E7820, a sulphonamide-type anticancer agent, was developed to inhibit angiogenesis by suppressing integrin α2 expression. Although early-phase trials outside Japan established 100 mg/day as the maximum tolerated dose in monotherapy, no objective responses were observed, and further development was not planned. Subsequent studies revealed that E7820 promotes DCAF15-mediated degradation of the splicing factor RBM39 and acts as a molecular glue, providing a novel mechanism and rationale for clinical evaluation. Preclinical screening using patient-derived xenograft models demonstrated antitumour activity in biliary tract and endometrial cancers and in tumours with homologous recombination repair gene alterations. Based on these findings, the CIRCUS trial, a multicentre investigator-initiated phase I study, was initiated to assess the safety, tolerability, and preliminary efficacy of E7820 in Japanese patients with unresectable solid tumours. If the proof of concept is demonstrated in biomarker-defined cohorts, E7820 may be repositioned for selected patients, providing insights into the development of previously intractable compounds.
Okada et al. (Thu,) studied this question.