PI: Annamaria Biroccio
Other IRE Principal Collaborators Involved: Patrizia Vici, Iachettini Sara

Project duration: 24 months

Project code: PNRR-POC-2023-12377476

This project aims to validate and optimize a novel therapeutic approach for Triple-Negative Breast Cancer (TNBC) using lipid nanoparticles (LNPs) to deliver a microRNA (miR-182-3p) that inhibits the telomere-binding protein TRF2. TRF2 is overexpressed in TNBC and contributes to tumor growth, angiogenesis, and immune evasion. Preliminary data demonstrates that LNPs-miR-182-3p reduces tumor growth in TNBC models, including patient-derived xenografts (PDXs), and can cross the blood-brain barrier, suggesting potential efficacy against brain metastases. This project will optimize the LNP formulation, evaluate synergistic effects with existing therapies, assess anti-metastatic activity, and scale up production for potential clinical translation.

LNP Formulation and Scale-Up: Identify the optimal LNP formulation for miR-182-3p delivery, focusing on lipid composition, surface functionalization for targeted delivery to TNBC cells, and develop a scalable GMP-compliant production method.

Evaluation of Anti-tumor Activity and Synergistic Effects: Evaluate the anti-tumor efficacy of LNPs-miR-182-3p alone and in combination with standard chemotherapy (platinums, taxanes, anthracyclines), targeted therapies (PARP inhibitors), and immunotherapy (checkpoint inhibitors) in vitro and in vivo. This includes assessing pharmacokinetics, toxicity, and biodistribution. High-throughput drug screening will be performed to identify additional synergistic combinations.

Evaluation of Anti-metastatic Activity: Assess the ability of LNPs-miR-182-3p to prevent and treat metastasis in preclinical models, including PDXs from metastatic sites. This will be evaluated using micro-PET/CT imaging to monitor metastasis development and response to treatment, both alone and in combination with Sacituzumab Govitecan.

Optimized LNP Formulation: The project expects to identify an optimized LNP formulation with high miRNA encapsulation efficiency, stability, and targeted delivery to TNBC cells. This will include a scalable production process suitable for GMP manufacturing.

Enhanced Anti-tumor Efficacy: The project anticipates demonstrating enhanced anti-tumor activity of LNPs-miR-182-3p, particularly in combination with existing therapies. This includes improved tumor growth inhibition, reduced DNA damage, and increased apoptosis.

Reduction of Metastasis: The project expects to show that LNPs-miR-182-3p can effectively prevent and treat metastasis in preclinical models, including brain metastases, addressing a critical unmet need in TNBC.

Preclinical Validation for Clinical Translation: The project aims to provide robust preclinical data to support a future phase I clinical trial for metastatic TNBC patients who have progressed on standard therapies. The results could also potentially extend to other TRF2-overexpressing tumors.