Our Science – Kebebew Website
Electron Kebebew, M.D.
Dr. Kebebew has published over 200 articles, chapters and textbooks, and serves on the editorial board and as a reviewer for more than 25 biomedical journals. He has received awards from the American Cancer Society, American Association for Cancer Research, American Thyroid Association, American Association of Endocrine Surgeons, and International Association of Endocrine Surgeons.
His laboratory investigates the genomic changes associated with endocrine cancers with the ultimate goal of identifying therapeutic targets and novel anticancer agents for endocrine cancers, and diagnostic and prognostic markers for endocrine tumors. Dr. Kebebew is a Fellow of the American College of Surgeons, and is an internationally recognized expert in Endocrine Surgery, and has performed more than two thousand operations on the adrenal, pancreas, parathyroid and thyroid.
While the incidence and mortality of most cancers has decreased, the incidence of endocrine cancers (thyroid, neuroendocrine pancreas) has increased dramatically, with significant gender disparity (thyroid), and with an increase (thyroid) or no significant improvement (adrenal, neuroendocrine, parathyroid) in mortality rates. There is even more of a pressing need to develop effective therapy for patients with rare and neglected endocrine cancers such as anaplastic thyroid cancer and adrenocortical carcinoma as the outcome of patients with these cancers has not improved in nearly 6 decades.
Incidentally detected endocrine neoplasms today encompass an even larger number of patients who require evaluation to exclude a cancer diagnosis. Unfortunately, current clinical, biochemical and imaging tests, and cytologic analysis of biopsy samples are commonly inconclusive. Thus, approximately 300,000 patients annually in the U.S. undergo an invasive procedure for definitive diagnosis on histologic examination. This results in significant morbidity and mortality, and health care expenditure as only about 5-30% of these patients are found to have a malignant endocrine tumor on histology, which in some types of endocrine neoplasms is still not reliable (pheochromocytoma/paraganglioma, pancreatic neuroendocrine tumors, adrenocortical tumors) in rendering a definitive diagnosis and patients require continued follow up with imaging studies and biochemical testing annually.
DIAGNOSTIC AND PROGNOSTIC MOLECULAR MARKERS OF ENDOCRINE NEOPLASMS
We are using a pan-genomic (mRNA and microRNA expression, and global methylation) profiling approaches in human tumor tissue samples to identify candidate diagnostic and prognostic markers for endocrine malignancies (thyroid, adrenal, neuroendocrine pancreas, parathyroid). Advanced bioinformatics approaches are being used to determine if distinct molecular signatures exist for accurate diagnosis and prognostication in well annotated samples with clinical follow up data. To translate our findings into clinical use, we are using animal models to evaluate serum markers and clinical tumor biopsy samples to validate candidate diagnostic and prognostic markers.
I. IDENTIFICATION OF ALTERED GENES/PATHWAYS IN ENDOCRINE NEOPLASMS
II. IDENTIFICATION OF THERAPEUTIC TARGETS AND NOVEL ANTICANCER AGENTS FOR ENDOCRINE CANCERS
The molecular basis for endocrine cancer initiation and progression is poorly understood. We are using an integrated approach of using the pan-genomic expression profiling data to better understand the gene expression regulation and candidate genes involved in the initiation and progression of endocrine cancers. The 'master' regulators of dysregulated genes/pathways in endocrine cancers will then be tested in vitro using functional genomic approaches to confirm their role in tumor cell biology. It is hoped such an integrated bioinformatics approach and functional genomics approach in in vitro models of endocrine cancer cells will shed light on the main mechanisms of gene expression deregulation in endocrine cancers.
Thyroid cancer: The incidence of thyroid cancer has doubled over the last two decades. Although most patients with thyroid cancer of follicular cell origin have an excellent prognosis, 10% - 15% will have refractory disease to conventional therapy (resection combined with radioiodine ablation and thyroid hormone for TSH suppression). Chemotherapy and external beam radiation are ineffective in patients with metastatic disease. The overall 10 year survival of patients with metastatic thyroid cancer of follicular cell origin is approximately 40-50%.
Adrenocortical carcinoma: Approximately two-thirds of patients who present with adrenocortical carcinoma have locoregional disease and metastasis. Unfortunately, despite combined multimodality therapy, the overall prognosis of patients with adrenocortical carcinoma remains dismal, with a 5-year survival of less than 35%. Summary We are using functional genomics approach to determine the role of candidate genes, differentially expression by mRNA and microRNA expression profiling in thyroid cancer and adrenocortical carcinoma human tumor samples, in in vitro and in vivo models. The role of the candidate genes in regulating the hallmarks of malignant phenotype such as cellular proliferation, invasion and migration, and tumor angiogenesis is being tested using gene knockdown and knockin experiments to identify critical regulators and thus targets for therapy. We are also performing studies to identify novel agents for thyroid cancer and adrenocortical carcinoma. These studies involve using the National Chemical Genomic Center pharmaceutical collection of 2,816 compounds to determine their antiproliferative effect in thyroid cancer and adrenocortical carcinoma cell lines. All of these compounds have either FDA approval for other indications or have investigational new drug designation by the FDA. Thus, translating these findings, after validation of their antiproliferative effect in animal models of thyroid cancer and adrenocortical carcinoma, into clinical trials for patients with advance thyroid cancer and adrenocortical carcinoma would be relatively efficient.
CLINICAL AND GENETIC STUDIES IN FAMILIAL NONMEDULLARY THYROID CANCER (FNMTC)
Thyroid cancer is one of the fastest growing cancer diagnoses in the United States. Non-medullary thyroid cancer accounts for 95% of all thyroid cancer cases. Up to 8% of all non-medullary thyroid cancers are hereditary. Familial non-medullary thyroid cancer (FNMTC) is more aggressive than sporadic disease. No susceptibility gene for FNMTC has been identified. The best approach for screening at risk family members for FNMTC is unknown. This protocol is designed to determine the natural history and best screening strategy for FNMTC, and to identify susceptibility gene(s) for FNMTC. Summary: This is a prospective study of individuals with or at risk for non-medullary thyroid cancer. Individuals will be studied over time within the context of their families in order to quantify prospective risks of cancers in family members, to establish the natural history of FNMTC, define the spectrum of diseases within the families, to identify precursor states, to try to assess the contribution of genetic and environmental components of risk, and to develop effective screening strategies. Our initial genomic analysis of human familial and sporadic cases of non-medullary thyroid cancer have identified several dysregulated genes which have important regulatory roles in thyroid cancer cell proliferation and cell cycle progression. We will further characterize the mechanism of gene expression regulation in FNMTC tumor samples and determine if these genes are modifier and or susceptibility genes. Germline genetic studies to identify the susceptibility gene(s) for FNMTC are also underway using a variety of genetic approaches including linkage, association, copy number variation search, and exome/whole-genome sequencing to identify both common and rare genetic variants.
This page was last updated on 2/20/2013.