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TRAIL is an endogenous protein that induces tumor cell apoptosis via its interaction with death receptors DR4 or DR5 ( ONC201 works by a unique mechanism of action, inhibition of dopamine receptors and direct activation of the enzyme ClpP ( Two pathways are consistently impacted by ONC201 administrationactivation of the ISR pathway ( via activation and nuclear translocation of Foxo3a and its receptor DR5 ( One of the most attractive aspects in the prospect of ONC201 as an emerging SCLC therapy is its low risk of toxicity when administered in both mice and humans ( via early-stage ISR activation in the tumor cells that seemingly spares healthy epithelial and organ tissue cells ( in vitro in mouse models and did not produce any significant toxicities in the mammals and did not induce DR5 or TRAIL in normal epithelial cells ( While approximately 10% of all SCLC patients present with brain metastases and 40% of all SCLC patients will experience brain metastases in their disease, it is crucial to consider which novel agents may cross into the central nervous system