ARTICLE | Distillery Therapeutics


December 13, 2016 8:02 PM UTC

Patient samples, cell culture and mouse studies suggest an engineered CTH variant could help treat CLL, breast cancer and prostate cancer. Combinatorial mutagenesis of the active site of human CTH followed by in vitro testing of mutants in enzymatic assays identified a PEGylated CTH variant that degraded L-cysteine and L-cystine - precursors to glutathione, which protects tumors from oxidative stress - with enzymatic efficiencies (Kcat/Km values) 25.5 and 50 times higher, respectively, than wild-type CTH. In primary leukemia cells from Fludara fludarabine-sensitive and Fludara-resistant CLL patients, the PEGylated CTH variant decreased viability compared with Fludara or no treatment and in mouse and human prostate cancer cell lines, the variant decreased viability compared with no treatment. In a mouse model of CLL, the PEGylated variant increased survival compared with Fludara. In xenograft mouse models of breast and prostate cancers, the PEGylated variant decreased tumor growth compared with vehicle. Next steps include testing the CTH variant in additional tumor models...