Therapeutic targets and novel anticancer agents for endocrine cancers

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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%. Anaplastic thyroid cancer is one of the most lethal solid malignancies with no currently available effective systemic therapy. 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%. We have completed a quantitative high-throughput screening of 4,292 newly assembled compounds containing clinically approved drugs and bioactive compounds in human cell lines, including thyroid cancer and adrenocortical carcinoma. We identified 100 pan-active compounds in a panel of thyroid cancer cell lines screened and have thus far identified 5 compounds with promising results in our preclinical studies, using a mouse model of metastatic thyroid cancer developed in our branch. CUDC-907, a first-in-class dual inhibitor of histone deacetylase and phosphatidylinositol 3-kinase, is one of these compounds. We found significant inhibition of growth and metastases in 6 thyroid cancer cells originating from poorly differentiated thyroid cancer and anaplastic thyroid cancer. Mechanistically, CUDC-907 induced caspase-dependent apoptosis and G2M arrest that was associated with increased p21 expression, and reduced N-cadherin and vimentin expression levels. CUDC-907 was utilized in a Phase I/II trial to test for safety and efficacy. The medication was found to be well-tolerated, but was not efficacious. From our high-throughput screening in 3 adrenocortical carcinoma cell lines using a drug library of 4,292 compounds, we have identified 40 pan-active compounds. Filtering based on IC50, serum achievable concentration, and drug efficacy 80% (as compared to tetraoctylammonium bromide), we have performed follow up studies in 3 drug candidates with niclosamide showing the best results in our preclinical studies and effectively targeting genetic driver events and signaling alterations common in adrenocortical carcinoma. Another progress we have made in our studies is a collaborative preclinical project evaluating a novel gold nanomedicine. This nanomedicine significantly reduced growth and metastasis, increased overall survival, and induced apoptosis and tumor vascular disruption in our metastatic model of thyroid cancer. We hope to translate these findings for niclosamide and gold nanomedicine into Phase I/II trial in the future.