American Association of Endocrine Surgeon| Volume 148, ISSUE 6, P1154-1162, December 2010

Thyroidectomy with neoadjuvant PLX4720 extends survival and decreases tumor burden in an orthotopic mouse model of anaplastic thyroid cancer


      B-RafV600E is a frequent mutation in anaplastic thyroid cancers and is a novel therapeutic target. We hypothesized that PLX4720 (an inhibitor of B-RafV600E) and thyroidectomy would extend survival and would decrease tumor burden in a mouse model.


      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.


      All 5 mice that received the vehicle developed cachexia, had invasive tumors (average 61 mm3)and were sacrificed by day 35. All 6 mice receiving PLX4720 + sham had small tumors (average 1.3 mm3) 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 mm3) and showed no signs of metastatic disease. All mice treated with PLX4720 were alive and well-appearing at 50 days.


      Thyroidectomy with neoadjuvant PLX4720 could be an effective therapeutic strategy for early anaplastic thyroid cancers that harbor the B-RafV600E mutation and are refractory to conventional therapeutic modalities.
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        • Neff R.L.
        • Farrar W.B.
        • Kloos R.T.
        • Burman K.D.
        Anaplastic thyroid cancer.
        Endocrinol Metab Clin North Am. 2008; 37: 525-538
        • Pichardo-Lowden A.
        • Durvesh S.
        • Douglas S.
        • Todd W.
        • Bruno M.
        • Goldenberg D.
        Anaplastic thyroid carcinoma in a young woman: a rare case of survival.
        Thyroid. 2009; 19: 775-779
        • Are C.
        • Shaha A.R.
        Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches.
        Ann Surg Oncol. 2006; 13: 453-464
        • Pasieka J.L.
        Anaplastic thyroid cancer.
        Curr Opin Oncol. 2003; 15: 78-83
        • Fagin J.A.
        Molecular genetics of human thyroid neoplasms.
        Ann Rev Med. 1994; 45: 45-52
        • Begum S.
        • Rosenbaum E.
        • Henrique R.
        • Cohen Y.
        • Sidransky D.
        • Westra W.H.
        BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment.
        Mod Pathol. 2004; 17: 1359-1363
        • Venkatesh Y.S.
        • Ordonez N.G.
        • Schultz P.N.
        • Hickey R.C.
        • Goepfert H.
        • Samaan N.A.
        Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases.
        Cancer. 1990; 66: 321-330
        • Nucera C.
        • Goldfarb M.
        • Hodin R.
        • Parangi S.
        Role of B-Raf(V600E) in differentiated thyroid cancer and preclinical validation of compounds against B-Raf(V600E).
        Biochim Biophys Acta. 2009; 1795: 152-161
        • Xing M.
        BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications.
        Endocr Rev. 2007; 28: 742-762
        • Tsai J.
        • Lee J.T.
        • Wang W.
        • Zhang J.
        • Cho H.
        • Mamo S.
        • et al.
        Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.
        Proc Natl Acad Sci U S A. 2008; 105: 3041-3046
        • Cartlidge R.A.
        • Thomas G.R.
        • Cagnol S.
        • Jong K.A.
        • Molton S.A.
        • Finch A.J.
        • et al.
        Oncogenic BRAF(V600E) inhibits BIM expression to promote melanoma cell survival.
        Pigment Cell Melanoma Res. 2008; 21: 534-544
        • Salerno P.
        • De Falco V.
        • Tamburrino A.
        • et al.
        Cytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells.
        J Clin Endocrinol Metab. 2010; 95: 450-455
        • Nucera C.
        • Nehs M.A.
        • Mekel M.
        • Nappi T.C.
        • Vecchio G.
        • Schweppe R.E.
        • et al.
        A novel orthotopic mouse model of human anaplastic thyroid carcinoma.
        Thyroid. 2009; 19: 1077-1084
        • Hatzivassiliou G.
        • Song K.
        • Yen I.
        • Brandhuber B.J.
        • Anderson D.J.
        • Alvarado R.
        • et al.
        RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.
        Nature. 2010; 464: 431-435
        • Poulikakos P.I.
        • Zhang C.
        • Bollag G.
        • Shokat K.M.
        • Rosen N.
        RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF.
        Nature. 2010; 464: 427-430
      1. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell;140:209-221.