171082-176

Dose-intensified ONC201 to exert anti-metastatic efficacy and to promote intra-tumoral recruitment of NK-cells in mice.

Subcategory: 
Category: 
Tumor Biology
Session Type and Session Title: 
Poster Session, Tumor Biology
Abstract Number: 

11550

Poster Board Number: 
Board #247
Citation: 
J Clin Oncol 34, 2016 (suppl; abstr 11550)
Author(s): 
Jessica Wagner, Christina Leah B. Kline, Wafik S. El-Deiry; Fox Chase Cancer Center, Philadelphia, PA

Abstract Disclosures

Abstract: 

Background: ONC201 is a novel, first-in-class, orally active anti-tumor agent that upregulates the cytotoxic ligand TRAIL and activates an integrated stress response, leading to upregulation of death receptor 5 in bulk tumor and cancer stem cells. ONC201 is being evaluated in multiple clinical trials, where it has demonstrated safety and a preliminary efficacy signal. In the first-in-human trial, patients were dosed every 3 weeks. We investigated dose-intensification of ONC201 to determine whether a higher dose and frequency schedule could impact efficacy with limited toxicity. Methods: HT-29-luciferase, HCT116 p53-null, and MDA-MB-231-luciferase xenografts were treated with ONC201 at doses ranging from 25 mg/kg to 100 mg/kg and frequencies ranging from twice per week to once every 1, 2, 3, or 4 weeks. Results: ONC201 exerted a dose- and schedule-dependent effect on tumor progression in vivo. ONC201 potently suppressed Akt and ERK in a dose- and frequency-dependent manner in vivo, and TRAIL serum levels were impacted by drug frequency. In mouse xenograft models we noted a potent anti-metastatic effect. In culture, ONC201 negatively impacted cancer cell migration and invasion, even in cells that are resistant to ONC201-induced apoptosis. We observed accumulation of CD3+/NK1.1+ cells within ONC201-treated tumors in athymic nude mice, and an upregulation of NK1.1+ cells in C57/BL6 mice without tumor xenografts. The accumulation of CD3+/NK1.1 cells within ONC201-treated tumors appeared more pronounced with dose intensification and is currently being investigated in syngeneic models. Conclusions: These results prompted a phase I dose intensification clinical trial at Fox Chase Cancer Center that is actively enrolling patients. We are evaluating the characteristics and function of the CD3+/NK1.1+ cells and the relationship of their intra-tumoral accumulation to the observed anti-tumor effects of ONC201. Our results present evidence of the unique and potent nature of ONC201 as an anti-tumor agent that demonstrates efficacy, reduces or prevents metastasis, and increases NK cell recruitment to tumors.