Cancer

In vitro, cell culture and mouse studies suggest inhibiting the DNAJ/Hsp70 chaperone axis could help treat castration-resistant prostate cancer (CRPC). Screening of a library of chalcone analogs and testing in cell-based signaling assays yielded a compound that decreased disease-associated androgen receptor- and AR-V7-dependent signaling compared with vehicle; in vitro binding assays identified the J domain of DNAJ family proteins as the compound’s probable target. In a human CRPC cell line, the DNAJ inhibitor decreased viability compared with the androgen receptor inhibitor Casodex bicalutamide and the androgen receptor antagonist Xtandi enzalutamide. In three patient-derived xenograft (PDX) mouse models of CRPC, the DNAJ inhibitor or a previously identified Hsp70 inhibitor decreased tumor volume compared with vehicle, and the DNAJ inhibitor plus the Hsp70 inhibitor decreased tumor volume compared with either agent alone. Next steps include testing DNAJ or Hsp70 inhibitors in combination with the standards of care Xtandi or Zytiga abiraterone acetate in animal models of CRPC.

AstraZeneca plc markets Casodex for prostate cancer...