BP1003 Decreases STAT3 Expression and Its Pro-Tumorigenic Functions in Solid Tumors and the Tumor Microenvironment

Area of Science:

• Oncology
• Molecular Biology
• Drug Development

Background:

• Signal transducer and activator of transcription 3 (STAT3) dysregulation drives cancer development, resistance, and immune evasion.
• Targeting STAT3 presents a promising strategy for novel cancer therapeutics.

Purpose of the Study:

• To evaluate the efficacy of BP1003, a STAT3-targeting antisense oligodeoxynucleotide (ASO), as a cancer therapeutic.
• To assess BP1003's impact on cancer cell sensitivity to chemotherapy and its effects on the tumor microenvironment.

Main Methods:

• BP1003, a P-ethoxy ASO encapsulated in neutral liposomes, was designed for enhanced stability and cellular uptake.
• Efficacy was tested in HER2+, triple-negative breast cancer, late-stage ovarian cancer, and patient-derived pancreatic ductal adenocarcinoma (PDAC) models.
• Effects on STAT3 expression, chemotherapy sensitivity (paclitaxel, 5-FU, gemcitabine), and immune cell differentiation (macrophages) were analyzed in 2D, 3D, ex vivo, and in vivo models.

Main Results:

• BP1003 significantly reduced STAT3 expression and enhanced chemotherapy sensitivity in breast and ovarian cancer cells.
• Combination treatment with BP1003 and gemcitabine reduced tissue viability and tumor volume in PDAC models.
• BP1003 suppressed monocyte differentiation into anti-inflammatory M2 macrophages, suggesting immunomodulatory potential.

Conclusions:

• BP1003 demonstrates broad anti-tumor activity across diverse solid tumor models by inhibiting STAT3.
• BP1003 enhances chemotherapy efficacy and modulates the tumor microenvironment, positioning it as a promising candidate for cancer immunotherapy.