(P 119) DEVELOPMENT OF AN EXTINCTION THERAPY APPROACH FOR OSTEOSARCOMA USING ECO-EVOLUTIONARY PRINCIPLES

Objective: Patients with high-grade osteosarcoma (OS) face high recurrence rates and significant treatment-related toxicity, despite multiagent chemotherapy (MAP: methotrexate, adriamycin (doxorubicin), cisplatin). Tumor recurrence is in part driven by chemoresistance, which can develop after a maximally tolerated dose (MTD) approach. In contrast, “extinction therapy” (ET) is an emerging strategy that leverages eco-evolutionary principles to drive heterogeneous tumors to extinction through multi-strike delivery of sub-MTD therapies targeting unique subpopulations. This study aims to develop an ET regimen that offers a rational path to improved OS outcomes with reduced toxicity.

Methods: The first strike of ET uses standard doxorubicin and cisplatin to reduce tumor size and heterogeneity. Subsequent strikes use sequential second-line agents selected from established guidelines. Efficacy of ET versus standard therapy is assessed using cell growth and post-treatment cell viability. In vitro modelling uses a 143B OS cell line; ex vivo uses a pulmonary metastasis assay (PuMA). Statistical analysis uses one-way ANOVA.

Results: Compared to standard therapy, ET significantly inhibits OS cell growth and significantly reduces OS cell viability in in vitro testing. ET stabilizes OS metastatic tumor burden within the PuMA ex vivo model. In regards to overall toxicity, multiple in vitro drug concentrations in the ET regimen were significantly lower than reported in published pharmacokinetic studies.

Conclusion: Current agents used in OS demonstrate chemoresistance with repeat use, leading to a need to explore new therapies. ET demonstrates efficacy in preclinical models and represents a promising approach to minimize toxicity and chemoresistance in OS. Future work aims to optimize the current ET regimen by incorporating novel agents and validate ET across multiple in vitro, ex vivo, and in vivo OS models.