Glioblastoma (GBM) remains a largely incurable disease, with a 5 year survival rate of less than 10%. Effective targeted therapies to complement already maximal radiation and chemotherapy are urgently needed. Converging evidence shows that the EphA2 receptor is an attractive target for GBM. The PI's lab and others recently uncovered dual roles of EphA2 in tumor etiology and malignant progression. When engaged with ligands (ephrin-As), EphA2 is a tumor suppressor and inhibits both ERK and Akt activities in GBM cells. However, in the absence of ligands, EphA2 is phosphorylated by AGC kinases including Akt and p90-RSK on serine 897, and S897 phosphorylation converts EphA2 from a tumor suppressor into an oncogenic protein that promotes glioma cell migration in vitro and intracranial invasion of glioma stem cells (GSC) in vivo. Moreover level of pS897-EphA2 is correlated with tumor grades. Mechanistically pS897- EphA2 regulates the stem properties of GSCs and promotes gliomagenesis in the absence of ligands. In contrast, upon ligand stimulation, EphA2 induces GSC differentiation and inhibits tumor development. Based on this series of observations, we propose that ligand-mimicking small molecule agonists of EphA2 can be novel therapeutic agents for GBM. Such agonists are expected to i) restore the intrinsic tumor suppressor functions of EphA2, ii) disrupt the pro- oncogenic Akt/RSK-EphA2 signaling axis, and iii) induce differentiation of GSCs. Using structure- guided virtual screening and cell-based assays, we reported that doxazosin (DZ), an ?1- adrenoceptor antagonist still in clinical use for hypertension, is a bona fide EphA2 agonist. DZ inhibits ERK and Akt and suppresses tumor cell dissemination in an EphA2-dependent manner. Much more potent derivatives of DZ have been characterized through medicinal chemistry, including BW27, which suppressed GBM in preclinical models and was capable of crossing the blood-brain barrier (BBB). The overarching goal of this proposal is to translate these basic and preclinical discoveries into nove GBM therapeutic agents. BW27 will be subject to systemic preclinical test across all four molecular subtypes of human GBM. The on-target effects of BW27 will be investigated using the genetically engineered mouse model. Finally the X-ray co-crystal structure of EphA2 in complex with BW27 will be determined to guide the design of next generation(s) of EphA2 agonists. Completion of the studies could lead to new mechanism-based small molecule drug(s) for therapeutic intervention of GBM.

Public Health Relevance

EphA2 has a dual roles in tumorigenesis, a tumor suppressor when engaged with ligands and oncogenic protein when ligands are absent. We have discovered a small molecule agonist for EphA2 that restores tumor suppressor functions of EphA2, is capable of crossing blood brain barrier, and displays therapeutic efficacy against GBM in preclinical models in preliminary studies. The proposal will subject the small molecule to systemic preclinical tests on all major subtypes of human GBM for on-target effects and interrogate potential cellular pathways affected by it.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fountain, Jane W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Shi, Xiaojun; Wang, Bingcheng (2018) Caught in the ""Akt"": Cross-talk between EphA2 and EGFR through the Akt-PIKfyve axis maintains cellular sensitivity to EGF. Sci Signal 11:
Alves, Daiane S; Westerfield, Justin M; Shi, Xiaojun et al. (2018) A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration. Elife 7:
Chen, Lechuang; Feng, Zhimin; Yue, Hong et al. (2018) Exosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA. Nat Commun 9:4585
Petty, Aaron; Idippily, Nethrie; Bobba, Viharika et al. (2018) Design and synthesis of small molecule agonists of EphA2 receptor. Eur J Med Chem 143:1261-1276
Zhong, Bo; Li, Yaxin; Idippily, Nethrie et al. (2018) A quantitative LC-MS/MS method for determination of a small molecule agonist of EphA2 in mouse plasma and brain tissue. Biomed Chromatogr :e4461
Herting, C J; Chen, Z; Pitter, K L et al. (2017) Genetic driver mutations define the expression signature and microenvironmental composition of high-grade gliomas. Glia 65:1914-1926