It is well recognized that deregulation of endogenous programmed cell death is fundamentally important in malignant transformation and tumor progression. The cell surface protein Fas can elicit apoptosis when engaged by its cognate ligand, FasL. First recognized as a critical regulator of immunohomeostasis and immunologic privilege, Fas has been recently implicated in the control of tumor development, growth, and metastasis. Our laboratory has documented that primary NSCLC in vivo express low to non-detectable levels of Fas while potently expressing FasL (Preliminary Data). As the induction of Fas expression can lead to apoptosis in FasL-expressing cells (1), the ability to upregulate Fas may be of major consequence for the development of novel therapeutic strategies aimed toward the treatment of malignancies (such as NSCLC) that are refractory to conventional treatments. In this regard, we have previously documented that both p53 and radiation can activate the transcription of Fas in human tumor cell lines in vitro (2). Wild-type p53 gene replacement therapy resulting in tumor apoptosis has been documented to have clinical utility for the treatment of patients with lung cancer (3). A combination treatment consisting of p53/radiation, shown to have super-additive therapeutic properties for tumor growth inhibition in pre-clinical nude mouse models, will now be tested in clinical trials. Such treatment may not be effective in all patients and individual patient responsiveness (such as the capacity to upregulate pro-apoptotic proteins including Fas) may influence clinical outcome. This proposal will address the overall hypothesis that wild-type p53/radiation-induced tumor apoptosis involves the Fas/FasL receptor ligand system. In the studies outlined below, we will systematically evaluate the molecular mechanisms underlying p53/radiation-induced Fas upregulation, the effects of bcl-2 overexpression on the upregulation of Fas after Ad-p53 nad Ad- p53/radiation, the role of Fas and FasL in Ad-p53/radiation- induced tumor cell killing in vitro and in vivo using a nude mouse model, the ability of Ad-Fas to induce tumor cell apoptosis in vitro and in vivo, and finally, Fas upregulation as a predictor of individual patient responses to radiation/p53 gene therapy for the treatment of lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA078778-01A1
Application #
6232830
Study Section
Subcommittee G - Education (NCI)
Project Start
1999-07-23
Project End
2004-04-30
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Pataer, Apar; Kalhor, Neda; Correa, Arlene M et al. (2012) Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy. J Thorac Oncol 7:825-32
Kadowaki, Yoshihiko; Chari, Nikhil S; Teo, Albert E K et al. (2011) PI3 Kinase inhibition on TRAIL-induced apoptosis correlates with androgen-sensitivity and p21 expression in prostate cancer cells. Apoptosis 16:627-35
Pataer, Abujiang; Swisher, Stephen G; Roth, Jack A et al. (2009) Inhibition of RNA-dependent protein kinase (PKR) leads to cancer cell death and increases chemosensitivity. Cancer Biol Ther 8:245-52
Pataer, Abujiang; Chada, Sunil; Roth, Jack A et al. (2008) Development of Ad-mda7/IL-24-resistant lung cancer cell lines. Cancer Biol Ther 7:103-8
Pataer, Abujiang; Hu, Wenxian; Xiaolin, Lu et al. (2008) Adenoviral endoplasmic reticulum-targeted mda-7/interleukin-24 vector enhances human cancer cell killing. Mol Cancer Ther 7:2528-35
Pataer, A; Bocangel, D; Chada, S et al. (2007) Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl- amino-17-demethoxy analogue. Cancer Gene Ther 14:12-8
Peng, Henry H; Wu, Shuhong; Davis, John J et al. (2006) A rapid and efficient method for purification of recombinant adenovirus with arginine-glycine-aspartic acid-modified fibers. Anal Biochem 354:140-7
Pataer, A; Fanale, M A; Roth, J A et al. (2006) Induction of apoptosis in human lung cancer cells following treatment with amifostine and an adenoviral vector containing wild-type p53. Cancer Gene Ther 13:806-14
Li, Zhongkui; Niu, Jiangong; Uwagawa, Tadashi et al. (2005) Function of polo-like kinase 3 in NF-kappaB-mediated proapoptotic response. J Biol Chem 280:16843-50
Sclabas, Guido M; Fujioka, Shuichi; Schmidt, Christian et al. (2005) Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells. Clin Cancer Res 11:440-9

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