FLC’s molecular drivers
Importantly, all cases of FLC ever analyzed share a common driver – an enzyme called protein kinase A (PKA). PKA plays a critical role in the chemical signaling that controls several cell processes including growth and metabolism. The vast majority of FLC tumors contain an aberrant form of PKA that results from the fusion of the DNAJB1 and PRKACA genes (see figure). Both genes are located on the short arm of chromosome 19, and an in-frame fusion occurs due to a 400 kb deletion. In the resulting fused or chimeric protein, a small portion of one end of PKA is replaced by a segment of an unrelated protein, named DNAJ (heat shock protein 40, HSP40). This “chimera,” which is referred to as DNAJ-PKAc, retains the essential chemical activity of PKA. However, something about the fusion dysregulates the enzyme in a way that promotes fibrolamellar carcinoma.
Implications for future treatment strategies
Elimination of this DNAJ-PKAc chimeric protein, or inhibition of its activity through the use of targeted molecular therapies would be expected to stop the cancerous growth of FLC cells. Unfortunately, normal PKA is critically important for the proper function of many tissues, including heart muscle. A drug that inhibits DNAJ-PKAc but also blocks activity of normal PKA would be expected to cause significant side effects, probably ruling it out as a useful cancer treatment. By contrast, a drug against DNAJ-PKAc that spares normal PKA might be safe and effective against FLC. The creation of such a selective therapy may be possible, however finding one presents considerable challenges.
Another strategy to attack FLC would be to inhibit a “downstream” cell signaling pathway controlled by DNAJ-PKAc that is important to the chimeric protein’s ability to drive cancer. Multiple signalling pathways activated in FLC cells have already been identified. These may contain steps that could be targeted without causing the broad side effects expected with the inhibition of PKA.
An alternative approach is to harness the power of the patient’s own immune system to eliminate the cancer. Over the last decade, such immunotherapies have revolutionized cancer treatment. Advantages of this approach include the robust and lasting protection seen in some patients, and the relatively mild side effects, especially in comparison with chemotherapy. While limited data implies that FLC is usually not very sensitive to current immune checkpoint inhibitor (ICI) therapy, there are suggestions that combining an ICI with other therapeutic agents could enhance anti-tumor immunity. Vaccines or adoptive cell therapies could also potentially be effective if they can directly enhance a patient’s anti-tumor responses to unique molecules in cancer cells. In FLC, the DNAJ-PKAc chimera, which is present in FLC tumors but absent from normal cells of the same patients, could serve as a target for specific immune attack.
Resulting FCF research priorities
To accelerate progress towards a cure, the Foundation, working with its Medical & Scientific Advisory Board and other researchers, prioritizes research efforts that are most likely to lead to the development of effective systemic therapies for the disease. Those efforts include building the critical “enabling” infrastructure necessary to efficiently support FLC research efforts, driving basic research that closes gaps in our knowledge about the pathways involved in the growth and survival of FLC tumors, and investigating the promise of new targeted therapy and immunotherapy approaches.
Currently, FCF has 5 specific areas of focus, as listed below. Click on each area for more information: