Fig. 2. ONC201 mechanism of action. (A) ONC201 affects bulk tumor cells, tumor stem cells and normal cells in the tumor microenvironment, including immune cells and fibroblasts, to elicit anti-cancer effects. DRD2 antagonism and ClpP activation by ONC201 are upstream events while downstream eve...
Recent demonstration that mechanism of action of small molecule imipridone ONC201 could be mediated through mitochondrial targeting (Graves et al., 2019; Greer et al., Ishizawa et al., 2019), was confirmed by identification of mitochondrial caseinolythic protease (ClpP), as the only target of...
image: Figure 8 shows the proposed mechanism of action of ONC201 (see detail in Discussion). Image: Stanley Lipkowitz TRAIL, a member of the TNF family of ligands, causes caspase-dependent apoptosis through activation of its receptors, death receptor 4 and DR5. ONC201 was originally ...
but the mechanism behind this remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/CSF correlate samples from patients treated in two completed multi-site clinical studies. Patients treated with ONC201 following initial
ONC201 was discovered as a p53-independent inducer of TRAIL gene transcription and had an anti-proliferative and anti-apoptotic effects against a broad range of tumor cells [19], [20], [21], [22]. The mechanism of action of ONC201 engages PERK-independent activation of the integrated ...
Onc201, a new compound, induces the gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and has an efficient anticancer effect in clinical trials. However, its effects on osteolytic disease and the mechanism of action are unclear. We examined the effect of Onc201 ...
A central finding from our work is that ONC201 primarily activates the mitochondrial protease, ClpP in DIPG patient-derived cell lines, an effect consistent with recently described ONC201 mechanism of action in other tumors. We further demonstrate that activation of ClpP by ONC201 leads to a ...
of tumor cells but not normal cells. The mechanism of action ofONC201involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand...
From a financial point of view, cross border health costs were covered by the European S2 mechanism of reimbursement (https://europa.eu/youreurope/citizens/health/planned-healthcare/right-to-treatment/index_en.htm) or by private funding. 2.2. ONC201 compounding Due to the absence of the ...
The detailed mechanism of action has been reported by Ishizawa et al. [19]. In this study, ONC201 activated the protease and facilitated the activation of ClpP and the ClpP mediated cleavage of substrates within the mitochondria. The induction of mitochondrial ClpP activation leads to the reductio...