung cells and this is associated with poor survival of lun...

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Lung cancer is the leading cause of cancer deaths worldwide and is caused by mutations that promote uncontrolled cell growth or inappropriate cell survival. Despite the recent successes in the development of targeted therapies and immunotherapies, disease progression is inevitable, underscoring the need for the identification of new approaches to treat this disease. Our lab is one of the first to investigate the role of the cell surface protein PCDH7 in lung cancer development. PCDH7 represents an attractive target for treating lung cancer for several reasons. PCDH7 is present at higher levels in lung cancer cells compared to normal lung cells and this is associated with poor survival of lung cancer patients. We showed that elevating or reducing PCDH7 levels in human lung cancer cells strongly increases or decreases their tumor-forming ability, respectively. Similarly, elevating PCDH7 in mouse models enhances lung tumor development, and removal of PCDH7 in an aggressive lung cancer mouse model significantly reduces tumor burden and extends survival. Finally, deletion of PCDH7 in healthy mice does not negatively impact normal development. PCDH7 expression can promote brain metastasis of lung cancer, further supporting the importance of this protein in multiple aspects of tumor biology and providing important rationale for therapeutic targeting of this protein. We successfully developed humanized antibodies that bind and block the function of PCDH7 and identified a leading candidate that reduces tumor burden and engages the immune system in multiple models. The goals of this proposal are to investigate the mechanisms of action of the lead PCDH7 antibody, investigate how the antibody impacts the immune system, and determine the extent that it can fight drug resistance in pre-clinical models. We will also engineer new PCDH7 antibodies that boost the ability of the antibody to enhance killing of tumor cells by the immune cells and fight therapy resistance in lung cancer.

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