From TRAIL to ONC201: Case study on the safety benefit of developing targeted agents against cancer-selective pathways

A major goal of drug development is to end up with a safe and effective therapy for a disease such as cancer. We describe our experience with taking the small molecule ONC201/TIC10 from the lab to clinical trials. The path involved a phenotypic drug screen to identify a small molecule that activates a pathway that has been established as cancer specific - the TRAIL pathway. In vitro experiments in multiple tumor types and in normal cells led to the identification of drug candidates that have a favorable therapeutic index, a key characteristic for any successful drug. ONC201 was chosen for in vivo testing in rodent species. It was tested via different routes of administration and different frequencies, and different tissues were analyzed after varying drug-exposure times. Valuable information was gained on drug efficacy, bioavailability, and impact on non-tumor tissue. Pharmacodynamic parameters were assessed in tumor xenografts and in normal tissue to understand the drug’s activity in both tumor and normal cells, and additional IND-enabling studies were performed before the drug entered into clinical trials. Ongoing efforts continue to unravel the mechanism of action of ONC201 with a goal of optimizing biomarkers of clinical response. ONC201 clinical development continues with observed single-agent safety and efficacy and with pursuit of combination therapy studies in various tumor types. Further understanding of the molecular mechanisms of ONC201 should lead to rationally designed combination therapy studies and a more comprehensive biomarker analysis that may improve patient selection and patient benefit.