Presenter Profile

Education:

Research and Professional Experience:

KEYNOTE SPEAKER
Zhenghe John Wang

Professor
Case Western Reserve University, Department of Genetics and Genome Sciences

Dr. John Wang is professor and chair of the Department of Genetics and Genome Sciences at Case Western Reserve University (CWRU) School of Medicine. He holds the Dale H. Cowan M.D. – Ruth Goodman Blum Professor of Cancer Research. He is also a co-leader of the Cancer Genome and Epigenome Program at Case Comprehensive Cancer Center. He obtained his PhD from the University of Virginia and trained as a postdoctoral fellow in Dr. Bert Vogelstein’s laboratory at Johns Hopkins University on cancer genetics. He became assistant professor at CWRU in 2005. He co-discovered PIK3CA oncogenic mutations in human cancer. His laboratory identifies novel mechanisms by which PIK3CA oncogenic mutations drive tumorigenesis. He has successfully translated these discoveries into active phase I/II clinical trials and another clinical trial that is expected to open very soon. He is a co-leader of the Stand Up to Cancer (SU2C) Colorectal Cancer Dream Team.

TALK TITLE
Killing cancer cells by suicidal bombing attack with neutrophil extracellular traps

KEYWORDS
Cancer, neutrophil

ABSTRACT
 Neutrophil extracellular traps (NETs) are extracellular web-like structures of cytosolic and granule proteins assembled on de-condensed chromatin. NETs trap and kill bacteria, fungi, viruses, and parasites. Although some studies implicate NETs in tumor metastasis, whether NETs can kill cancer cells is largely unexplored. We previously showed that PIK3CA mutations render colorectal cancers (CRCs) more dependent on glutamine and that a combination of CB-839, a glutaminase inhibitor, and 5-FU induced tumor regression of PIK3CA mutant CRCs. Here, we report the combination of CB-839 and 5-FU induced NETs in PIK3CA mutant CRCs in xenograft, syngeneic, and genetically engineered mouse models. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRC tumors attenuated the efficacy of the drug combination. Mechanistically, the drug combination induced the expression of IL-8 preferentially in PIK3CA mutant CRCs to attract neutrophils into the tumors. Moreover, the drug combination increased the levels of reactive oxygen species in neutrophils, thereby inducing NETs. Cathepsin G, a serine protease localized in NETs, enters CRC cells by binding to a cell surface protein RAGE. The internalized cathepsin G cleaves 14-3-3 proteins, releases Bax, and triggers apoptosis in CRC cells (Fig. 1). We have completed a phase II clinical trial of the combination of CB-839 and capecitabine, an oral prodrug of 5-FU, in PIK3CA mutant metastatic CRC patients who were refractory to prior 5-FU treatment. An analysis of tumor biopsies from these patients showed that NETs were significantly up-regulated in post-treatment biopsies compared to their pre-treatment counterparts. Moreover, increased levels of NETs were associated with longer progression-free survival of the patients, suggesting that NETs induced by the drug combination inhibit tumor growth in patients. Lastly, we found that a variety of other chemotherapy drugs, including camptothecin/irinotecan, gemcitabine, daunorubicin, epirubicin, oxaliplatin, and regorafenib, also induced NETs, suggesting that NET induction may be a general mechanism by which chemotherapy inhibits tumor growth. In summary, our studies illuminated a paradigm-shifting concept that drug treatment-induced NETs kill cancer cells through a previously unrecognized molecular mechanism.