Retinoic Acid-Induced Loss of DNAJB1-PRKACA Fusion Protein Expression

Principal Investigator: Andrew Yen

Co-PI: Praveen Sethupathy

Department of Biomedical Sciences
Sponsor: Fibrolamellar Cancer Foundation
Title: Retinoic Acid-Induced Loss of DNAJB1-PRKACA Fusion Protein Expression
Project Amount: $33,104
Project Period: September 2019 to August 2020

DESCRIPTION (provided by applicant): 

Fibrolammellar hepatocellular carcinoma, FLC, is a rare fatal metastatic liver tumor arising from a cytogenetic aberration that results in a fusion protein seminal to the disease. This fusion of the N-terminal of an Hsp40 (heat shock protein 40) with the carboxyl end of PKA (protein kinase A) catalytic subunit α resulting in a rogue protein is the transformative event for tumorigenesis. We made the serendipitous discovery that retinoic acid causes loss of the fusion protein expressed in a stably transfected hepatocarcinoma cell line. This suggests the possibility that retinoic acid could have therapeutic activity against FLC by causing loss of the transforming protein for this tumor, thereby relieving the hepatic cells of the tumor phenotype. The proposed work will exploit the observation in this experimental model and extend it to primary cultured FLC cells. The milestone goals are to: 1. Determine if retinoic acid causes loss of the fusion protein in FLC cells and 2. Characterize the molecular signature and cellular attributes of the retinoic acid-induced FLC cell response. If successful this will (1) demonstrate that retinoic acid, a drug already approved and used in leukemia therapy, has an off label application for FLC, and (2) Identify candidates to target for more sophisticated combination therapy, an emerging therapeutic modality that is proving effective in retinoic acid based therapy against other tumors. The basic rationale is that if a drug relieves the FLC cells of the tumor causing protein, then the tumor phenotype would be relieved. The strategy is ergo to modify the tumor cell and render it harmless using a relatively non-toxic agent instead of trying to kill it with very toxic agents that engender considerable host morbidity.