My laboratory group is investigating the role of the RB tumor suppressor pathway in human cancer focusing primarily on the model of lung cancer since the clinical trials at the NCI-Navy Oncology Branch is a unique resource for patient material. In the past year, we have i) demonstrated that inactivation of the RB:p16 pathway occurs in 100% of lung cancer samples and have shown that inactivation of p16 can be reversed in vitro in a subset of lung cancer samples using the DNA demethylating agent, 5-aza2'deoxycytidine (AZAdc). We have characterized the kinetics of p16 induction with AZAdc and now plan to conduct a small clinical trial to test if p16 protein can also be induced in vivo; ii) We have studied the functional properties of several RB mutant alleles from families with the phenotype of low penetrance and have identified a unique type of """"""""partial"""""""" mutant that characterizes these mutant proteins. We believe these mutants will address the molecular mechanisms that result in the phenotype of incomplete penetrance and will also be an invaluable resource in studying functional properties underlying the tumor suppressor activity of the RB product; iii) To study animal models of lung cancer, we have generated a colony of mice that are double heterozygous for null RB and p53 genes (common lesions in human small cell and non-small cell lung cancer) and have back-crossed these mice four times into the AJ mouse strain which is highly susceptible to lung tumor. We plan to study the pattern of tumor development and to analyze precursor cells for lung cancer; iv) We have characterized a novel pattern of post-translational modifications of the RB protein during apoptosis and are currently investigating the cellular localization of these specific cleavage products and whether they have a direct biological role in the process of programmed cell death.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC007256-08
Application #
2456839
Study Section
Special Emphasis Panel (NMOB)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1996
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Komiya, T; Coxon, A; Park, Y et al. (2010) Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer. Oncogene 29:1672-80
Kaye, Frederic J (2009) Mutation-associated fusion cancer genes in solid tumors. Mol Cancer Ther 8:1399-408
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Kaye, Frederic J (2006) Emerging biology of malignant salivary gland tumors offers new insights into the classification and treatment of mucoepidermoid cancer. Clin Cancer Res 12:3878-81
Komiya, T; Park, Y; Modi, S et al. (2006) Sustained expression of Mect1-Maml2 is essential for tumor cell growth in salivary gland cancers carrying the t(11;19) translocation. Oncogene 25:6128-32
Chute, John P; Taylor, Elizabeth; Williams, John et al. (2006) A metabolic study of patients with lung cancer and hyponatremia of malignancy. Clin Cancer Res 12:888-96
Kaye, Frederic J (2005) A curious link between epidermal growth factor receptor amplification and survival: effect of ""allele dilution"" on gefitinib sensitivity? J Natl Cancer Inst 97:621-3
Paez, J Guillermo; Janne, Pasi A; Lee, Jeffrey C et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497-500

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