Imaging-Guided Therapy Simultaneously Targeting HER2 and EpCAM with Trastuzumab and EpCAM-Directed Toxin Provides...

Area of Science:

• Oncology
• Biotechnology
• Molecular Biology

Background:

• Disseminated ovarian cancer (OC) presents significant treatment challenges due to tumor heterogeneity and chemoresistance.
• Human epidermal growth factor receptor 2 (HER2) and epithelial cell adhesion molecule (EpCAM) are overexpressed in a substantial proportion of OC cases, presenting viable therapeutic targets.

Purpose of the Study:

• To evaluate the therapeutic potential of a novel EpCAM-targeting agent, Ec1-LoPE, in combination with the HER2-targeting antibody trastuzumab for ovarian cancer treatment.
• To assess the in vitro and in vivo efficacy, biodistribution, and toxicity of Ec1-LoPE.

Main Methods:

• Ec1-LoPE, a designed ankyrin repeat protein (DARPin) fused to a Pseudomonas exotoxin A variant, was developed and radiolabeled.
• In vitro and in vivo studies were conducted using ovarian cancer cells and SKOV3 xenografts expressing EpCAM and HER2.
• SPECT/CT imaging was used to visualize target expression, and therapeutic efficacy was assessed through tumor growth inhibition and survival analysis.

Main Results:

• SPECT/CT imaging confirmed EpCAM and HER2 expression in tumors.
• Combined treatment with Ec1-LoPE and trastuzumab demonstrated superior efficacy in reducing tumor growth compared to monotherapy or control groups.
• Repeated administration of Ec1-LoPE was well-tolerated, showing no significant hepatic or kidney toxicity.

Conclusions:

• Co-treatment with trastuzumab and Ec1-LoPE represents a promising therapeutic strategy for HER2- and EpCAM-positive ovarian cancer.
• This combination therapy offers a potential approach to overcome chemoresistance and improve treatment outcomes in ovarian cancer.