Overcoming physical barriers in cancer therapy

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• Solid tumors often originate from epithelial cells, maintaining intercellular junctions that shield them from immune responses and drug penetration.
• Desmoglein 2 (DSG2) is a crucial protein in epithelial junctions and is consistently upregulated across various cancers.
• Certain adenoviruses utilize DSG2 as a primary attachment receptor for cell infection.

Purpose of the Study:

• To develop a therapeutic agent that targets DSG2 to disrupt epithelial intercellular junctions.
• To investigate the potential of this agent in enhancing the efficacy of existing cancer treatments.
• To assess the safety and toxicity profile of the developed agent.

Main Methods:

• Creation of a recombinant protein, JO-1, derived from adenovirus serotype 3, designed to bind DSG2.
• Administration of JO-1 via intravenous injection in over 25 xenograft tumor models.
• Evaluation of JO-1's impact on the efficacy of monoclonal antibodies and chemotherapy.
• Safety assessments in human DSG2-transgenic mice and monkeys.

Main Results:

• JO-1 effectively binds to and clusters DSG2, inducing a transient opening of epithelial junctions.
• Intravenous injection of JO-1 significantly improved the efficacy of chemotherapy and monoclonal antibody treatments in xenograft models.
• The use of JO-1 allowed for a reduction in therapeutic doses, leading to decreased treatment-related toxic side effects.
• Safety studies indicated no associated toxicities in preclinical models.

Conclusions:

• JO-1 represents a promising therapeutic strategy for enhancing solid tumor treatment by targeting DSG2-mediated intercellular junctions.
• This approach offers a method to overcome physical barriers in tumors, improving drug delivery and therapeutic outcomes.
• JO-1 demonstrates a favorable safety profile, suggesting its potential for clinical application in combination cancer therapy.