ONC201 is a small molecule that is being developed as a novel anticancer drug based on its compelling antitumor activity (Allen et al, Sci Transl Med, 2013). ONC201 possesses a mutation-agnostic efficacy profile that is not impaired by oncogenic mutations that commonly drive disease progression and therapeutic resistance. Given the strong apoptotic potential of ONC201 in a variety of human malignancies, there was a potential concern for normal cell toxicity based on historical experience with potent cytotoxic agents.

To establish the safety profile of ONC201, a series of studies was conducted with ONC201 in normal human cells at efficacious and exaggerated doses. With respect to cell viability, dose response relationships between normal human fibroblasts and tumor cell lines revealed a similar inflection point at ~2-5 µM that subsequently saturated in all tested cell lines. Interestingly, saturation of the effects occurred at a much higher level of viability reduction in tumor cells as compared to normal cells. Further investigation revealed that ONC201 does not cause any appreciable levels of cell death in normal cells, which are drastically increased in tumor cells, and that the small effect on normal cell viability is transient and reversible. Studying downstream signaling effects in tumor vs normal cells revealed that ONC201 did not induce DR5 in normal cells under conditions that induced DR5 in tumor cells. This differential DR5 induction is explained by recent mechanistic findings with ONC201 that implicate the ER stress response in its antitumor mechanism, which activates CHOP that positively regulates the human DR5 gene as part of the maladaptive response (Ishizawa J et al, ASH 2014). Thus ONC201 induces a strong apoptotic response in tumor cells at doses that do not affect normal cells, which is reflective of an attractive therapeutic window.

The lack of cytotoxicity in normal cells was also confirmed in a panel of normal human bone marrow specimens, including examination of normal progenitor cells. The absence of bone marrow toxicity despite extremely high apoptotic activity in refractory primary human lymphoma samples is a unique and compelling feature of ONC201 compared to available clinical agents in this setting. The genotoxic potential of ONC201 was also assessed in normal and tumor human cell lines. Unlike chemotherapy positive controls, ONC201 did not induce gamma-H2AX, the genotoxic stress marker, in tumor or normal cell lines. The lack of genotoxicity in addition to absence of normal cell toxicity exhibited by ONC201 in preclinical studies enables a range of potential therapeutic settings for application, such as pediatric indications as well as adjuvant and neoadjuvant settings.

To enable translation and confirm the safety profile of ONC201, GLP toxicology studies were conducted in Sprague Dawley rats and beagle dogs with single oral doses of ONC201. Dogs received a single dose of 0, 4.2, 42, or 120 mg/kg by oral gavage, which represents a human equivalent of 0, 125 mg, 1.25 g, and 3.57 g, respectively. Rats received 0, 12.5, 125, or 225 mg/kg ONC201 by oral gavage, which represents a human equivalent of 0, 125 mg, 1.25 g, and 2.25 g, respectively. There were no deaths or dose-limiting toxicities. The only findings that were observed in both rats and dogs occurred at the highest doses tested and were mild and reversible: decreased activity (no indications of anemia), decreased food consumption (weight loss only seen in rats), and salivation. The NOAEL was at least 42 mg/kg in dogs and at least 125 mg/kg in rats. Based on regulatory guidance documents, the starting dose in human clinical trials will be a 125 mg oral dose given once every three weeks, which represents a starting efficacious dose based on preclinical tumor xenograft studies in mice. The strong cytotoxic potential of ONC201 in human cancer cells without compromising safety bodes well for its scalability into clinical settings where traditional therapies are too toxic to be implemented.


Allen:Oncoceutics: Employment, Equity Ownership, Patents & Royalties. El-Deiry:Oncoceutics: Equity Ownership, Patents & Royalties. Andreeff:Oncoceutics: Equity Ownership.

Author notes


Asterisk with author names denotes non-ASH members.

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