Timeframe: 2022 – 2025
Goals: Identifying how the DNAJ-PKAc/SIK/p300 program controls mitochondrial function and define how these abnormal mitochondria affect the metabolism of FLC cells
Principal Investigator: Nabeel M. Bardeesy, PhD
Study overview: Signals that control the growth and metabolism of cells often are relayed through a series of reactions in which proteins are sequentially modified with a chemical tag, a phosphate group. Each of the reactions in a cascade of phosphate-transfers is carried out by a specific “protein kinase,” the major class of signaling enzymes. In fibrolamellar carcinoma (FLC), an abnormal protein kinase (labeled DNAJ-PKAc) that results from FLC’s DNAJB1-PKACA gene fusion drives the development and growth of tumor cells. The functions of that kinase remain incompletely understood. Another characteristic of FLC is the presence of exceptionally large numbers of abnormal mitochondria, organelles that play a key role in cellular energy generation and metabolism.
Past studies by Dr. Bardeesy revealed that DNAJ-PKAc inactivates three related protein kinases, the Salt-Inducible Kinases (SIKs). In turn, inactivation of the SIKs leads to the mitochondrial abnormalities in FLC. Additional data indicate that an important element of this signaling cascade is the activation of a protein called P300 histone acetyltransferase (abbreviated simply as P300). P300 exerts broad effects in controlling gene expression by modifying proteins in chromatin, the complex structure in which DNA is packaged and organized in living cells.
In this study, Bardeesy proposes to “explore precisely how the DNAJ-PKAc/SIK/P300 program controls mitochondrial function” and to define how the mitochondrial abnormalities associated with P300 activation contribute to cancerous growth in FLC. Most importantly, his preliminary data suggests that the mitochondrial abnormalities could potentially be exploited in a novel approach to therapy for this cancer. He proposes to further characterize the functional impact of aberrant mitochondria in tumor cells, and to test whether FLC is sensitive to drugs against P300 and drugs that target the altered mitochondria.
Successful completion of the study aims should have three key benefits:
- Improving our understanding of a key signaling pathway central to the metabolism, growth, and survival of FLC cancer cells
- Validating P300 as a therapeutic target for FLC and selection of a best-in-class inhibitor with potential to treat patients
- Defining the metabolic changes in FLC mitochondria that are likely to contribute to the cancer’s growth, survival, and resistance to therapy.