There are two major goals in this proposal. One is to elucidate if Akt-EphA2 signaling axis is a """"""""driver"""""""" mechanism underlying malignant progression of human prostate cancer (PCa);the other is to evaluate therapeutic efficacy of EphA2-targeted small molecules against PCa. Approximately 70% of primary PCa exhibit a loss of at least one PTEN allele and loss of both alleles is associated with advanced disease. PTEN loss leads to activation of PI3K/Akt. While Akt is well-known to control cell proliferation and survival, how it may regulate tumor progression is not well understood. We discovered that Akt may promote tumor cell migration and invasion by co-opting EphA2 kinase. EphA2 has been extensively studied in cancer. It is frequently overexpressed in many different types of human cancer, which is often correlated with tumor progression. While these data suggest EphA2 is an oncogene, strong evidence also exists demonstrating tumor suppressor functions of EphA2. Shedding light on this apparent paradox, we reported recently that EphA2 has diametrically opposite roles in regulating PCa cell migration and invasion. In the presence of ligands called ephrin-As, EphA2 inhibited cell migration and invasion. In contrast, in the absence of ligands EphA2 promoted chemotactic migration and invasion instead. Interestingly the ligand-independent stimulation of cell motility was correlated with phosphorylation of EphA2 on a single serine residue (S897) by Akt. S897A mutation abolished this ligand-independent effect. Preliminary studies show that S897 phosphorylation is detected at invasive front of high grade human PCa and mouse PCa induced by PTEN deletion, suggesting pathological relevance of Akt-EphA2 signaling axis in PCa. The data in aggregate led us to hypothesize that the Akt-EphA2 crosstalk contributes to invasion and metastasis of PCa and can be targeted for PCa therapy.
Three aims are proposed.
Aim will test the hypothesis that Akt-EphA2 signaling axis is a """"""""driver"""""""" mechanism in promoting malignant progression of human PCa.
In Aim 2, we will determine ephrin-As can repulse disseminating PCa cells.
Aim 3 will investigate whether small molecule targeting EphA2 can be used as potential therapeutic agents to suppress PCa metastasis in vivo.

Public Health Relevance

Prostate cancer (PCa) is the most prevalent type of tumors in the US men with an estimated 186,320 new cases and 28,660 deaths in 2009. At the time of diagnosis, prostate cancer (PCa) patients generally fall into one of two groups. For most PCa patients, the disease is benign. However, in a minority of patients, the disease undergoes rapid malignant progression leading to metastasis with bones as the most frequently affected site. Although the majority of men with metastatic prostate cancer will initially respond to androgen depletion therapy, the development of castration-resistant PCa almost always occurs, accompanied by further metastatic progression. Integral to tumor metastasis is the acquisition of migratory and invasive phenotype. The central goal of this proposal is to investigate the newly characterized Akt-EphA2 crosstalk as a novel """"""""on and off switch"""""""" in controlling PCa cell migration, and whether it can targeted for therapy of malignant PCa. Completion of the proposed studies will not only lead to better understanding of prostate cancer biology, but also potentially novel therapeutic agents treatment strategies for the more malignant subgroup of the disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA155676-01
Application #
8034022
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2011-09-01
Project End
2016-06-30
Budget Start
2011-09-01
Budget End
2012-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$325,775
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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
Chen, Yang; Gao, Zhen; Wang, Bingcheng et al. (2016) Towards precision medicine-based therapies for glioblastoma: interrogating human disease genomics and mouse phenotypes. BMC Genomics 17 Suppl 7:516
Miao, H; Gale, N W; Guo, H et al. (2015) EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties. Oncogene 34:558-67
Lee, Hyeong J; Hota, Prasanta K; Chugha, Preeti et al. (2012) NMR structure of a heterodimeric SAM:SAM complex: characterization and manipulation of EphA2 binding reveal new cellular functions of SHIP2. Structure 20:41-55
Petty, Aaron; Myshkin, Eugene; Qin, Haina et al. (2012) A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo. PLoS One 7:e42120
Lin, Samantha; Wang, Bingcheng; Getsios, Spiro (2012) Eph/ephrin signaling in epidermal differentiation and disease. Semin Cell Dev Biol 23:92-101

Showing the most recent 10 out of 13 publications