Vulnerabilities in osteosarcoma and breast cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

In fiscal year 2025, we made substantial progress across all three specific aims outlined in our Goals and Objectives. For Aim 1, we identified a critical transcriptional cofactor for RUNX2. Inhibition of this cofactor impaired the growth of human osteosarcoma xenografts, and its deletion in a mouse model significantly delayed disease onset, suggesting an evolutionarily conserved role in osteosarcoma development. We are now exploring therapeutic strategies to target this mechanism. For Aim 2, we uncovered a RUNX2-mediated epigenetic repression of interferon pathways, providing new insight into the mechanisms underlying osteosarcoma resistance to immunotherapy. Mechanistic studies revealed that RUNX2 recruits epigenetic co-repressors, such as HDACs, to silence interferon signaling via histone deacetylation. Treatment with an HDAC inhibitor restored interferon pathway activity and sensitized osteosarcomas to anti-PD-1 therapy. This study has been submitted for publication, and we plan to collaborate with clinicians to advance this combination therapy into clinical trials. In Aim 3, we identified a RUNX2-regulated cell-surface protein that is highly expressed in osteosarcoma cells. Its depletion impaired tumor growth only in immunocompetent hosts. Mechanistically, the protein enhances RUNX2 activity, which in turn induces immune checkpoint molecules to facilitate immune evasion, defining a positive feedback loop between the cell-surface protein, RUNX2, and immune checkpoints. In collaboration with Dr. Mitchell Ho's laboratory, we designed a nanobody targeting this protein. Preliminary data show that the nanobody inhibits osteosarcoma growth in an immune-dependent manner, suggesting it may serve as a next-generation agent to potentiate anti-tumor immunity. We are nearing submission of this study for publication. In summary, we have achieved significant milestones across all three aims and provided novel insights that could inform future immunotherapeutic strategies for osteosarcoma.