Inhibitor library screening identifies ispinesib as a new potential chemotherapeutic agent for pancreatic cancers.

Screening custom-made libraries of inhibitors may reveal novel drugs for treating pancreatic cancer. In this manner, we identified ispinesib as a candidate and attempted to determine its clinical efficacy and the biological significance of its functional target Eg5 in pancreatic cancer. One hundred compounds in our library were screened for candidate drugs using cell cytotoxicity assays. Ispinesib was found to mediate effective antitumor effects in pancreatic cancer. The clinical significance of the expression of the ispinesib target Eg5 was investigated in 165 pancreatic cancer patients by immunohistochemical staining and in Eg5-positive pancreatic cancer patient-derived xenograft (PDX) mouse models. Patients with Eg5-positive tumors experienced significantly poorer clinical outcomes than those not expressing Eg5 (overall survival; P < .01, recurrence-free survival; P < .01). Ispinesib or Eg5 inhibition with specific siRNA significantly suppressed cell proliferation and induced apoptosis in pancreatic cancer cell lines. Mechanistically, ispinesib acted by inducing incomplete mitosis with nuclear disruption, resulting in multinucleated monoastral spindle cells. In the PDX mouse model, ispinesib dramatically reduced tumor growth relative to vehicle control (652.2 mm3 vs 18.1 mm3 in mean tumor volume, P < .01 by ANOVA; 545 mg vs 28 mg in tumor weight, P < .01, by ANOVA). Ispinesib, identified by inhibitor library screening, could be a promising novel therapeutic agent for pancreatic cancer. The expression of its target Eg5 is associated with poorer postoperative prognosis and is important for the clinical efficacy of ispinesib in pancreatic cancer.

Usefulness of on-site cytology of liver tumor biopsy in specimen sampling for cancer genomic profiling test.

AIM: Appropriate sample selection with a tumor fraction ≥20% without necrosis contamination is required for successful cancer genomic profiling (CGP). Rapid on-site evaluation (ROSE) is performed to assess adequate sampling. METHOD: This retrospective study included 54 patients who underwent CGP using liver tumor biopsy specimen with ROSE. RESULT: The sampling success rate (98.1%) was higher than the previously reported 77.5%-88.9%. ROSE was performed once in 51 patients and twice in three patients; for those undergoing ROSE twice, the first ROSE was negative for malignancy, or showed few tumor cells with necrotic cell contamination, while the second ROSE obtained from another location showed abundant malignant cells. In these patients, the CGP was successful using the second specimen, though the first sample did not meet the required criteria for CGP test. CONCLUSION: Performing ROSE during liver tumor biopsy may be useful for CGP test sampling because ROSE prevents sampling errors and contributes to adequate sampling.