Ex Vivo Modelling of Therapy Efficacy for Rare Krukenberg Tumors – A Report of Two Cases

Krukenberg tumor (KT) is a rare subtype of ovarian neoplasms that manifests as secondary ovarian cancer.\r\nMost frequently, KTs originate from a primary in the gastrointestinal tract and account for 30 to 40% of all\r\nsecondary ovarian cancers. A key histologic characteristic finding used in the diagnosis of KT is the\r\npresence of mucin-laden signet-ring cells. Bilateral metastasis into both ovaries has been reported in more\r\nthan 80% of KTs, and a significant fraction of these cases are reported to receive no survival benefit from\r\nchemotherapy. Despite clinical evaluation of several chemotherapeutic treatments for the management of\r\nKT, the general prognosis of the disease is poor and radical surgery remains the main treatment shown to\r\nimprove the overall survival. As no targeted therapies have been reported for KT, we performed an ex vivo\r\ndrug screen to assess the efficacy of targeted therapeutics with patient-derived Krukenberg tumor cells.\r\nTumor cells isolated from a coarse needle biopsy and tumor-associated immune cells derived from\r\nmalignant ascites effusion from two patients with a gastric cancer derived KT were used for the analysis of\r\nresponses to 120 drugs. A comparison of the results showed that tumor cells from both patients showed\r\nsystematic sensitivity toward topoisomerase inhibition, epigenetic modulators, statins and alkaloid tubulin\r\ninhibitors. Ascites-derived immune cells displayed selective sensitivity to a number of targeted agents,\r\nincluding VEGFR inhibitor sunitinib. Flow cytometry analysis identified the effect of sunitinib to be\r\nimmunomodulatory and targeted on the immunosuppressive M2 type macrophages. The\r\nimmunomodulatory effect of sunitinib was confirmed from analysis of the patient ascites following\r\ntreatment and was accompanied by sustained clinical response. These results support the concept of\r\nharnessing the immunomodulatory effects of VEGFR-TKI for cancer therapy and suggest further analysis\r\nalso in the context of Krukenberg tumors.