Mechanistic Pharmacology

The fundamental focus of our lab is on mechanisms of targeted therapeutics. Our goal is to identify novel therapeutic agents and understand the mechanism of target blockade. This knowledge allows us to better understand how to effectively administer the compound to patients and at the same time develop mechanistically focused combination therapies. We believe that a deep mechanistic understanding of a given compound is required to effectively move compounds from the preclinical setting to patients.

Trabectedin, Lurbinectedin and analogs:  Our studies of trabectedin, lurbinectedin and other analogs are emblematic of our approach. We identified trabectedin as an EWS-FLI1 inhibitor almost a decade ago. 

We reported the synergistic combination of trabectedin and irinotecan and related the synergy to EWS-FLI1.  Trabectedin exposure suppresses EWS-FLI1 to block expression of the WRN helicase and sensitize the cells to the DNA damaging effects of irinotecan. Irinotecan feeds back to amplify and sustain EWS-FLI1 suppression. Both effects require EWS-FLI1 which is only found in Ewing sarcoma cells.

We found that trabectedin causes a redistribution of EWS-FLI1 within the nucleus to the nucleolus likely accounting for the suppression of activity. Importantly, we identified lurbinectedin as a second-generation compound with an improved toxicity profile that also causes this phenotype.

Clinical anecdotal responses to trabectedin/irinotecan have been described.

We have determined that this class of compounds triggers an epigenetic switch leading to an increase and redistribution of histone post-translational modifications associated with gene silencing, H3K27me3 and H3K9me3. Importantly, these effects are schedule dependent and require a threshold concentration. This provides the justification for our clinical study of trabectedin and the basis for the use of lurbinectedin in the clinic in this disease type. 

Future directions, goals and current projects:  We continue to delve into the mechanism of EWS-FLI1 suppression of this class of compounds as a means to understand therapeutic response and resistance and an opportunity to discover new drug combinations. In addition, we are exploring the activity in related tumor types.