Retinoic Acid-Induced Loss of DNAJB1-PRKACA Fusion Protein Expression 2019-2020
Principal Investigator: Andrew Yen, PhD, Professor, Department of Biomedical Sciences
Co-Principal Investigator: Praveen Sethupathy, PhD, Associate Professor, Department of Biomedical Sciences
Fibrolamellar carcinoma (FLC) is driven by the DNAJ-PKAc fusion protein. A potential therapeutic strategy would be to induce loss of this key driver protein of the cancer. One approach to substantially alter gene expression in cancer cells is differentiation induction therapy, in which a well-tolerated agent with low toxicity causes malignant cells to acquire more mature, specialized characteristics and to stop proliferating. The most successful differentiation therapy agent in current use is retinoic acid (RA), which has been the standard of care for acute promyelocytic leukemia (APL). RA, a metabolite of Vitamin A, induces APL cells to convert from a transformed/proliferating malignant state resembling certain immature white blood progenitor or stem cells to a non-transformed/cell cycle-arrested state resembling the corresponding normal, mature white blood cells.
Our preliminary observations in a model cell line engineered to stably express DNAJ-PKAc showed that RA causes loss of the fusion protein. We now will assess whether RA similarly decreases the level of DNAJ-PKAc in cultured human FLC cells and determine the optimal concentration and duration of RA treatment to effect a response that may suffice to mitigate the tumor phenotype and the virulence of FLC. We will then characterize the molecular signature of this response through high-throughput sequencing of messenger RNAs and small RNA species. Because they are known downstream effectors of RA action, we will look in particular for prominent responses in three classes of molecules, namely cyclin-related cell cycle regulators, MAPK pathway signaling regulators, and stemness/developmental regulators.
Micro RNAs and long non-coding RNAs role in fibrolamellar and evaluation of RNA-based therapeutics 2017 – Current
Principal Investigator: Praveen Sethupathy Associate Professor Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine
Fibrolamellar carcinoma (FLC) is a rare liver cancer that is characterized by multi-drug resistance, early onset, and high metastatic capacity. We are leveraging genome-scale approaches to discover the most critical molecular factors that promote and maintain these key features of FLC. Specifically, we are: (1) identifying microRNAs and long, non-coding RNAs (lncRNAs) that facilitate FLC tumor formation and/or invasion and evaluating the potential of RNA-based therapeutics; (2) mapping the chromatin activity patterns in FLC to identify master transcriptional regulators; (3) defining the super enhancer landscape in FLC to identify the regulatory elements and genes most critical for driving tumor behavior; and (4) integrating different types of large-scale datasets, including metabolomics data, to identify critical druggable pathways. We are actively engaged in collaborative ventures that bring together researchers with a shared commitment to tackle this devastating disease and bring relief and hope for patients. For a description of some of our recently published work, we encourage you to visit here <https://www.cmghjournal.org/article/S2352-345X(19)30010-4/fulltext> and here<http://news.cornell.edu/stories/2019/02/key-rare-aggressive-liver-cancer-found-rna-molecule>.