SMYD2 Epigenetic Complex as a Novel Target in Cholangiocarcinoma
Abstract
Cholangiocarcinoma (CCA) is a rare and aggressive cancer that arises from the cells that line the bile duct. The major cause of death from CCA is metastases (cancer cells migrate and expand to nearby or distal sites and organs) that are resistant to therapy. As an aggressive type of bile duct cancer, CCA is characterized by a high mortality rate due to difficulty in early diagnosis and ineffective treatment. The pathogenesis and progression of CCA are not fully understood. The U.S. Food and Drug Administration-approved drugs futibatinib, pemigatinib, and infigratinib, have limited effects in advanced and metastatic bile duct cancer. Therefore, there is an urgent need to develop a novel and/or combination therapy that could enhance the efficacy of the current anti-fibrotic and anti-tumorigenic drugs to treat CCA. As with other solid tumors, growth and metastasis of bile duct cancer is dependent on the tumor microenvironment (i.e., hepatic stroma). Cancer stromal-associated fibroblasts have been reported to play predominant roles in shaping the malignant tumor microenvironment via secreting a variety of active factors (such as cytokines and chemokines), and extracellular matrix. This project addresses two fiscal year 2022 Rare Cancers Research Program Focus Areas: improve our current knowledge of the biology and etiology in a rare cancer (CCA), and exploit a novel SMYD2 epigenetic complex - targeted strategy for anti-CCA therapy. The objectives of this application are to define a novel role of SMYD2, an epigenetic regulator, and the underlying mechanisms in regulating bile duct cancer fibroblast activation in metastatic CCA, and to explore the therapeutic efficacy of targeting SMYD2 epigenetic complex in combating advanced bile duct cancer. The ultimate applicability of this research is to help a subset of CCA patients with excessively upregulated SMYD2 and/or BRD4 expression and/or activity to improve the overall survival rate of patients afflicted with bile duct cancer. The short-term impact from this proposal is the identification of a previously unrecognized role of SMYD2 in hepatic stromal fibroblast activation and differentiation and CCA progression, and the establishment of a mechanistic link between upregulated SMYD2-mediated activation of pro-fibrotic and pro-tumorigenic genes in connection with BRD4/p300-mediated histone acetylation and the persistent fibroblast activation as observed in advanced CCA. Such results are expected to have an important translational long-term impact in advanced and metastatic bile duct cancer, because the mechanistic characterization of the SMYD2-mediated epigenetic regulation of profibrotic and pro-tumorigenic gene transcription is likely to identify SMYD2-BRD4-p300 epigenetic complex as a key therapeutic target for inhibiting reactive stroma in localized and metastatic CCA.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310429
Entities
People
- Chunying Li
Organizations
- Georgia State University
- United States Army