Sunday, May 11, 2025
5/11/2025
Targeting Epigenomic Regulators at the Replication Fork in PDAC - Pancreatic adenocarcinoma (PDAC) remains a therapeutic challenge, making the identification of new targets and development of novel treatment strategies for this disease of paramount importance. Our LONG-TERM GOAL is to advance context-dependent, mechanism-based paradigms for the improved use of epigenomic inhibitors in cancer. Epigenomic machinery, and hence their inhibitors, are typically only considered within the context of their actions in gene expression, or interphase, even though they are operational during different stages of the cell cycle. During the process of DNA replication, for instance, not only is the entire genome replicated, but the accompanying chromatin structure is duplicated as well. Thus, conceptually, DNA replication represents a vulnerable moment for challenging genomic and epigenomic integrity, which relies heavily on the proper functioning of the S-phase DNA replication checkpoint (DRC) and DNA damage response (DDR) as critical components of this process. Early in tumorigenesis, higher proliferation rates driven by activated oncogenes, such as KRAS, trigger replication stress (RS), which if not tolerated causes cell senescence or death. RS tolerance, consequently, becomes vital to tumor progression, yet the underlying mechanisms remain poorly understood. Here, we will test the CENTRAL HYPOTHESIS that the epigenomic regulator G9a promotes RS tolerance in PDAC via a mechanism which involves interactions with S-phase DRC-DDR pathways, representing actionable vulnerabilities for therapeutics. Completion of these studies will significantly advance the field by: 1. revealing mechanisms by which G9a functions in the tolerance to oncogene-induced RS, a key understudied event in tumorigenesis, 2. providing novel mechanistic insight into how G9a-mediated function in DDR signaling protects replication fork integrity to offer additional targeting strategies for the subset of patients with inherent DDR deficiencies, and 3. leveraging the function of epigenetic regulators during oncogene-driven RS as a mechanistic opportunity to synergize with RS- enhancing drugs, such as DDR-inhibitors. In summary, we seek to extend our studies on new mechanisms that represent previously unrecognized actionable vulnerabilities for cancer cells. We are optimistic that the outcome of this research will impact planning for future clinical testing of therapies that may share similar mechanisms to offer much-needed, novel treatments for PDAC.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).