The research of Jin-San Zhang, M.D., Ph.D., is mainly focused on pancreatic ductal adenocarcinoma (PDA), the most common type of pancreatic tumor and the most lethal human solid tumor with a death rate almost equal to its incidence.
Dr. Zhang is interested in understanding the early genetic and epigenetic events leading to pancreatic carcinogenesis. He is also interested in identifying the aberrant signaling mechanisms critical in driving pancreatic cancer cell proliferation, dedifferentiation and survival, which can be targeted for therapy.
Various animal models are used to achieve Dr. Zhang's research goals. These include primary pancreatic cancer xenografts, genetically engineered mouse models (such as pancreas-specific conditional gene knockout and transgenic expression), high-throughput kinase-inhibitor screening, as well as proteomic analysis and RNA and ChIP-sequencing techniques.
- The contribution of GSK-3b to pancreatic carcinogenesis. The glycogen synthase kinase-3 beta (GSK-3b) gene is overexpressed during progression of PDA from pancreatic intraepithelial neoplasia (PanIN) to metastatic lesions. Dr. Zhang's team has uncovered that GSK-3b participates in regulation of a key stem cell factor, SOX2, and is required for the development of acinar-to-ductal metaplasia (ADM) induced by the TGFA gene in vitro. The focus of this project is to use pancreas-specific inducible knockout and transgenic mice to investigate the role and molecular mechanism of GSK-3b in cerulein-induced ADM and PanIN or PDA development in KRas (G12D) mouse models.
- Implication for cancer therapy in GSK-3b and NF-kappa B signaling. The activation of the NF-kappa B protein is a signature occurrence in PDA contributing to cell proliferation, survival, invasion and metastasis, as well as drug resistance. The NF-kappa B activation is also responsible for tumor necrosis factor-alpha (TNF-alpha) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell death in many tumor cells. This project aims to understand the role and mechanism of GSK-3 depletion and inhibition in the TNF-alpha gene and TRAIL-induced apoptotic signaling. It will also provide mechanistic rationale to combine the GSK-3 inhibitor with TRAIL (agonist), as a more effective regimen for the treatment of PDA.
Significance to patient care
Pancreatic cancer is characterized by both its aggressive disease progression and absence of specific symptoms for an early diagnosis and curative treatment. Pancreatic ductal adenocarcinoma also presents inherent resistance to conventional chemotherapy or radiotherapy due to its characteristic feature of escaping from apoptosis induction, together making it the most lethal of all human malignancies. Dr. Zhang's research is intended to provide new insight into the action of GSK-3b during pancreatic carcinogenesis as well as to identify novel therapeutic targets for treatment of this dismal disease.
- Member, American Association for Cancer Research (AACR) and American Pancreatic Association (APA)
- Reviewer, Pancreatology, Clinical Cancer Research, International Journal of Nanomedicine, PLOS One, Drug Delivery Letters, Journal of Molecular Biology and Surgical Oncology