Chunzhang Yang, Ph.D.

Investigator

Neuro-Oncology Branch

NCI/CCR

Building 37, Room 1142E
Bethesda

240-760-7083

yangc2@mail.nih.gov

Research Topics

Glioma, a devastating disease affecting thousands of lives in the United States, is the most common form of central nervous system cancer, with an estimated 20,000 newly diagnosed cases each year. It causes multiple neurological symptoms ranging from headache, nausea to drowsiness, dysphagia, epilepsy, and mortality. Gliomas are difficult to treat and exhibit unfavorable disease outcomes. For example, patients with WHO Grade IV glioblastoma (GBM), the median survival is < 18 months, with a 5% five-year survival rate. While the prognosis for patients with lower grade gliomas is better, these cancers remain incurable. Although advances in glioma research have revealed the genetic, epigenetic, and metabolic signatures of different glioma molecular subtypes, the standards of care in glioma management remain limited and nonselective. There are many caveats to the translation of knowledge on glioma molecular subtypes into effective therapeutics. Therefore, there is an urgent need to improve the present therapeutic regimen based on molecular signatures to achieve better selectivity and efficacy with prolonged patient survival.

The goal of our research program is to identify the therapeutic vulnerabilities in the major glioma molecular subtypes. In particular, we focused on glioma with isocitrate dehydrogenase (IDH) mutations, which is the most prevalent genetic abnormality in over 80% of patients with WHO II/III glioma. Several findings suggested that mutations in IDH result in distinctive changes in tumor biology, such as overproduction of oncometabolite 2-hydroxyglutarate (2-HG), development of a hypermethylation phenotype, and redox imbalance. Based on the knowledge of IDH1-mutated glioma, we hypothesize that the distinctive pattern of cancer biology, metabolism, and therapeutic resistance in IDH-mutated glioma offer novel therapeutic targets, suggesting that the present therapeutic regimen could be optimized/enhanced by targeted therapy. Based on this hypothesis, we began our investigation by comparing the transcriptomic and metabolomic profiles between IDH1 wild type and mutated cells. In addition, we have been developing patient-derived cells, intracranial xenograft models, and genetically engineered mouse models for IDH1-mutated glioma, which serve as useful tools to validate cancer-susceptible and -resistant genes. Our findings demonstrate that several protective mechanisms, including macropinocytosis-derived nutrient uptake, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-governed detoxification, and DNA repair pathways, play central roles to prevent metabolic stress and apoptotic changes in IDH1-mutated cells. Based on our preliminary findings, we identified novel therapeutic targets and validated them using in vitro assays and preclinical animal models. Our findings suggest novel therapeutic strategies that can result in optimized efficacy and selectivity for IDH1-mutated cancer. Our research on IDH1-mutated glioma cells and mouse models will introduce complementary techniques and impart knowledge that can be extended to future glioma translational research.

We believe that our contribution will be of great significance because our research introduces conceptual advances in glioma biology and therapeutics. In addition, the portfolio of this research platform, including IDH1-mutated cells and genetically engineered mouse models, will serve as foundational resources for the emerging field of cancer metabolism. We expect that our immediate results, as well as subsequent work, will improve the quality of life and medical outcomes for patients with glioma.

Biography

Dr. Chun Zhang Yang received his Philosophy Doctorate (Ph.D.) degree in neurobiology with a focus on glial cell biology and glutamate metabolism from Peking University (PKU) in 2009. In 2010, Dr. Yang joined the Surgical Neurology Branch (SNB) at the National Institute of Neurological Disorders and Stroke (NINDS) at the NIH. He has been active in a diverse set of research fields including tumor genetics, cell biology, and biochemistry. Dr. Yang was the first to identify HIF2A mutations in human cancers, which act as key genetic events in tumor formation. In addition, he has led many breakthroughs in understanding the molecular basis of human cancers in the nervous system. In 2015, Dr. Yang joined the Neuro-Oncology Branch as a tenure track investigator. The goal of Dr. Yang’s research is to understand the distinctive genetic and metabolic aspects of different types of brain tumors, such as glioblastoma, meningioma, and hemangioblastoma, and uncover unique small molecular antagonists as possible chemotherapeutic agents for brain tumors.

Selected Publications

  1. Yang C, Huntoon K, Ksendzovsky A, Zhuang Z, Lonser RR. Proteostasis modulators prolong missense VHL protein activity and halt tumor progression. Cell Rep. 2013;3(1):52-9.

  2. Yang C, Rahimpour S, Lu J, Pacak K, Ikejiri B, Brady RO, Zhuang Z. Histone deacetylase inhibitors increase glucocerebrosidase activity in Gaucher disease by modulation of molecular chaperones. Proc Natl Acad Sci U S A. 2013;110(3):966-71.

  3. Yang C, Asthagiri AR, Iyer RR, Lu J, Xu DS, Ksendzovsky A, Brady RO, Zhuang Z, Lonser RR. Missense mutations in the NF2 gene result in the quantitative loss of merlin protein and minimally affect protein intrinsic function. Proc Natl Acad Sci U S A. 2011;108(12):4980-5.

  4. Yang C, Iyer RR, Yu AC, Yong RL, Park DM, Weil RJ, Ikejiri B, Brady RO, Lonser RR, Zhuang Z. β-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas. Proc Natl Acad Sci U S A. 2012;109(18):6963-8.

  5. Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, Popovic V, Stratakis CA, Prchal JT, Pacak K. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med. 2012;367(10):922-30.


This page was last updated on September 12th, 2019