The root of Dr. Zhuang’s research is based on the inherited and somatic mutations that result in cancer. He aims to understand how these mutations contribute to the development and progression of tumors, particularly in brain tumors. His Cancer Stem Cell Biology Research Program at the Neuro-Oncology Branch (NOB) utilizes clinical, translational, and basic approaches to study the basic science as a foundation for understanding the pathological changes present in tumors. He has three ongoing multidisciplinary projects: 1) investigating hypoxia signaling and tumor development, 2) examining the impact of patient-derived IDH1 mutant mosaicism on brain tumor development, and 3) developing therapeutics for cancers of the central nervous system.

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The first project investigates gain-of-function mutations in the gene encoding the hypoxia inducible factor 2α (HIF2α) protein, which was first found in a combined clinical and scientific effort culminating in the discovery of Pacak-Zhuang syndrome. Using mouse models, Dr. Zhuang’s lab is investigating the unusual phenotypes recently identified in patients with Pacak-Zhuang syndrome, including sexual dimorphism and HIF2α genomic imprinting. These studies will substantially advance our understanding of HIF2α’s impact on biology and pathobiology, including Pacak-Zhuang syndrome and hypoxia signaling in brain tumors. 

The second project began with a critical observation in identical twins with low-grade IDH-mutant gliomas. This observation showed that an IDH1 mutation in early development can have two possible outcomes: 1) it may remain quiescent or in the “pre-tumor state” throughout development, or 2) it may acquire additional mutations that allow the cell to transform into a tumor. Because Dr. Zhuang discovered glutamine synthetase, which is important in IDH-mutant tumors (and astrocytoma specifically), his lab is primed to deduce the basic physiology resulting in a brain tumor. His team used deep PCR techniques to show that an inherent and embryonic IDH1 mutation triggered a tumor with p53. His lab has also used induced pluripotent stem (iPS) cells to determine how IDH mutations drive tumor growth by studying the 2-hydroxyglutarate (2-HG) and glutamate cycle. 

The third project has several arms: First, Dr. Zhuang’s lab is working to develop an immunomodulator called LB100, which acts by inhibiting protein phosphatase 2A and has entered clinical trials. Second, his lab has developed CAR-T cells targeting the hypoxia signaling downstream product, carbonic anhydrase IX. Third, he has developed a modulator of HIF2a, which has allowed to his lab to further explore this pathway.