BioCentury
ARTICLE | Distillery Therapeutics

Cancer

April 13, 2017 5:15 PM UTC

Cell culture and mouse studies suggest SLC7A11 inhibitors could help treat p53-mutant esophageal cancer and other cancers that are resistant to p53 activators. In 10 p53-mutant esophageal cancer cell lines, high levels of SLC7A11 correlated with low levels of mutant p53 and high resistance to the p53 activator APR-246, which targets mutant p53 to restore wild-type p53 function. In three of the cell lines, SLC7A11 knockdown plus APR-246 increased apoptosis compared with SLC7A11 knockdown or APR-247 alone. In one of the cell lines, Azulfidine sulfasalazine - which inhibits SLC7A11 - plus APR-246 increased apoptosis compared with either agent alone. In a xenograft and patient-derived xenograft (PDX) mouse models of p53-mutant esophageal cancer, tumor-specific SLC7A11 knockdown plus APR-246 decreased tumor growth compared with either strategy alone, and in the xenograft model, the combination increased survival. Also in the models, Azulfidine plus APR-246 decreased tumor growth compared with either agent alone. Next steps could include testing SLC7A11 inhibition in models of other p53-mutant cancers resistant to p53 activation.

Aprea Therapeutics AB has APR-246 in Phase II testing to treat ovarian cancer and Phase I testing to treat esophageal cancer and myelodysplastic syndrome (MDS)...