A UW-Madison researcher has developed an oral combination therapy for treating fibrolamellar carcinoma (FLC) that utilizes a CDK7 inhibitor and a CDK9 inhibitor. The researcher created a cancer cell line using HepG2, human cells, modified to induce the DNAJ-PKAc in the cells. He noted that CDK7 was aberrantly expressed. This observation was confirmed using human FLC cells. Treating FLC cells with a specific reversable inhibitor of CDK7, an inhibitor that covalently attaches to CDK7, and an siRNA construct against CDK7 all led to FLC cell death. Additional work showed that CDK9 could also be a target based on the phosphorylation patterns of proteins the researcher identified as being overactivated in cells containing the pathogenic DNAJ-PKAc fusion. The combination of the two molecules provides a synergistic effect which should expand the therapeutic window (could use lower doses which should avoid toxicity and off target effects) when treating this cancer.
SY5609 and VIP152 are the drugs he’s tested in this model with good initial response. These drugs are owned by Syros and Vincerx, respectively. Sean has determined the mechanism of tumorigenicity for these kinases; how they function as signaling molecules that are overactivated by the fusion oncogene. He has interest in taking these molecules into the clinic.