Background: 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 have completed a quantitative high throughput screening strategy for the identification of novel agents for thyroid cancer and adrenocortical carcinoma. In collaboration with the Chemistry group at the NIH Chemical Genomic Center, we screened 2,816 compounds to determine their antiproliferative effect in thyroid cancer and adrenocortical carcinoma cell lines. All of the compounds have either FDA approval for other indications or have investigational new drug designation by the FDA. We have identified over 30 compounds with high confidence activity against thyroid cancer and adrenocortical carcinoma cell lines. We are currently validating the anticancer activity of the most potent compounds and plan to translate these findings into clinical trials for patients with advance thyroid cancer and adrenocortical carcinoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011286-02
Application #
8349445
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2011
Total Cost
$796,197
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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Kebebew, Electron (2018) Thyroid Cancer: Is It All in the Genes? J Natl Cancer Inst 110:327-328
Tirosh, Amit; El Lakis, Mustapha; Green, Patience et al. (2018) In silico VHL Gene Mutation Analysis and Prognosis of Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease. J Clin Endocrinol Metab 103:1631-1638
El Lakis, Mustapha; Nockel, Pavel; Guan, Bin et al. (2018) Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure. Surgery 163:31-34
Nockel, Pavel; El Lakis, Mustapha; Gaitanidis, Apostolos et al. (2018) Preoperative genetic testing in pheochromocytomas and paragangliomas influences the surgical approach and the extent of adrenal surgery. Surgery 163:191-196

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