Utility of a PI3K/mTOR inhibitor (NVP-BEZ235) for thyroid cancer therapy.
BACKGROUND
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.


RESULTS
Eight 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.


CONCLUSIONS
BEZ235 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.
Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, Republic of China. mmg@cgmh.org.tw
Shu-Fu
SF
Lin
Yu-Yao
YY
Huang
Jen-Der
JD
Lin
Ting-Chao
TC
Chou
Chuen
C
Hsueh
Richard J
RJ
Wong
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib