University of California at San Diego

Goal: Determine the molecular mechanisms of FLC and identify new pharmacological agents that could lead to effective therapeutics

Principal Investigator: Jin Zhang, PhD

Grant length: Two years

Study overview: In recent studies, the investigation team discovered that the presence of the FLC oncogenic fusion protein disrupts a membraneless organelle. They showed that loss of this membraneless organelle in normal cells results in aberrant signaling as well as increased cell proliferation and transformation. Based on these data, they hypothesize that loss of this membraneless organelle induced by the oncogenic fusion leads to defects in cellular functions and drives tumor formation. The identification of pharmacological agents that recover this membraneless organelle in the presence of the oncogenic fusion protein, could provide useful leads for developing new therapeutics. In this research, the team will test these hypotheses by combining a variety of novel approaches, including live-cell biochemistry. They will undertake mechanistic studies in the established model systems and perform drug screens, in conjunction with additional collaborators with complementary expertise. The study should provide new insights into the cause of FLC and enable new therapeutic strategies to tackle this lethal cancer.

Goal: Uncover the function of SLC16A14, a protein uniquely expressed in fibrolamellar carcinoma (FLC) and absent from normal tissues and other cancers

Principal Investigator: Avner Schlessinger, PhD

Grant length: One year

Study overview: Prior FCF-funded research demonstrated that the transporter protein, SLC16A14, is essential for FLC cell survival and appears to be regulated by FLC’s DNAJ-PKAc fusion protein, making it an attractive therapeutic target. However, the molecule(s) transported by SLC16A14 remain unknown, classifying it as an “orphan” transporter.

Dr. Schlessinger’s team will use advanced artificial intelligence, structural modeling, and computational biology approaches to predict the three-dimensional structure of SLC16A14, identify substrate-binding sites, and determine the molecule(s) transported. The investigators will also conduct virtual screening of metabolites, prescription drugs, and chemical libraries to identify compounds that may inhibit SLC16A14 function.

Successful completion of the project will:

• Identify the substrate(s) transported by SLC16A14, providing critical insight into its biological role in FLC.
• Identify chemical tool compounds and inhibitors that could disrupt SLC16A14 function.
• Establish a foundation for future therapeutic development targeting this FLC-specific protein.

Goal: To identify and optimize targeted protein degraders that selectively eliminate the cancer-driving DNAJ-PKAc fusion protein in fibrolamellar carcinoma while sparing normal proteins

Principal Investigator: Fleur Ferguson, PhD

Grant length: Six months

Study overview: Dr. Fleur Ferguson (UC San Diego), in collaboration with Dr. Nabeel El-Bardeesy (Massachusetts General Hospital), is exploring whether targeted protein degradation can be used to treat fibrolamellar carcinoma (FLC). Unlike traditional drugs that simply block a protein’s activity, targeted degraders eliminate disease-causing proteins from the cell. The team has developed a lead degrader, JEK-01-186, that selectively targets overactive forms of PKACA. This selectivity is critical because normal PKACA plays essential roles in healthy tissues, including the the heart, and previous PKACA inhibitors have been limited by toxicity. A goal is to determine if JEK-01-186 reduces DNAJ-PKAc levels in FLC cell models and inhibits tumor cell growth, while having minimal effects on healthy cells.

The proposed work will:

• Develop high-throughput cellular assays to measure degradation of DNAJ-PKAc in FLC models.
• Determine how cellular signaling pathways affect degrader activity and selectivity.
• Screen and validate a library of PKACA-targeted degraders to identify the most potent and selective candidates.

If successful, the project could identify promising drug candidates and establish a robust platform for future therapeutic development. More broadly, it could determine if selective degradation of the fusion protein is a feasible therapeutic strategy for FLC.