Abstract 3196: STAT3 inhibitor WP1066 as a novel therapeutic for medulloblastoma
Authors: Laura K. Metrock, Jingbo Liu, Liangping Yuan, Hongying Zhang, Abhinav Dey, Tobey MacDonald.
Journal: Cancer Research (2016)

Abstract The purpose of this study is to determine the efficacy of the STAT3 inhibitor WP1066 on the sonic-hedgehog (SHH) subtype of medulloblastoma (MB). STAT3, or signal transducer and activator of transcription 3, is a potential novel target for the treatment of SHH-MB. We have generated substantial preliminary data showing that STAT3 activation promotes the survival of SHH-MB cancer stem cells (CSCs) that are critical for treatment resistance and tumor recurrence. Smoothened (SMO) antagonists have shown efficacy in treating subtypes of SHH-MB, however all tumors develop resistance and SMO inhibitors are ineffective for patients with SHH-MB harboring mutations downstream of SMO. Our preliminary in vitro data suggests that combined SMO and STAT3 inhibition has synergistic activity, and that constitutively activated STAT3 is protective against SHH-MB cell death mediated by SMO inhibition. Methods: The effect of increasing concentrations of WP1066 on Shh-responsive MB cells was assessed by Western blot analysis for STAT3 phosphorylation, WST assay for cell proliferation, and soft agar colony formation. The effect of WP1066 on apoptosis and the cell cycle was assessed by flow cytometry. An ex vivo murine SmoA1 SHH-MB brain slice culture method was used to assess the effects of WP1066 alone and in combination with radiation. In vivo studies consist of mice treated with 1) WP1066, 2) SMO inhibitor LDE225 3) WP1066 in combination with LDE225 and 4) vehicle alone. All mice are imaged by MRI prior to treatment and every 3 weeks after treatment. Tumor volume is calculated and rate of tumor growth and survival are measured. The mice are followed until death or the end of the experiment at 36 weeks. Results: In human Shh-responsive MB cells in vitro, WP1066 blocked IL6-induced STAT3 activation (phosphorylation), decreased cell proliferation and abrogated tumor colony formation. Results regarding the mechanism of inhibition of cell proliferation/viability by WP1066 (i.e. apoptosis and cell cycle analysis) are pending. In the SHH-MB brain tumor slice cultures, WP1066 treatment induced potent tumor cell kill, especially of the CSCs within the perivascular niche. WP1066 also showed synergy with radiation, but did not add toxicity to normal brain cells. Preliminary in vivo data indicate a statistically significant decrease in the rate of tumor growth and prolonged survival in mice treated with WP1066 compared to vehicle control. Results of the efficacy of WP1066 with LDE225 are pending. Conclusions: WP1066 has potent efficacy against Shh-responsive MB cells in vitro and SHH-MB tumors ex vivo, without toxicity to normal brain cells. Preliminary data is promising for WP1066 activity against SHH-MB in vivo, suggesting WP1066 is a novel therapeutic for SHH-MB. Citation Format: Laura K. Metrock, Jingbo Liu, Liangping Yuan, Hongying Zhang, Abhinav Dey, Tobey MacDonald. STAT3 inhibitor WP1066 as a novel therapeutic for medulloblastoma. [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 3196.