Jing An, MD, PhD
- Associate Professor of Pharmacology
Research Programs and Affiliations
- Cancer Research Institute
Education & Fellowships
- PhD: McGill University, Montreal, Quebec, 1997, Experimental Medicine
- MD: China Medical University, Shenyang, China, 1984, Medicine
Therapeutic strategies targeting cancer stem cells; three dimensional authentic-tissue-mimicking drug screening systems; combined structure-based and ligand-based drug design and development approaches for G-protein coupled receptors (CXCR4 & CCR5) and gene transcriptional regulators (beta-catenin and TCFs).
Project 1: Role of chemokine receptors in stem cell functions and discovery of novel stem cell mobilizers
The long-standing interests and goals in this project are to understand the structure-function relationship and mechanism of chemokines and their receptors in various pathologies and to translate such information into the development of new intervention strategies. During the past 12 years, we have made significant progress towards these goals. We have developed novel agonist molecules of CXCR4 receptor (a member of the GPCR family) and completed a series of studies to characterize the in vitro and in vivo biological activities of these novel agonists in activating and directing stem cell migration. As CXCR4 plays a critical role in the migration of neural stem cells during tissue repairs, our novel CXCR4 agonist molecules have opened new possibilities for studying the mechanism of targeted human neural stem cell migration mediated by CXCR4 and developing new therapeutics for tissue repairs.
Project 2: Stem-cell-based anticancer therapies targeting beta-catenin
Current treatments, such as chemo- and radiotherapies, while successful at destroying bulk cancer cells, are unable to completely eliminate self-renewable, cancer stem cells (CSCs). Targeted disruption of cancer self-renewal represents a novel therapeutic strategy that is worth developing. The Wnt/beta-catenin pathway is a potent candidate target for drug design because it plays a critical role in tumorigenesis and cancer progression. Identifying small-molecule inhibitors of the Wnt/beta-catenin pathway would enable a chemical-genetic approach for studying the function of Wnt/beta-catenin pathway in a way not possible with conventional genetic approaches. Such a strategy of using chemical genetic alteration can combine with de novo organ regeneration approaches and allows us to investigate the complicated molecular mechanisms that regulate stem cell fate and develop novel approaches to treating cancer patients based upon CSC targeted therapies. This project is built on the extensive studies during the past 5 years that my laboratory has identified two new classes of small molecule beta-catenin/Tcf4 inhibitors (Biochemistry, 2012; J. Med. Chem., 2012). Our compounds represent new leads for developing anticancer therapeutics that target beta-catenin/Tcf-4 interaction.
Project 3: Development of new inhibitors of breast cancer metastasis mediated by CXCR4
This project addresses a major concern of breast cancer patients: metastasis. No current therapeutic strategy significantly prevents metastasis or improves the survival rate of patients with metastatic breast cancer. We have recently discovered two new classes of breast cancer metastasis inhibitors that interfere with the cell surface molecule CXCR4: a synthetic bivalent ligand (Biochemistry, 2012) and an organic small molecule inhibitor. Specifically, the synthetic bivalent peptide inhibitor showed very high affinity for CXCR4 and inhibited HIV infection via CXCR4 coreceptor. Furthermore, it displayed potent inhibitory activity in breast cancer cell migration in cell cultures. Molecular modeling of the interaction between this novel bivalent peptide inhibitor and CXCR4 receptor dimer showed that the bivalent ligand is able to interact with CXCR4 dimeric structure through its two N-termini reaching into the binding pockets of two CXCR4 monomers. The development of this bivalent ligand provides a tool to further probe the functions of CXCR4 homodimerization as well as heterodimerization with other receptors. These results, together with our recently published data, demonstrate that synthetic bivalent ligands are promising therapeutic candidates for cancer metastasis blockade and that they merit further evaluation and development.
Project 4: Roles of CXCR4 and beta-catenin in de novo organogenesis
Organogenesis and drug responses depend on a complex dialogue between multiple cell types that operate within a dynamic three-dimensional (3-D) microenvironment. However, the precise molecular and cellular mechanisms of the stromal microenvironment regulates the fate of normal and cancer cells under physiological and drug treatment conditions in vivo remain largely unexplored. This knowledge gap is largely due to the lack of adequate models and technologies that can mimic and maintain a precise facsimile of the 3-D microenvironment that occurs in real organs. We have proved in principle that a de novo regenerated 3-D bone/bone marrow model can be established using bioscaffolds, biologics, and novel stem cell-mobilizers. Our results strongly support the continuing development of these de novo biomimetic organs as potential platforms for studying the molecular mechanisms of SDF-1α/CXCR4 and Wnt/beta-catenin mediated signaling. Our goals are to construct specific microenvironments using paired isogenic human stromal cells and to use a combination of biological and chemical approaches to further characterize and dissect the molecular mechanisms of how the molecular signaling of these molecules regulates the proliferation, differentiation, release/invasion, and vascularization properties of normal and cancer stem cells.
Project 5: GPCR mediated and bio-networking-guided biomechanical approaches to human chronic diseases
The long term goals of this project are to employ systemic and regional approaches that apply more natural and non-invasive (or less invasive) protocols to the study and management of human chronic diseases caused by complicated dysfunctions of the circulation, immune, and neuroendocrine systems. We aim to establish biomechanical receptor/unit mediated bi-networking profiles and to explore how committed biomechanical approaches affect local and systemic bioelectricity changes, molecular signaling (CXCR4, GPCRs of the neural system, ion channels-Ca++, K+, Na+, CI-), and biological function. These alternative approaches will point a new direction in biomedical research aimed at the discovery of new treatment strategies for chronic diseases or aging-related issues.