Abstract 1105: A chemotherapeutic approach to kill cancer stem cell rich ovarian ascites
Authors: Siddik Sarkar, Obeid M. Malekshah, Arash Hatefi
Journal: Cancer Research (2017)

Abstract Purpose: More than one third of ovarian cancer patients present with cancer cells in the abdomen (also known as ascites) at diagnosis, and almost all have ascites at recurrence (Ahmed and Stenvers 2013). It is well-documented that subpopulations of the ascites show cancer stem cell-like characteristics which possess enhanced resistance to chemotherapies and the capacity for distal metastatic spread and recurrent disease. Therefore, ascites are a major source of morbidity and mortality for ovarian cancer patients. The major deficiency that currently exists is that there is no effective and safe therapy for ascites since they are rich in cancer stem cells (CSCs) and resistant to chemotherapy. To overcome this deficiency, it is our objective to develop an effective chemotherapy approach that can destroy the CSC-rich ascites and inhibit recurrence. Methods: Several established human ovarian cancer cells as well as ascites obtained from the abdomen of an ovarian cancer patient (ASCITES) were cultured. Cells were sorted by FACS Cell Sorter to determine the percentage of cancer stem cells (CSCs) in each cell line. Dose response curves of different chemotherapeutic drugs such as Cisplatin (CDDP), 6-Methylpurine (6-MP), 5-Flurouracil (5-FU), SN-38, Monomethyl auristatin E (MMAE) and Etoposide were studied in suspension culture enriched with cancer stem cells. The relative change in total CSC-rich spheroid mass which considers both number and volume of spheroids was used to determine Killing Index for each chemotherapeutic drug. To investigate inhibition of recurrence, the spheroids were monitored for 30 days post treatment and the viability of CSC-rich spheroids were studied by fluorescent microscopy. Results: Primary human ovarian A2780 and ASCITES (derived from ovarian cancer patient Ascitic fluid) were found to have CSCs with unlimited renewal capacity in suspension culture. While Cisplatin, 5-FU, 6-MP and Etoposide showed efficacy in killing CSC spheroids at effective doses around 1-10 μM, but MMAE and SN-38 showed the ability to either significantly diminish or completely eradicate CSC spheroids with effective doses as low as 10 nM. Importantly, no evidence of recurrence (repopulation of spheroids) was observed in MMAE and SN-38 treated group even after 30 days of post treatment. Conclusion: These promising results with the two chemotherapeutic drugs that show their ability to kill highly drug-resistant CSC-rich ovarian spheroids open the door to further investigate their use in the clinic. Currently, we are investigating the potential use of these two drugs in combination but at very low concentrations for the treatment of abdominal ovarian metastasis. Citation Format: Siddik Sarkar, Obeid M. Malekshah, Arash Hatefi. A chemotherapeutic approach to kill cancer stem cell rich ovarian ascites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1105. doi:10.1158/1538-7445.AM2017-1105