Professor of Surgery, Cancer Biology
Director of Surgical Oncology Research
Dr. El-Rifai has a long-standing interest in understanding the modulation of molecular pathways through genetic and epigenetic events. His research is focused on upper gastrointestinal carcinomas (UGCs) with two main goals:
1. Translational OncoGenomics in upper gastrointestinal carcinomas
The El-Rifai laboratory has extensive expertise in the dissection of genetic and epigenetic alterations in upper gastrointestinal carcinomas (UGC). This group of tumors includes distal gastric tumors and proximal adenocarcinomas of the gastroesophageal junctional (GEJ) and lower esophagus. Proximal adenocarcinomas are the fastest rising tumors in the United States and in the rest of the western world. In his laboratory, comprehensive, molecular-analysis-approaches are applied with the integration of data in order to understand the molecular anatomy of these tumors. Several high-throughput technologies are utilized in his research. These include comparative genomic hybridization, microarrays, serial analysis of gene expression, and proteomic approaches. The El-Rifai laboratory identified a number of genomic hot spots and has systematically characterized the 1q, 17q, and 20q amplicons by combining the genomic data with gene expression data. At 17q21 he identified and characterized a 168 kb critical amplicon region that contains several known oncogenes side-by-side such as ERBB2, GRB7, and TOP2A. Dr. El-Rifai's lab was the first group of investigators to reveal Darpp-32 and its isoforms as novel cancer genes.
Our research extends to encompass animal models as tools of identification of tumor development and progression. In this direction, Dr. El-Rifai obtained TFF1 knockout mice that develop premalignant gastric dysplasia. Dr. El-Rifai laboratory has characterized this model and used it to identify alterations in molecular pathways that occur in a premalignant state. Using this approach, his research group discovered a number of previously unknown genes in gastric tumorigenesis and was able to validate the findings in human premalignant conditions. These genes include GPx3, Claudin-7, and Caveolin.
Dr. El-Rifai has demonstrated DNA promoter hypermethylation as a mechanism of down-regulation and loss of expression of several novel genes such as MT3, MGMT, DAPK, and GPX3. He has further shown that some of these changes are early events initiated in premalignant states such as in Barrett's dysplasia. Recently, the El-Rifai laboratory added the cutting-edge, pyrosequencing technology (Biotage) for a high through-put, robust, quantitative analysis of promoter CpG methylation sites.
2. Cellular effects and signaling transduction in UGCs
In line with his translational research component, Dr. El-Rifai laboratory is primarily interested in identifying anti-apoptotic/pro-survival targets that contribute to drug resistance. At this time, the work is focused in understanding the p53-dependent and independent mechanisms that contribute to this phenotype. Dr. El-Rifai work has demonstrated that Darpp-32 is a potent antiapoptotic gene that provides a phenotype that is drug resistant to cancer cells against several chemotherapeutic agents. This drug resistant phenotype was through a p53-independent mechanism that included up-regulation and activation of mitochondrial Bcl2 prosurvival proteins. In his laboratory, normal and transformed cells, specific antibodies and purified protein kinases are used to show phosphorylation controls activity. His research group continues to establish the oncogenic properties and downstream targets of Darpp-32 and/or t-Darpp in order to understand the signaling pathways that are regulated by Darpp-32 in cancer. In addition to studies on Darpp-32, our lab has identified COBRA1 as a novel gene that regulates the transcription of TFF1 expression in UGCs. His research work continues to focus on investigating the oncogenic properties of both DARPP-32 and COBRA1 in these tumors.
MD: 1986 (General Medicine)
M.Sc.: 1991 (Human Genetics)
DM: 1993 (Pediatric Genetics)
Ph.D.: 1996 (Cancer Genetics)
Dr. El-Rifai's CV is available in PDF format.
Vanderbilt University Medical Center
760 PRB, 2220 Pierce Ave
Nashville , TN 37232-6308
Fax: 615-322 7852