Abstract
BackgroundWe assessed the utility of the dual PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235) as single agent therapy and in combination with conventional chemotherapy for thyroid cancer.Methodology/Principal FindingsEight cell lines from four types of thyroid cancer (papillary, follicular, anaplastic, medullary) were studied. The cytotoxicity of BEZ235 and five conventional chemotherapeutic agents alone and in combination was measured using LDH assay. Quantitative western blot assessed expression of proteins associated with cell cycle, apoptosis and signaling pathways. Cell cycle distribution and apoptosis were measured by flow cytometry. Murine flank anaplastic thyroid cancers (ATC) were treated with oral BEZ235 daily. We found that BEZ235 effectively inhibited cell proliferation of all cancer lines, with ATC exhibiting the greatest sensitivity. BEZ235 consistently inactivated signaling downstream of mTORC1. BEZ235 generally induced cell cycle arrest at G0/G1 phase, and also caused apoptosis in the most sensitive cell lines. Baseline levels of p-S6 ribosomal protein (Ser235/236) and p27 correlated with BEZ235 sensitivity. Growth of 8505C ATC xenograft tumors was inhibited with BEZ235, without any observed toxicity. Combination therapy of BEZ235 and paclitaxel consistently demonstrated synergistic effects against ATC in vitro.ConclusionsBEZ235 as a single therapeutic agent inhibits thyroid cancer proliferation and has synergistic effects in combination with paclitaxel in treating ATC. These findings encourage future clinical trials using BEZ235 for patients with this fatal disease.
Highlights
Thyroid cancer is the most common endocrine malignancy, originating from thyroid follicular cells or parafollicular C cells
BEZ235 at 100 nmol/L arrested more than 80% cell growth in Anaplastic thyroid cancer (ATC) lines, 78% in medullary (TT) and more than 74% in well-differentiated thyroid cancer lines
Dm of BEZ235 on day 4 was calculated for each cell line (Figure 1B)
Summary
Thyroid cancer is the most common endocrine malignancy, originating from thyroid follicular cells (papillary, follicular, poorly differentiated and anaplastic cancer) or parafollicular C cells (medullary cancer). The incidence of thyroid cancer has increased over the past 3 decades, primarily from an increase in the detection of papillary cancer. The incidence of follicular and poorly differentiated thyroid cancer remains unchanged [1,2]. Most patients with well-differentiated cancer, including papillary (PTC) and follicular (FTC) thyroid cancer have a favorable prognosis. Anaplastic thyroid cancer (ATC) is a rare, highly aggressive, and often fatal disease, with a median survival of just 6 months. Medullary thyroid cancer (MTC) accounts for 3– 5% of thyroid malignancy. Novel therapies for refractory and aggressive thyroid cancer are needed to improve currently poor outcomes for these patients. We assessed the utility of the dual PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235) as single agent therapy and in combination with conventional chemotherapy for thyroid cancer
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