Targeting tumor tight junctions: The Junction Opener protein

Abstract

With the advent of new approaches - including cellular therapy and immunotherapies - cancer treatment has entered a new era. However, solid epithelial tumors have yet to benefit from these new modalities, and new tools for diagnosis and treatment are sorely needed. Desmoglein-2 (DSG2) is a desmosomal protein involved in cellular structure integrity and junction formation, contributing to the formation of tight physical barriers. Several cancers have been observed to upregulate its expression to resist therapies and the immune system, representing its potential as a biomarker and target. This dissertation explores the identification of DSG2 as a biomarker and prognostic indicator for ovarian cancer, which commonly manifests as an epithelial solid tumor. DSG2 overexpression was linked to survival, chemoresistance, and prognosis. A recombinant, engineered adenoviral protein, Junction Opener (JO) targets DSG2 and causes the transient opening of tight junction allowing easier passage of chemotherapeutics. JO’s ability to home to overexpressed DSG2 and to compromise one of a tumor’s defense mechanisms makes it an attractive co-therapeutic with monoclonal antibodies or chemotherapeutics. A conjugatable form of JO, JOC-x, was developed and confirmed to retain JO’s properties and binding characteristics. JOC-x was then successfully conjugated to PEGylated liposomal doxorubicin (PLD) and was shown to have enhanced efficacy over the separate combination, thus indicating its potential as a chemotherapeutic candidate. Finally, we explored the pharmacokinetic and immunogenic properties of JO and PLD in Macaca fascicularis to ascertain parameters for future use in humans. Macaque studies indicated induction of anti-JO antibodies and inflammatory cytokines, but these could be suppressed with an immunosuppressive regimen commonly found in the clinic. In short, this dissertation explores the establishment of DSG2 as an ovarian cancer biomarker and therapeutic target for the JO protein as tools to use in ovarian cancer diagnosis and treatment.