We and others have described amplification and overexpression of genes at chromosome 20q in several tumors. We have recently shown that this region is amplified in majority of upper gastrointestinal adenocarcinomas (UGCs;stomach and esophagus) and identified Aurora kinase A (AURKA) as a cancer cell pro-survival protein that is located in chromosome 20q13. Approximately 80% of patients in the United States present with regional or distant metastases. Unfortunately, the mortality rates for UGCs approach incidence rates, suggesting that the available clinical management options are limited and often ineffective. Our studies demonstrate overexpression of AURKA in more than half of the tumors that we tested. We have demonstrated that AURKA protects cancer cells from drug-induced apoptosis through inhibiting both p53- and TAp73- dependent apoptosis. Based on our original findings and preliminary data, we hypothesize that AURKA over- expression provides cancer cells with a potent survival advantage through inhibition of TAp73- dependent apoptosis. In this proposal, we plan to investigate the molecular, biological, and therapeutic potential of AURKA in UGCs. In the first aim, we plan to determine the role of AURKA in regulating TAp73- dependent apoptosis. We will investigate the effects of AURKA expression and knockdown on TAp73- dependent apoptosis. We will also determine the effects of AURKA on TAp73 transcription activity and determine the mechanism(s) by which AURKA regulates TAp73 in UGCs. In the second aim, we will investigate the biological and molecular effects of AURKA inhibition in vivo. We have shown that AURKA protein regulates several critical signaling pathways. AURKA inhibitors can represent a novel and effective treatment for patients with UGCs that improve the current response and survival rates associated with chemotherapy for this disease. Our results using AURKA shRNA knockdown and small molecule specific inhibitor of AURKA (MLN8054) have shown promising results in vitro and in vivo (preliminary data). We will test whether AURKA shRNA knockdown or inhibition (MLN8054) alone or in combination with the existing chemotherapeutics can boost the therapeutic response in vivo using the xenografted tumors animal model. In the third aim, we will investigate the clinical value of AURKA in UGCs. We plan to analyse the mRNA expression, DNA amplification, and the haplotypes of the SNPs in the coding sequence of AURKA in UGCs. We will also analyse the mRNA expression of AURKA and the TAp73 pro-apoptotic transcription targets. In addition, immunohistochemical analysis will be performed to evaluate the protein expression of AURKA, p53, and TAp73 on tissue microarrays that contain more than 600 annotated UGC samples. Statistical analysis will be performed to determine significant associations with molecular targets, histopathological, and clinical information. We expect that completion of this proposal will provide important clinical, molecular, and pathobiological information that can have significant impact on the clinical management of patients with adenocarcinomas of the stomach and esophagus.

Public Health Relevance

We have recently characterized overexpression of Aurora Kinase A (AURKA) as a common molecular target in upper gastrointestinal adenocarcinomas. In this proposal, we plan to characterize the role of AURKA in upper gastrointestinal tumorigenesis in order to identify its biological, diagnostic, prognostic, and therapeutic values.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131225-05
Application #
8453440
Study Section
Special Emphasis Panel (ZRG1-ONC-A (04))
Program Officer
Forry, Suzanne L
Project Start
2009-06-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$295,150
Indirect Cost
$105,951
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Sehdev, Vikas; Katsha, Ahmed; Arras, Janet et al. (2014) HDM2 regulation by AURKA promotes cell survival in gastric cancer. Clin Cancer Res 20:76-86
Katsha, Ahmed; Arras, Janet; Soutto, Mohammed et al. (2014) AURKA regulates JAK2-STAT3 activity in human gastric and esophageal cancers. Mol Oncol 8:1419-28
Sehdev, Vikas; Katsha, Ahmed; Ecsedy, Jeffrey et al. (2013) The combination of alisertib, an investigational Aurora kinase A inhibitor, and docetaxel promotes cell death and reduces tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas. Cancer 119:904-14
Katsha, Ahmed; Soutto, Mohammed; Sehdev, Vikas et al. (2013) Aurora kinase A promotes inflammation and tumorigenesis in mice and human gastric neoplasia. Gastroenterology 145:1312-22.e1-8
Sehdev, Vikas; Peng, DunFa; Soutto, Mohammed et al. (2012) The aurora kinase A inhibitor MLN8237 enhances cisplatin-induced cell death in esophageal adenocarcinoma cells. Mol Cancer Ther 11:763-74
Dar, Altaf A; Goff, Laura W; Majid, Shahana et al. (2010) Aurora kinase inhibitors--rising stars in cancer therapeutics? Mol Cancer Ther 9:268-78
Soutto, Mohammed; Peng, Dunfa; Razvi, Mohammad et al. (2010) Epigenetic and genetic silencing of CHFR in esophageal adenocarcinomas. Cancer 116:4033-42
Mukherjee, Kaushik; Chakravarthy, A Bapsi; Goff, Laura W et al. (2010) Esophageal adenocarcinoma: treatment modalities in the era of targeted therapy. Dig Dis Sci 55:3304-14
Dar, A A; Belkhiri, A; El-Rifai, W (2009) The aurora kinase A regulates GSK-3beta in gastric cancer cells. Oncogene 28:866-75
Dar, Altaf A; Belkhiri, Abbes; Ecsedy, Jeffrey et al. (2008) Aurora kinase A inhibition leads to p73-dependent apoptosis in p53-deficient cancer cells. Cancer Res 68:8998-9004