Fibrolamellar carcinoma (FLC) is a cancer that doesn’t respond well to current treatments. In past research, the Rockefeller University team conducted a broad-based, small-molecule drug screen to identify potential drug candidates to use against FLC. That effort identified several potential drugs including napabucasin, panobinostat, irinotecan (a topoisomerase I inhibitor), and navitoclax (an inhibitor of the proteins BCL-XL and Bcl-2).
In this study, the team identified the compounds from that drug screen that they felt were most clinically translatable and tested them on a series of different human FLC cell lines derived from xenograft models. They discovered that inhibiting a protein called BCL-XL can enhance the effectiveness of various treatments for FLC. However, targeting BCL-XL in cancer treatment using the drug navitoclax can cause a severe decrease in blood platelets.
To overcome this issue, the scientists tested a new drug called DT2216, that specifically targets BCL-XL over Bcl-2 and has lessened impact on blood platelet counts. DT2216 is a PROTAC under development by Dialectic Therapeutics and is currently in Phase I clinical trials. PROTACs (Proteolysis Targeting Chimeras) are protein degraders. Instead of inhibiting a target protein, they bind to a target protein and use a cell’s own “waste disposal machinery” to eliminate it.
This research showed that combining DT2216 and irinotecan could be a promising approach to treat FLC. It also noted that FLC registry data has shown that at least 3 patients with advanced FLC treated with irinotecan had some degree of clinical benefit. Clinical trials of this combination therapy are now in development based on these findings.
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