Novel mithramycin derivatives for cancer chemotherapy
The development of Ewing Sarcoma therapeutics revolves around the natural product anticancer agent mithramycin (MTM), which was recently shown to be a potent inhibitor of Ewing sarcoma cells in culture and mice, by disrupting the activity of the aberrant transcription factor EWS-FLI1. However, MTM is highly toxic and modestly selective against Ewing sarcoma cells. A recent phase I/II clinical trial of MTM monotherapy against Ewing sarcoma did not progress due to toxic side effects. MTM suffered from rapid drug clearance, precluding reaching efficacious concentrations in plasma. We have developed MTM analogues with improved pharmacologic properties and are in process of evaluating their efficacy in animal models. Specifically, these analogs have improved pharmacokinetics (concentration over time), decreased systemic toxicity and preferential toxicity for Ewing Sarcoma over other cancer cells. Importantly, these molecules are preferentially toxic to cells expressing transcription factors such as EWS-FLI1 (eg, prostate cancer, which presents a much higher population).
Next steps are to a) test the pharmacokinetics of these molecules in non-human primates; b) Test the toxicity and efficacy to these analogues in a mouse with deficient esterase activity. (Mice have much higher esterase activity in their blood than humans and the designed analogues have ester moieties that are susceptible to premature degradation. The esterase deficient mice will mimic the human blood environment.); c) Scale-up the synthesis of the molecules via third party (Contract research organization); d) Perform studies required to file IND application.