Research: Our research group is interested in studying the genetic basis for thoracic and head and neck cancers. We had previously discovered the role of the RB/p16 cancer gene pathway which is inactivated in 100% of human lung cancer cases and, more recently, we identified a novel t(11;19) chromosomal translocation as the etiologic basis for the most common malignant head and neck salivary gland cancer. This work is of broad interest to the field of cancer research since fundamental discoveries on isolated cancer syndromes have revealed unexpected insights and potential therapeutic targets for many common adult malignancies. For example, inactivation of the retinoblastoma (RB) gene pathway underlies the genesis of a rare pediatric eye tumor as well as common types of adult lung cancer. Similarly, we now propose that the new fusion oncogene identified by the Kaye lab in salivary gland cancers identifies an unexpected gene pathway that is also deregulated in common epithelial tumors including lung cancer. We have demonstrated that this mect1-maml2 fusion protein can transform primary epithelial cells by activating a group of cAMP/CREB regulated genes. Some of these CREB inducible genes are associated with gluconeogenesis pathways and the normal mect gene family (also known as torc and crtc genes) is now identified as essential components of glucose control mechanisms during both feeding and starvation and is an important target of certain anti-diabetes drugs. This suggests a new link between anabolic glucose metabolism and cancer. In addition, the tumor suppressor gene LKB1, which underlies the rare Peutz-Jegher colon cancer syndrome, may serve as a suppressor of mect function by regulating its phosphorylation and cellular localization. Since we and others have observed that LKB1 is mutated in approximately 30% of common adult lung cancers we are actively studying the implications of deregulated mect activity in these tumor samples. Further, since mect activity is tightly correlated with its subcellular localization we have conducted molecular analyses to define the nuclear import and nuclear export mechanisms of the mect gene family in normal and tumor cells. This work will identify a distinct type of molecular target that may offer new therapeutic strategies for cancer treatment. For example, we have already shown that the sustained expression of Mect1-Maml2 is essential for the viability and growth of tumors with the reciprocal t(11;19) translocation. Accordingly, this suggests that mect activation through chromosomal translocation or deregulated subcellular localization may be an important target for future translational research in tumors with inactivation of the LKB1 pathway. Our work has also shown that mect-maml2 has both important diagnostic and prognostic information for clinicians treating patients with malignant tumors of major and minor salivary glands. Mect-maml2 has also been identified in selected skin, lung, and thyroid tumors suggesting that this molecular entity will be increasingly recognized in the future. This work continues an important collaboration between the NCI, NIH and the Naval Hospital, Bethesda to study the genetic basis for uncommon human cancers that lack known effective treatments and which are not adequately investigated in the extramural research community. Another research goal within our project to study the mechanism of oncogene activation in thoracic tumors, is a comprehensive analysis of the genetic and biological basis for malignant mesothelioma. Using intramural and extramural collaborations we are analyzing the RB/p16, NF2/merlin pathways, and novel cancer pathways in a large collection of mesothelioma samples collected at the NCI and Naval Hospital. Using CGH and SNP analyses we have identified regions of consistent DNA loss and are characterizing the functional consequences of these alterations. We have also defined a detailed protein binding network for NF2/merlin signaling in mesothelioma and this data may provide further insights into diagnosis and therapy for this disease
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