RESUMEN
BACKGROUND: Selectively increased radioiodine accumulation in thyroid cells by thyrotropin (TSH) allows targeted treatment of thyroid cancer. However, the extent of TSH-stimulated radioiodine accumulation in some thyroid tumors is not sufficient to confer therapeutic efficacy. Hence, it is of clinical importance to identify novel strategies to selectively further enhance TSH-stimulated thyroidal radioiodine accumulation. METHODS: PCCl3 rat thyroid cells, PCCl3 cells overexpressing BRAF(V600E), or primary cultured tumor cells from a thyroid cancer mouse model, under TSH stimulation were treated with various reagents for 24 hours. Cells were then subjected to radioactive iodide uptake, kinetics, efflux assays, and protein extraction followed by Western blotting against selected antibodies. RESULTS: We previously reported that Akt inhibition increased radioiodine accumulation in thyroid cells under chronic TSH stimulation. Here, we identified Apigenin, a plant-derived flavonoid, as a reagent to further enhance the iodide influx rate increased by Akt inhibition in thyroid cells under acute TSH stimulation. Akt inhibition is permissive for Apigenin's action, as Apigenin alone had little effect. This action of Apigenin requires p38 MAPK activity but not PKC-δ. The increase in radioiodide accumulation by Apigenin with Akt inhibition was also observed in thyroid cells expressing BRAF(V600E) and in primary cultured thyroid tumor cells from TRß(PV/PV) mice. CONCLUSION: Taken together, Apigenin may serve as a dietary supplement in combination with Akt inhibitors to enhance therapeutic efficacy of radioiodine for thyroid cancer.
Asunto(s)
Apigenina/metabolismo , Radioisótopos de Yodo/metabolismo , Moduladores del Transporte de Membrana/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Glándula Tiroides/efectos de los fármacos , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Apigenina/uso terapéutico , Transporte Biológico/efectos de los fármacos , Línea Celular , Suplementos Dietéticos , Humanos , Cinética , Moduladores del Transporte de Membrana/uso terapéutico , Ratones , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Radiofármacos/metabolismo , Ratas , Glándula Tiroides/metabolismo , Glándula Tiroides/patología , Neoplasias de la Tiroides/dietoterapia , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Tirotropina/metabolismo , Células Tumorales Cultivadas , Regulación hacia Arriba/efectos de los fármacosRESUMEN
PURPOSE: Mutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC. PATIENTS AND METHODS: In this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily. RESULTS: Of 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21+ months, four patients had SD >or= 15 months, four patients had SD Asunto(s)
Bencenosulfonatos/uso terapéutico
, Carcinoma Medular/tratamiento farmacológico
, Inhibidores de Proteínas Quinasas/uso terapéutico
, Piridinas/uso terapéutico
, Neoplasias de la Tiroides/tratamiento farmacológico
, Administración Oral
, Adulto
, Anciano
, Bencenosulfonatos/administración & dosificación
, Bencenosulfonatos/efectos adversos
, Biomarcadores de Tumor/metabolismo
, Carcinoma Medular/enzimología
, Carcinoma Medular/genética
, Carcinoma Medular/mortalidad
, Carcinoma Medular/secundario
, Supervivencia sin Enfermedad
, Femenino
, Humanos
, Estimación de Kaplan-Meier
, Imagen por Resonancia Magnética
, Masculino
, Persona de Mediana Edad
, Mutación
, Niacinamida/análogos & derivados
, Compuestos de Fenilurea
, Tomografía de Emisión de Positrones
, Inhibidores de Proteínas Quinasas/administración & dosificación
, Inhibidores de Proteínas Quinasas/efectos adversos
, Proto-Oncogenes Mas
, Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores
, Proteínas Proto-Oncogénicas c-ret/genética
, Piridinas/administración & dosificación
, Piridinas/efectos adversos
, Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
, Sorafenib
, Neoplasias de la Tiroides/enzimología
, Neoplasias de la Tiroides/genética
, Neoplasias de la Tiroides/mortalidad
, Neoplasias de la Tiroides/patología
, Factores de Tiempo
, Tomografía Computarizada por Rayos X
, Resultado del Tratamiento
, Estados Unidos
, Adulto Joven
RESUMEN
PURPOSE: Based on the pivotal role of Ras-Raf-MAP-ERK signaling and vascular endothelial growth factor (VEGF) in papillary thyroid cancer (PTC), we conducted a phase II clinical trial of sorafenib targeting RAF and VEGF receptor kinases in PTC. PATIENTS AND METHODS: The primary end point was the objective response rate. Secondary end points included response correlation with serum thyroglobulin (Tg); functional imaging; tumor genotype; and signaling inhibition in tumor biopsies. Using a Simon minimax two-stage design, 16 or 25 chemotherapy-naïve metastatic PTC patients were to be enrolled in arm A (accessible tumor for biopsy). Arm B patients had other subtypes of thyroid carcinoma or prior chemotherapy, and did not require tumor biopsies. Patients received 400 mg orally twice per day of sorafenib. Response was assessed every 2 months using RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: Of 41 PTC patients, six patients had a partial response (PR; 15%; 95% CI, 6 to 29) and 23 patients (56%; 95% CI, 40 to 72) had stable disease longer than 6 months. Median duration of PR was 7.5 months (range, 6 to 14). Median progression-free survival was 15 months (95% CI, 10 to 27.5). In 14 (78%) of 18 Tg-assessable PTC patients, Tg declined more than 25%. Common grade 3 adverse events included hand-foot skin reaction, musculoskeletal pain, and fatigue. BRAF mutation was detected in 17 (77%) of 22 PTCs analyzed. Four of 10 paired tumor biopsies from PTC patients showed a reduction in levels of vascular endothelial growth factor receptor phosphorylation, ERK phosphorylation, and in VEGF expression during sorafenib therapy. No PRs were noted among non-PTC patients. CONCLUSION: Sorafenib is reasonably well-tolerated therapy with clinical and biologic antitumor activity in metastatic PTC.