FY2025 SBIR CONCEPT CLEARANCE AWARD OR TOPIC DEVELOPMENT OF THERAPEUTIC OR PREVENTATIVE TECHNOLOGIES FOR TREATMENT OR PREVENTION OF PEDIATRIC CANCERS AND/OR RARE CANCERS

Chordoma is a malignant sarcoma originating from residual embryonic notochord cells in the spine and is ultra rare. There are no approved systemic therapies for chordoma, and consequently, patients with advanced disease face poor prognoses. The TBXT gene, encoding the brachyury transcription factor, is aberrantly overexpressed and is a key driver and vulnerability of this cancer. A systemic therapy that directly inhibits TBXT has enormous potential to revolutionize the chordoma treatment paradigm. ASO Therapeutics is addressing this unmet patient need by developing a direct antisense (ASO) inhibitor of TBXT expression. ASO has developed locked nucleic acid “mixmer” technology to enable broad tissue access. Using this technology, we have demonstrated that ASOs delivered systemically can accumulate within solid tumors without accompanying kidney or liver toxicities. Our lead ASO (AT027) demonstrated profound suppression of the TBXT protein and inhibition of growth in cultured chordoma cells. During the anticipated project period, we will employ murine xenograft models to 1) establish an effective in vivo dose range of anti-TBXT ASO AT027, and 2) evaluate effects of AT027 on chordoma tumor growth. Our targeted technology aims to establish a new treatment paradigm applicable to nearly all patients with advanced chordoma and other TBXT +/ positive cancers.