Rewiring oncogenic signalling to precision ablation of metastatic cancer

Area of Science:

• Oncology
• Virology
• Biotechnology

Background:

• Metastatic carcinomas like ovarian cancer have limited long-term survival due to targeted therapy toxicities and poor immunotherapy response.
• Engineered synthetic proteins can recognize oncogenic signaling states, but their in vivo therapeutic application for metastatic disease is unclear.

Purpose of the Study:

• To develop an oncolytic virus engineered to selectively target and kill cancer cells with aberrant ErbB signaling.
• To evaluate the safety and efficacy of this novel virus, ErbB oncogene-selective virus (ErbB-OSV), against ErbB2/HER2-positive ovarian cancer.

Main Methods:

• Engineered proteins were used to restrict the replication of a viral backbone to cancer cells exhibiting aberrant ErbB signaling (EGFR, HER2).
• ErbB-OSV efficacy and safety were assessed in ovarian cancer xenograft and syngeneic models.
• Combination therapy with chemotherapy and B cell depletion for repeated dosing was investigated in advanced ovarian cancer models.

Main Results:

• ErbB-OSV demonstrated superior safety compared to a benchmark oncolytic virus.
• The virus showed superior efficacy against ErbB2/HER2-positive ovarian cancer xenografts.
• Combination therapy with chemotherapy and B cell depletion resulted in a 180% greater survival benefit than chemotherapy alone in advanced ovarian cancer models; single-agent ErbB-OSV cured most early-stage cases.

Conclusions:

• Restricting viral replication to ErbB-hyperactive cells using synthetic signaling proteins creates a highly specific therapeutic agent.
• ErbB-OSV effectively ablates metastatic tumors in vivo, outperforming existing treatments.
• This engineered virus represents a promising new strategy for treating metastatic cancers driven by ErbB family receptor tyrosine kinases.