Abstract 2504: Assessing the efficacy of the anti metabolic drug, CPI-613, for targeting of ovarian cancer stem cells
Authors: Bellio Chiara , Foster Rosemary , Growdon Whitfield B. , Rueda Bo R. 
Published: July 2016

Cancer stem cells (CSC) are believed to contribute to the recurrent and often platinum resistant ovarian cancer (OvCa). Moreover, it has been suggested that some anticancer treatments result in an increased frequency of CSC relative to non-CSC. More recently, we have determined that the PARP inhibitor olaparib increased the frequency of CD133, CD117 and ALDH positive cells in the established serous OvCa cell lines OVCAR4 and CaOV4 and in primary cell lines derived from serous carcinomas obtained with IRB approval at the time of initial surgery. We also showed that olaparib treatment increased sphere forming capacity, expression of stemness genes and CSC proliferation suggesting that olaparib has the unintended effect of stimulating CSC function. Previous work has shown that the metabolic inhibitor CPI-613 preferentially targets ovarian CSCs due to their altered metabolism. Our objective here was to determine whether CPI-613 could negate the effect of olaparib on CSC function.

OVCAR4 and CaOV4 cells were treated with 50 μM CPI-613 and the relative frequency of CD133+ and CD177+ cells was assessed at 72 hours post treatment by flow cytometry with cell viability analyzed by MTT. Additionally, the sphere forming capacity of CPI-613 treated cells relative to that of vehicle treated cells was determined in an extreme limiting dilution assay. Finally, the expression of stemness genes in the CPI-613 treated and vehicle treated cells was evaluated by RT-PCR.

Treatment of OVCAR4 and CaOV4 cells with CPI-613 decreased the frequency of CD133+ and CD117+ positive cells relative to untreated cells (p &lt;0.001) without affecting cell viability. Additionally, sphere forming capacity was reduced in the CPI-613 treated cells. The decrease in both CD133+ and CD117+ cell frequency and sphere forming capacity suggests that CPI-613 is targeting the CSC population in these cells. Dual treatment with olaparib and CPI-613 blunted the increase in CD133+ and CD117+ cell frequency induced by single agent olaparib. Parallel treatment of CSC-rich spheres resulted in a considerable decrease in cell viability and frequency of CD133+ and CD117+ cells

Clinical trials with olaparib in OvCa have resulted in increased progression free survival but no significant difference in overall survival has been observed. This raises the question of whether treatment with olaparib selects for the recurrence of more resistant disease, driven in part by the proliferation of CSCs. Our results suggest that CPI-613-mediated disruption of the mitochondrial respiratory pathway preferentially targets CSC and suppresses olaparib's effects on CSC function. In conclusion, targeting CSCs with non-traditional strategies could augment clinical outcomes and CPI-613 represents a promising candidate for combination with FDA approved olaparib treatment in OvCa.

Citation Format: Chiara Bellio, Rosemary Foster, Whitfield B. Growdon, Bo R. Rueda. Assessing the efficacy of the anti metabolic drug, CPI-613, for targeting of ovarian cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2504.