Late intervention with anti-BRAF(V600E) therapy induces tumor regression in an orthotopic mouse model of human anaplastic thyroid cancer.
Human anaplastic thyroid cancer (ATC) is a lethal disease with an advanced clinical presentation and median survival of 3 months. The BRAF(V600E) oncoprotein is a potent transforming factor that causes human thyroid cancer cell progression in vitro and in vivo; therefore, we sought to target this oncoprotein in a late intervention model of ATC in vivo. We used the human ATC cell line 8505c, which harbors the BRAF(V600E) and TP53(R248G) mutations. Immunocompromised mice were randomized to receive the selective anti-BRAF(V600E) inhibitor, PLX4720, or vehicle by oral gavage 28 d after tumor implantation, 1 wk before all animals typically die due to widespread metastatic lung disease and neck compressive symptoms in this model. Mice were euthanized weekly to evaluate tumor volume and metastases. Control mice showed progressive tumor growth and lung metastases by 35 d after tumor implantation. At that time, all control mice had large tumors, were cachectic, and were euthanized due to their tumor-related weight loss. PLX4720-treated mice, however, showed a significant decrease in tumor volume and lung metastases in addition to a reversal of tumor-related weight loss. Mouse survival was extended to 49 d in PLX4720-treated animals. PLX4720 treatment inhibited cell cycle progression from 28 d to 49 d in vivo. PLX4720 induces striking tumor regression and reversal of cachexia in an in vivo model of advanced thyroid cancer that harbors the BRAF(V600E) mutation.
Thyroid Cancer Research Laboratory, Endocrine Surgery Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Matthew A
MA
Nehs
Carmelo
C
Nucera
Sushruta S
SS
Nagarkatti
Peter M
PM
Sadow
Dieter
D
Morales-Garcia
Richard A
RA
Hodin
Sareh
S
Parangi
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002453:Cell Cycle; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D013449:Sulfonamides / Q000627:therapeutic use*; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015431:Weight Loss
D000970:Antineoplastic Agents; D007211:Indoles; C528407:PLX 4720; D013449:Sulfonamides; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf