Bladder cancer metastasis is virtually incurable with current
platinum-based
chemotherapy. We used the novel COXEN informatic approach for in silico
drug discovery and identified NSC-637993 and NSC-645809 (
C1311), both imidazoacridinones, as agents with high-predicted activity in human
bladder cancer. Because even highly effective monotherapy is unlikely to cure most patients with
metastasis and NSC-645809 is undergoing clinical trials in other
tumor types, we sought to develop the basis for use of
C1311 in rational combination with other agents in
bladder cancer. Here, we demonstrate in 40 human
bladder cancer cells that the in vitro cytotoxicity profile for
C1311 correlates with that of NSC-637993 and compares favorably to that of standard of care chemotherapeutics. Using genome-wide patterns of synthetic lethality of
C1311 with open reading frame knockouts in budding yeast, we determined that combining
C1311 with a
taxane could provide mechanistically rational combinations. To determine the preclinical relevance of these yeast findings, we evaluated
C1311 singly and in doublet combination with
paclitaxel in human
bladder cancer in the in vivo hollow fiber assay and observed efficacy. By applying COXEN to gene expression data from 40
bladder cancer cell lines and 30 human
tumors with associated clinical response data to
platinum-based
chemotherapy, we provide evidence that signatures of
C1311 sensitivity exist within nonresponders to this regimen. Coupling COXEN and yeast chemigenomics provides rational combinations with
C1311 and
tumor genomic signatures that can be used to select
bladder cancer patients for clinical trials with this agent.