Scientific Publications and Presentations

Targeting BCL-XL in fibrolamellar hepatocellular carcinoma

September 8, 2022

Sheb, Ng, Lalazar, Rosemore, Finkelstein, ... & Simon
Journal article published in JCI Insight

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.

The full text of the publication can be accessed here.