Late Intervention with anti-BRAF V600E Therapy Induces Tumor Regression in an Orthotopic Mouse Model of Human Anaplastic Thyroid Cancer

Thyroid Cancer Research Laboratory, Endocrine Surgery Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Endocrinology (Impact Factor: 4.5). 12/2011; 153(2):985-94. DOI: 10.1210/en.2011-1519
Source: PubMed


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.

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Available from: Sareh Parangi, Apr 21, 2015
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    • "The inactivation of RASAL1 (encoding a RAS GTPase-activating protein) by hypermethylation and mutations provides a new genetic background for FTCs and ATCs (72). Besides nuclear β-catenin accumulation and p53 inactivation, oncogenic activation of MAPK and PI3K/Akt/Foxo3a are frequently found in ATCs (2, 73, 74). The acquisition of a TERT promoter mutation was recently associated with clinical–pathological aggressiveness in FTCs and BRAF mutation-positive PTCs (72, 75). "
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    ABSTRACT: Recent discoveries highlight the emerging role of estrogens in the initiation and progression of different malignancies through their interaction with stem cell (SC) compartment. Estrogens play a relevant role especially for those tumors bearing a gender disparity in incidence and aggressiveness, as occurs for most thyroid diseases. Although several experimental lines suggest that estrogens promote thyroid cell proliferation and invasion, their precise contribution in SC compartment still remains unclear. This review underlines the interplay between hormones and thyroid function, which could help to complete the puzzle of gender discrepancy in thyroid malignancies. Defining the association between estrogen receptors' status and signaling pathways by which estrogens exert their effects on thyroid cells is a potential tool that provides important insights in pathogenetic mechanisms of thyroid tumors.
    Frontiers in Endocrinology 07/2014; 5:124. DOI:10.3389/fendo.2014.00124
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    • "It was shown that the tumors developing in this animal model undergo the glycolytic shift known as Warburg effect and are highly sensitive to the therapeutic use of glycolytic inhibitors, which synergize with standard chemotherapy [77]. Later, Nehs et al. [78] elegantly demonstrated the remarkable efficacy of PLX4720 compound, which is an ATP analog that selectively inhibits B-Raf V600E by stabilizing it in an inactive conformation [79] "
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    ABSTRACT: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers. Actually, ATC is refractory to conventional therapies, including surgery, chemotherapy, radiotherapy, and radioiodine ((131)I) therapy. Accordingly, genetic and molecular characterizations of ATC have been frequently and periodically reviewed in order to identify potential biological markers exploitable for target therapy. This review briefly focuses on main molecular events that characterize ATC and provides an update about preclinical studies. In addition, the overexpression of transferrin receptor 1 (TfR1/CD71) by neoplastic cells of ATC is emphasized in that it could represent a potential therapeutic target. In this regard, new therapeutic approaches based on the use of monoclonal or recombinant antibodies, or transferrin-gallium-TfR1/CD71 molecular complexes, or lastly small interfering RNAs (siRNAs) are proposed.
    International Journal of Endocrinology 07/2014; 2014:685396. DOI:10.1155/2014/685396 · 1.95 Impact Factor
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    • "While the effectiveness of BRAFV600E-inhibition in melanoma has spurred investigation in thyroid cancer, there are important differences between melanoma and thyroid cancer. Nanomolar concentrations of BRAFV600E-inhibitors are sufficient to inhibit proliferation in melanoma cell lines whereas micromolar doses are required for a similar effect in thyroid cancer cell lines [6-8, 13, 14]. Furthermore, unlike melanoma cells, thyroid cancer cells do not undergo apoptosis when treated with BRAFV600E-inhibitors suggesting the persistence of additional signaling pathways that permit or promote survival [5, 6]. "
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    ABSTRACT: Anaplastic (ATC) and refractory papillary thyroid cancer (PTC) lack effective treatments. Inhibition of either oncogenic BRAF or SRC has marked anti-tumor effects in mouse models of thyroid cancer, however, neither drug induces notable apoptosis. Here we report that the SRC-inhibitor dasatinib further sensitizes BRAFV600E-positive thyroid cancer cells to the BRAFV600E-inhibitor PLX4720. Combined treatment with PLX4720 and dasatinib synergistically inhibited proliferation and reduced migration in PTC and ATC cells. Whereas PLX4720 did not induce robust apoptosis in thyroid cancer cells, combined treatment with dasatinib induced apoptosis in 4 of 6 lines. In an immunocompetent orthotopic mouse model of ATC, combined PLX4720 and dasatinib treatment significantly reduced tumor volume relative to PLX4720 treatment alone. Immune cell infiltration was increased by PLX4720 treatment and this effect was maintained in mice treated with both PLX4720 and dasatinib. Further, combined treatment significantly increased caspase 3 cleavage in vivo relative to control or either treatment alone. In conclusion, combined PLX4720 and dasatinib treatment induces apoptosis, increases immune cell infiltration and reduces tumor volume in a preclinical model of ATC, suggesting that the combination of these FDA-approved drugs may have potential for the treatment of patients with ATC or refractory PTC.
    Oncotarget 06/2014; 5(12). DOI:10.18632/oncotarget.2130 · 6.36 Impact Factor
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