FCF Funded Projects

Targeting CDK7 in Fibrolamellar Carcinoma (FLC)

Status: Active

Timeframe: 2024 – 2026

Goal: Determine if targeting CDK7 could be a useful treatment approach for FLC.

Principal Investigator: Sean Ronnekleiv-Kelly, MD

Study overview: Unregulated proliferation of cells is a hallmark of cancer. In other words, cancer cells continue to divide and increase in number when normal cells would stop dividing. A family of 20 proteins known as cyclin-dependent kinases (CDKs) play key roles in the regulation of cell division and other fundamental cellular processes. While CDKs are found in both normal and cancer cells, they are frequently present at elevated levels in cancers and may promote uncontrolled cell proliferation. A particular CDK, CDK7, has been associated with rapid progression and poor prognosis of various cancers. CDK7 acts as a gatekeeper for cell division, and also regulates gene expression. For these reasons, it has become an attractive potential anticancer drug target.

Dr. Ronnekleiv-Kelly observed that CDK7 is present at significantly higher levels in FLC cells than in normal liver cells. Furthermore, collaborative studies indicate that CDK7 is required for the expression of certain genes that become “locked on” at high levels in FLC tumor cells due to the fusion protein that is found in virtually every case of FLC. Thus, CDK7 appears to be a element in the pathway that drives the transformation of normal liver cells into FLC cells.

The principal goal of the proposed work is to determine whether a drug that blocks the action of CDK7 has potential value to treat FLC. Specifically, the investigators will test the hypothesis that an inhibitor of CDK7’s protein kinase activity will prevent the production of crucial “downstream” proteins that are “turned on” by FLC’s fusion protein, thereby halting the proliferation of the cancer cells.

Syros Pharmaceuticals, Inc. (Cambridge, MA) has developed a selective inhibitor of CDK7, SY-5609, that already has advanced into clinical trials in cancer patients. Preliminary data shows encouraging activity of SY-5609 against FLC cells. The study team will examine effects of CDK7 inhibition in several FLC cell model systems, PDX models, and slice cultures prepared from fresh human FLC tumors. They also will also work to understand the role of CDK7 in controlling the biochemical pathways that underlie the growth of FLC tumors.

If the results of this study are promising, they could set the stage for a clinical trial of CDK7 inhibition, alone or in combination with other drugs, in FLC patients.