Late intervention with anti-BRAF(V600E) therapy induces tumor regression in an orthotopic mouse model of human anaplastic thyroid cancer.
ABSTRACT 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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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 01/2014; 2014:685396. · 1.52 Impact Factor
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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.
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ABSTRACT: Context: Anaplastic thyroid cancer (ATC) is the most lethal of all thyroid cancers and one of the most aggressive human carcinomas. In the search for effective treatment options, research towards targeted, personalized therapies is proving to be a path with great potential. As we gain a deeper understanding of the genetic (e.g. BRAF(V600E), PIK3CA, TP53 mutations, hTERT mutations, etc.) and epigenetic alterations (e.g. microRNAs) driving ATC, we are able to find targets when developing novel therapies to improve the lives of patients. Beyond development, we can look into the effectiveness of already approved targeted therapies (e.g. anti-BRAF(V600E) selective inhibitors, tyrosine kinase inhibitors, histone deacetylase inhibitors, inhibitors of DNA methylation, etc.) to potentially test in ATC after learning the molecular mechanisms that aid in tumor progression. Design: We performed a literature analysis in Medline through the PubMed website for studies published between 2003 and 2014, using the main key-words: anaplastic thyroid cancer, genetic and epigenetic alterations. Objective: Here, we outline the common pathways that are altered in ATC, including the BRAF(V600E)/ERK1/2-MEK1/2 and PI3K-AKT pathways. We then examined the current research looking into personalized, potential targeted therapies in ATC, mentioning those that have been tentatively advanced into clinical trials and those with the potential to reach that stage. We also reviewed side effects of the current and potential targeted therapies used in patients with advanced thyroid cancer. Conclusions: DNA and RNA next generation sequencing analysis will be fundamental to unravel a precise medicine and therapy in patients with ATC. Indeed, given the deep biological heterogeneity/complexity and high histological grade of this malignancy and its tumor microenvironment, personalized therapeutic approaches possibly based on the use of combinatorial targeted therapy will provide a rational approach when finding the optimal way to improve treatments for patients with ATC.Journal of Clinical Endocrinology & Metabolism 10/2014; · 6.31 Impact Factor