Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies. Currently, there is no standard or effective therapy for ATC. Drug repurposing for cancer treatment is an emerging approach for identifying compounds that may have antineoplastic effects. The aim of this study was to use high-throughput drug library screening to identify and subsequently validate novel therapeutic agents with anticancer effects in ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines (SW-1736, 8505C, and C-643), using a compound library of 3282 drugs. qHTS identified 100 compounds that were active in all three ATC cell lines. Proteasome inhibitors were one of the most active drug categories according to enrichment analysis. Of the three proteasome inhibitors screened, a second-generation proteasome inhibitor, carfilzomib, was the most active. Treatment of ATC cells with carfilzomib significantly inhibited cellular proliferation and induced G2/M cell cycle arrest and caspase-dependent apoptosis. Mechanistically, carfilzomib increased expression of p27 (CDKN1B) and decreased expression of the anti-apoptotic protein ATF4. Pretreatment with carfilzomib reduced in vivo metastases (lung, bone, liver, and kidney) and disease progression, and decreased N-cadherin expression. Carfilzomib treatment of mice with established, widely metastatic disease significantly increased their survival, without significant toxicity. Our findings support the use or clinical study of carfilzomib as a therapeutic option in patients with advanced and metastatic ATC.
Amit Mehta, Lisa Zhang, Myriem Boufraqech, Yaqin Zhang, Dhaval Patel, Min Shen and Electron Kebebew
Douglas Wiseman, James D McDonald, Dhaval Patel, Electron Kebebew, Karel Pacak and Naris Nilubol
Postoperative hypotension frequently occurs after resection of pheochromocytoma and/or paraganglioma (PPGLs). Epidural anesthesia (EA) is often used for pain control in open resection of these tumors; one of its side effects is hypotension. Our aim is to determine if EA is associated with an increased risk of postoperative hypotension after open resection of PPGLs. We conducted a retrospective review of patients who underwent open resection of PPGLs at the National Institutes of Health from 2004 to 2019. Clinical and perioperative parameters were analyzed by the use of EA. The primary endpoint was postoperative hypotension. Ninety-seven patients (46 female and 51 male; mean age, 38.5 years) underwent open resection of PPGLs and 69 (71.1%) received EA. Patients with EA had a higher rate beta-blocker use (79.7% vs 57.1%, P = 0.041), metastasis (69.6% vs 39.3%, P = 0.011), and were more frequently hypotensive after surgery (58.8% vs 25.0%, P = 0.003) compared to those without EA. Patients with postoperative hypotension had higher plasma normetanephrines than those without (7.3 fold vs 4.1 fold above the upper limit of normal, P = 0.018). Independent factors associated with postoperative hypotension include the use of beta-blockers (HR = 3.35 (95% CI: 1.16–9.67), P = 0.026) and EA (HR = 3.49 (95% CI: 1.25–9.76), P = 0.017). Data from this retrospective study suggest that, in patients with open resection of PPGLs, EA is an independent risk factor for early postoperative hypotension. Special caution is required in patients on beta-blockade. A prospective evaluation with standardized protocols for the use of EA and management of hemodynamic variability is necessary.
Myriem Boufraqech, Lisa Zhang, Meenu Jain, Dhaval Patel, Ryan Ellis, Yin Xiong, Mei He, Naris Nilubol, Maria J Merino and Electron Kebebew
The expression and function of miR-145 in thyroid cancer is unknown. We evaluated the expression and function of miR-145 in thyroid cancer and its potential clinical application as a biomarker. We found that the expression of miR-145 is significantly downregulated in thyroid cancer as compared with normal. Overexpression of miR-145 in thyroid cancer cell lines resulted in: decreased cell proliferation, migration, invasion, VEGF secretion, and E-cadherin expression. miR-145 overexpression also inhibited the PI3K/Akt pathway and directly targeted AKT3. In vivo, miR-145 overexpression decreased tumor growth and metastasis in a xenograft mouse model, and VEGF secretion. miR-145 inhibition in normal primary follicular thyroid cells decreased the expression of thyroid cell differentiation markers. Analysis of indeterminate fine-needle aspiration samples showed miR-145 had a 92% negative predictive value for distinguishing benign from malignant thyroid nodules. Circulating miR-145 levels were significantly higher in patients with thyroid cancer and showed a venous gradient. Serum exosome extractions revealed that miR-145 is secreted. Our findings suggest that miR-145 is a master regulator of thyroid cancer growth, mediates its effect through the PI3K/Akt pathway, is secreted by the thyroid cancer cells, and may serve as an adjunct biomarker for thyroid cancer diagnosis.