Zhengping Zhuang, M.D., Ph.D.
Dr. Zhuang’s research program focuses on the study of molecular mechanisms of tumor pathogenesis and on the development of cancer therapeutic agents. He is experienced in integration of clinical, translational, and basic research approaches and has led and participated in several multidisciplinary efforts to gain insight into cancer genetics and cancer biology. Dr. Zhuang is also involved in the discovery of novel small molecule compounds and development of new technology leading to clinical advances.
My laboratory had made several multidisciplinary efforts to gain insight into the pathophysiology of central nervous system (CNS) and other tumors. As an overview, my lab has three major aims: First, we focus on inherited and somatic mutations in the cancer genome with the intent to demonstrate their critical roles in tumor formation and progression (Functional Genomics). Second, we develop and apply cutting edge techniques to identify novel genetic and functional changes in cancer cells (Biotechnological Advancements and Applications). Third, through collaborations with clinicians and scientists, we translate our laboratory findings into experimental drug development and human clinical trials (Drug Development and Clinical Translation).
Functional Genomics: Inherited and somatic mutations form the basis for many cancers, playing critical roles in tumor formation and progression. Much of our research efforts have been dedicated towards the identification and characterization of cancer causative gene mutations. As an example, we were the first to discover a novel multi-organ human disorder, characterized by development of multiple paragangliomas, somatostatinomas, and congenital polycythemia (Pacak-Zhuang Syndrome). We worked closely with NIH intramural physicians and scientists to explore the genetic basis of a group of patients with similar tumor manifestations and polycythemia. We successfully identified a cluster of mutations in the gene encoding human hypoxia-inducible factor 2α (HIF2A) as critical and sufficient to induce tumorigenesis and polycythemia. We have also analyzed tumor samples from neuroendocrine neoplasms and demonstrated that germline mutations of MEN1 were responsible for familial forms of multiple endocrine neoplasia type 1 (MEN1). Utilizing our own original, cutting-edge microdissection techniques, we were the first to demonstrate that different patterns of loss of heterozygosity existed for the various tumors that occurred in individual patients with MEN1.
Biotechnological Advancements and Applications: The second major aim of our lab has been to develop and improve techniques in the study of human cancers. As an example, we addressed the inherent problem of isolating tumor cells from the morphologic heterogeneous solid tumor specimens. Such samples are typically composed of neoplastic cells in a background or intermixed with reactive, vascular, lymphocytic, histiocytic cells as well as necrotic areas. To overcome this problem, we developed manual and laser microdissection techniques to obtain pure populations of tumor cells from clinical specimens. As a result, the accuracy of scientific results from the studies of tumors in clinical specimens had improved dramatically. The application of microdissection techniques had gained traction as a powerful tool for genomic and proteomic studies and is now widely accepted worldwide as a reliable and useful method. We have also developed a novel proteomics technique to investigate the functional changes of proteins in brain tumors. Specifically, we established a new method of “multidimensional” capillary isoelectric focusing nano-reversed-phase liquid chromatography with tandem mass spectroscopy (CIEF-nRPLC-MS) to compare the proteomes of primary tumor stem-like cell cultures before and after induction of differentiation. The application of CIEF-nRPLC-MS has permitted highly sensitive and reliable identification and quantitative comparison of proteins between different isolated cell populations. Based on the technique, we have identified numerous gene signatures among the protein expression profiles of tumor stem-like cells and across differing tumor grades.
Drug Development and Clinical Translation: The critical step in translational research is to push forward theoretical concepts into experimental drug development and clinical trials. Our group has been on the forefront of the development of small molecule compounds for therapeutic applications. In collaboration with Lixte Biotechnology (East Setauket, NY), we developed the drug, LB100, a novel protein phosphatase 2A (PP2A) inhibitor. PP2A is a serine/threonine phosphatase involved in abrogating mitotic progression and initiating cellular responses to DNA damage. We demonstrated that LB100 effectively induced mitotic activity of quiescent tumor cells and concomitantly prevented DNA repair mechanisms, allowing for therapeutic sensitization to traditional chemo- and radio-therapies. Considering LB100 holds promising potential as a novel means of overcoming treatment resistant cancer, the compound has been approved by the FDA for clinical study in a Phase I clinical trial (online at: https://clinicaltrials.gov/ct2/show/NCT01837667) which has been recently completed without noticeable safety issues.
Selected Key Publications
- New Engl J Med. 367(10): 922-30, 2012. [ Journal Article ]
β-catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas.Proc Natl Acad Sci U S A. 109(18): 6963-8, 2012. [ Journal Article ]
- J Clin Oncol. 31(13): 1690-8, 2013.
Mutant glucocerebrosidase in Gaucher disease recruits Hsp27 to the Hsp90 chaperone complex for proteasomal degradation.Proc Natl Acad Sci U S A. 112(4): 1137-42, 2015. [ Journal Article ]
Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms.Proc Natl Acad Sci U S A. 106(28): 11697-702, 2009. [ Journal Article ]
Dr. Zhuang received his M.D. degree from Shanghai Second Medical University in China and his Ph.D. in Pharmacology from Wayne State University in Michigan. His postgraduate training included residency training in General Surgery in Shanghai Ruijin Hospital; a postdoctoral fellowship at Harvard Medical School in Boston, a transitional residency year at Henry Ford Hospital in Detroit, followed by a full residency in Anatomic Pathology at the NCI. Since 1996, Dr. Zhuang has been a member of the NIH community, first as staff pathologist at NCI, then the Head of the Molecular Pathogenesis Unit of the National Institute of Neurological Diseases and Stroke (NINDS), a role he has held since 1999. He recently joined the Neuro-Oncology Branch, a collaborative effort of the NCI and the NINDS as a Senior Investigator.
Dr. Zhuang has made several specific and unique contributions to the fields of experimental pathology, cancer genetics, and cancer biology. In his early career, Dr. Zhuang pioneered unique molecular genetic approaches to study human cancer biology; combining his expertise in anatomic pathology with experimental biology. Dr. Zhuang developed a tissue microdissection technique and co-invented laser-capture microscopy (LCM) to facilitate procurement of highly purified specific cell types from histological tissue samples. During his activity at the NCI and NINDS, Dr. Zhuang has led and participated in several multidisciplinary efforts to gain insight into cancer genetics and cancer biology. He co-discovered the menin gene for Multiple Endocrine Neoplasia Type 1; c-MET for Papillary Renal Carcinoma and its role in trisomy 7; and HIF2A for a novel tumor-associated syndrome of Multiple Paraganglioma, Somatostatinoma, and Polycythemia, a disease that is now referred to as the Pacak-Zhuang syndrome. Dr. Zhuang is also a co-inventor of novel drugs LB100 (PP2A inhibitor), LB201 (HDAC inhibitor) and a novel HIF2 alpha inhibitor. These agents are in active clinical and preclinical drug trials.
|Rebecca Breese Ph.D.||Postdoctoral Fellow (CRTA)|
|Jing Cui Ph.D.||Postdoctoral Fellow (Visiting)|
|Qi Song||Predoctoral Visting Fellow (Graduate Student)|
|Emeline Tabouret M.D., Ph.D.||Special Volunteer|
|Herui Wang Ph.D.||Postdoctoral Fellow (Visiting)|
|Yang Wang||Special Volunteer|
|Timothy J. Westlake||Special Volunteer|
|Kaiyong Yang Ph.D.||Research Collaborator|