Research: Our research group is interested in studying the genetic basis for thoracic and head and neck cancers. One goal of our group is to identify and collects samples from young patients who present with these tumors. We recently identified the genetic basis for pulmonary mucoepidermoid carcinoma by isolating and cloning the chromosomal breakpoint of a t(11;19) translocation detected in three of our patients at the National Naval Medical Center. We have cloned the two novel genes that form a mutant gene fusion protein in these tumors and have shown that this Mect1-Maml2 chimeric protein underlies the most common type of malignant salivary gland tumor in humans. We also showed that the fusion protein is oncogenic for primary epithelial cells and that RNAi inhibition of Mect1-Maml2 induces rapid cell death of mucoepidermoid cancer cell line, but show no effect on other primary or tumor cells that do not carry the Mect1-Maml2 rearrangement. Recent data shows that the Maml2 component is part of an essential co-activator for the NOTCH signaling pathway and the Mect1 component is part of an essential co-activator for cyclic-AMP/CREB signaling. Future work will help define a mouse model and candidate pre-clinical and clinical studies. In addition, we have studied the role of the RB tumor suppressor pathway in human cancer and have demonstrated that the RB/p16 tumor suppressor pathway is inactivated in 100% of small cell lung cancer (SCLC) and non-SCLC. We are currently interested in examining the interrelationships between RB/p16 and the cyclin d/ras pathways in neuroendocrine tumorigenesis by defining abnormalities in these pathways within the immortalized tumor lines developed at the National Naval Medical Center. We are also interested in conducting a pilot study at the naval Hospital to detect somatic alterations within thoracic mesothelioma samples using complementary high-resolution genomic methodologies.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC007256-16
Application #
7068379
Study Section
(GB)
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2004
Total Cost
Indirect Cost
Name
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
Chen, M; Rahman, L; Voeller, D et al. (2007) Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas. Oncogene 26:4817-24
Tirado, Yamilet; Williams, Michelle D; Hanna, Ehab Y et al. (2007) CRTC1/MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin's tumors: implications for histogenesis and biologic behavior. Genes Chromosomes Cancer 46:708-15
Thomas, Roman K; Baker, Alissa C; Debiasi, Ralph M et al. (2007) High-throughput oncogene mutation profiling in human cancer. Nat Genet 39:347-51
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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