Thyroidectomy with neoadjuvant PLX4720 extends survival and decreases tumor burden in an orthotopic mouse model of anaplastic thyroid cancer.
BACKGROUND
B-Raf(V600E) is a frequent mutation in anaplastic thyroid cancers and is a novel therapeutic target. We hypothesized that PLX4720 (an inhibitor of B-Raf(V600E)) and thyroidectomy would extend survival and would decrease tumor burden in a mouse model.


METHODS
Orthotopic anaplastic thyroid tumors were induced in severe combined immunodeficient mice. Mice were treated with PLX4720 or vehicle after 7 days of tumor growth, and thyroidectomy or sham surgery was performed at day 14. The neck space was re-explored, and tumor volume was measured at day 35. Mice were sacrificed when they lost >25% of their initial weight.


RESULTS
All 5 mice that received the vehicle developed cachexia, had invasive tumors (average 61 mm(3))and were sacrificed by day 35. All 6 mice receiving PLX4720 + sham had small tumors (average 1.3 mm(3)) and maintained their weight. Three out of 6 mice receiving PLX4720+thyroidectomy had no evidence of tumor at 35 days; the other 3 mice had small tumors (average 1.4 mm(3)) and showed no signs of metastatic disease. All mice treated with PLX4720 were alive and well-appearing at 50 days.


CONCLUSIONS
Thyroidectomy with neoadjuvant PLX4720 could be an effective therapeutic strategy for early anaplastic thyroid cancers that harbor the B-Raf(V600E) mutation and are refractory to conventional therapeutic modalities.
Thyroid Cancer Research Laboratory, Division of Endocrine Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Matthew A
MA
Nehs
Sushruta
S
Nagarkatti
Carmelo
C
Nucera
Richard A
RA
Hodin
Sareh
S
Parangi
D000818:Animals; D001835:Body Weight; D002455:Cell Division; D003131:Combined Modality Therapy; D017281:Cost of Illness; D004195:Disease Models, Animal; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D020360:Neoadjuvant Therapy / Q000379:methods; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013449:Sulfonamides / Q000627:therapeutic use*; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000601:surgery; D013965:Thyroidectomy / Q000379:methods*
D007211:Indoles; C528407:PLX 4720; D013449:Sulfonamides; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf