(P 116) A DUAL-TARGETED SYSTEMIC THERAPEUTIC APPROACH FOR THE SELECTIVE ELIMINATION OF TUMOR CELLS IN PRIMARY AND METASTATIC SARCOMA.

Objective: Osteosarcoma (OS), the most common primary bone cancer in children and adolescents, has a poor prognosis, especially in metastatic cases, with a 5-year survival rate of only ~20%. Around 20% of patients present with metastases at diagnosis, and most others are presumed to have micrometastases, with nearly half progressing to clinical metastasis. Despite aggressive treatment, outcomes have not improved since the 1970s, highlighting an urgent need for novel therapies targeting disseminated disease.

Methods: We propose a dual-targeted systemic therapy using a modified bacteriophage vector for intravenous delivery of therapeutic genes to primary and metastatic tumors. The non-pathogenic phage is engineered to bind tumor-specific receptors with minimal normal tissue interaction. It carries a gene for secreted TRAIL (sTRAIL), which selectively induces apoptosis in cancer cells, enabling targeted and localized treatment following systemic administration.

Results: We evaluated the efficacy of our sTRAIL-encoding gene delivery vector against osteosarcoma (OS) using both in vitro human tumor cell models and in vivo murine models following intravenous administration. Our initial analysis demonstrated that the majority of human OS cell lines and patient-derived specimens expressed the αvβ3 integrin, the molecular target receptor of our delivery system. This receptor-mediated interaction enabled selective homing of the vector to both primary and metastatic tumor sites in mice after systemic administration.
As a result, sTRAIL was effectively delivered and locally released at the tumor sites, while healthy tissues remained largely unaffected. Repeated systemic administrations of the therapy were well tolerated, with no significant toxicity observed. Importantly, this approach led to the selective and efficient elimination of both primary tumors and metastatic lesions. These findings highlight the potential of this dual-targeted gene therapy as a safe and effective strategy for personalized treatment of osteosarcoma.

Conclusion: Our dual-targeted systemic therapy, using a bacteriophage vector to deliver sTRAIL to αvβ3-expressing osteosarcoma cells, achieved selective tumor targeting and effective elimination of both primary and metastatic lesions with no observed toxicity. These results highlight its potential as a safe, personalized treatment for advanced osteosarcoma and warrant further preclinical and clinical development.