Abstract A62: TRX-1 targets chemoresistant tumor-initiating cells and prolongs survival in a recurrent ovarian cancer animal model.

Abstract

Abstract Background: Ovarian cancer is the leading cause of mortality from gynecologic cancers due to the high incidence of chemoresistance and disease recurrence. Disease recurrence is thought to occur due to the presence of residual disease following first-line standard of care (i.e. optimal debulking and chemotherapy). Residual disease post chemotherapy is composed of a unique population of chemoresistant cancer cells with stemness properties and a high capacity for tumor repair. Currently, there are no available options that can target these cells. The objective of this study was to develop a new therapeutic modality that will target chemoresistant ovarian cancer stem cells (OCSC) and consequently prevent recurrence and improve survival. To achieve this objective we developed a library of super-benzopyran (SBP) analogues and identified TRX-1 as the most potent analogue able to induce OCSC cell death in a short period of time. Moreover, in contrast to Cisplatin and Paclitaxel, TRX-1 is able to induce a persistent growth inhibitory effect both in vitro and in vivo thus improving overall survival in a mouse model of recurrent ovarian cancer. Materials and methods: A panel of SBP analogues were generated and activity was determined by testing against pure clones of CD44+/MyD88+ OCSC. In vitro efficacy was assessed using the IncucyteTM kinetic imaging platform complemented by CelltoxTM dye labeling. In vivo efficacy was tested using an intra-peritoneal (i.p.) a mouse model of recurrent ovarian cancer1. Results: TRX-1 was the most potent analogue identified and is able to induce cell death in all OCSC clones tested (IC50 of 136 nM). We observed that 2h in vitro exposure to 2μM TRX-1 was sufficient to induce a sustained growth inhibitory effect in OCSC, hence the cells were not able to recover growth potential even after removal of the drug. In contrast, OCSC exposed for up to 24h with the same dose of Cisplatin or Paclitaxel were able to recover. In vivo, animals bearing residual tumors after Paclitaxel treatment demonstrated tumor progression when further maintained with vehicle or Paclitaxel indicating Paclitaxel resistance. In contrast, maintenance with TRX-1 was able to effectively decrease tumor burden (p = 0.02) and prevent recurrence. In addition, combination treatment with TRX-1 and Cisplatin was able to significantly improve survival (p<0.001) compared to Cisplatin alone. Conclusion: We describe the in vitro and in vivo anti-tumoral effect of a novel compound, TRX-1, which exhibits significant efficacy against chemoresistant OCSC and is able to prevent recurrence in a chemoresistant in vivo model. Recurrence characterized by chemoresistance is the main cause of mortality in ovarian cancer patients. Previous studies from our laboratory have shown that conventional chemotherapy is not effective against OCSC and cannot prevent recurrence. Our finding that TRX-1, by targeting OCSC can prevent recurrence in vivo as maintenance therapy or in combination with chemotherapy provides a new opportunity for developing new therapeutic strategies that can improve survival in ovarian cancer patients. Citation Format: Ayesha Alvero, Eydis Lima, Mary Pitruzzello, Yang Yang-Hartwich, David Brown, Andrew Heaton, Gil Mor. TRX-1 targets chemoresistant tumor-initiating cells and prolongs survival in a recurrent ovarian cancer animal model. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A62.