Abstract
Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer
Highlights
ONC201 is a promising first-in-class small molecule that has been reported to have antineoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP)
These results suggest that ONC206 may be a promising therapeutic agent to be explored in future clinical trials in high grade serous Ovarian cancer (OC)
Given that ONC201 has unique features including broad-spectrum activity independent of mutations or tumor type, oral administration and excellent safety profile, our objective was to evaluate the effect of ONC201 on cell proliferation, cellular stress, apoptosis, invasion and tumor growth in OC cell lines and a genetically engineered mouse model of high grade serous OC; given the inter-relationship between mitochondrial dysfunction and obesity as well as ONC201’s impact on the mitochondrial modulator ClpP, we studied the anti-tumorigenic effects of ONC201 in both obese and lean mice with OC
Summary
ONC201 is a promising first-in-class small molecule that has been reported to have antineoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP). ONC201 is a promising first-in-class small molecule that was identified in a high-throughput phenotypic cell-based screen as an efficacious anti-tumorigenic therapeutic agent[5]. The mechanism of action of ONC201 results from stimulation of activating transcription factor 4 (ATF4) as well as the C/EBP homology protein (CHOP)-mediated integrated stress response (ISR), leading to induction of death receptor 5 (DR5) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and inhibition of Akt/ERK signaling pathways[5, 6]. Multiple phase II clinical trials are underway to evaluate the single agent therapeutic efficacy of ONC201, including trials in endometrial and OC [5, 16]
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