Treatment Of Anaplastic Thyroid Cancer Research Articles

Changes of Clinicopathologic Characteristics and Survival Outcomes of Anaplastic and Poorly Differentiated Thyroid Carcinoma

This study aimed to analyze the temporal changes of the clinicopathologic characteristics, and the long-term outcomes, of various types of anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC). A retrospective analysis was conducted on patients with ATC and PDTC who were treated from 1985 to 2013. The outcome measures included the clinical response to treatment and the survival rates of three separate thyroid cancer groups: ATC, PDTC, and differentiated thyroid cancer (DTC) with anaplastic foci. The five-year disease-specific survival rate was significantly higher, both in DTC with anaplastic foci and in PTDC (81.3% and 65.8%, respectively), than it was in ATC (14.3%; p < 0.001). The proportion of cases of DTC with anaplastic foci has been increasing over time, while that of ATC has decreased. The survival rate was found to be significantly higher in resectable tumors (71.4% and 26.5%, respectively; p < 0 .001). In ATC, external beam radiation therapy showed longer survival rates than did surgery-based treatment in unresectable tumors (19.2 vs. 7.7 months, p = 0.006). Adjuvant treatment with external beam radiation or radioactive iodine increased survival duration in PDTC and in DTC with anaplastic foci. Lymphatic invasion was the most significant postoperative prognosticator in ATC (p = 0.013). The choice of treatment of ATC and PDTC could be modified according to resectability and lymphatic invasion of the cancer.

Targeting the Small Ubiquitin-Like Modifier Pathway as a Novel Treatment of Anaplastic Thyroid Cancer

METHODS: The NCDB was queried from 1998 to 2006 to include patients with T1-4M0 PTC undergoing near, sub, or total thyroidectomy, who had a minimum of 5 cervical LN concomitantly removed. MLNR was calculated by dividing the number of positive LN by the total number of LN removed. Patient survival was analyzed using Kaplan-Meier method. The impact of MLNR on overall survival (OS) was analyzed using a multivariate Cox regression analysis adjusted for relevant covariates.

Tyrosine Kinase Inhibitors for the Therapy of Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) is often incurable so new therapeutic approaches are needed. Tyrosine kinases inhibitors (such as imanitib, sunitinib or sorafenib) are under evaluation for the treatment of ATC. Other vascular disrupting agents, such as combretastatin A4 phosphate, and antiangiogenic agents, such as aplidin, PTK787/ZK222584 and human VEGF monoclonal antibodies (bevacizumab, cetuximab), have been evaluated. Small-molecule adenosine triphosphate competitive inhibitors directed intracellularly at EGFRs tyrosine kinase, such as erlotinib or gefitinib, are also studied. Furthermore, new molecules have been shown to be active against ATC, such as CLM94 and CLM3. However, more research is needed to finally identify therapies able to control and to cure this disease.

Surgical treatment of anaplastic thyroid cancer

Anaplastic thyroid cancer is the least common but also the most lethal malignancy of the thyroid gland. At the time of diagnosis, all patients are considered as stage IV patients, while nodal disease does not affect the staging of the disease. Surgery is only indicated in cases without infiltration of adjacent structures or distant metastasis. R0 resection is considered as providing the favourable surgical result, but R1 resection is also acceptable since adjuvant postoperative radiotherapy has a mainly palliative role. Radioactive Iodine ablation is not considered beneficial for these patients and is of no use. Central and/or lateral compartment dissection is recommended as an option in surgical treatment since anaplastic cancer has a tendency for regional nodal spread. Tracheotomy and/or tracheal stenting is still debatable and can be used in some cases as part of palliative therapy in order to avoid suffocation. The aggressiveness of anaplastic cancer along with its invasive character make preoperative laryngoscopy necessary as many patients already have vocal cord palsy caused by tumour invasion of the recurrent laryngeal nerve. Proper staging prior to surgery with CT, MRI or other imaging modalities to exclude or confirm infiltration of adjacent structures or distant metastasis is also required. In the majority of patients, there is insufficient time to plan the appropriate therapy because of the tumour’s aggressive behaviour. Patients have a median survival of 4 to 6 months, while over 80% fail to survive more than a year.

Fosbretabulin for the treatment of anaplastic thyroid cancer.

Fosbretabulin tromethamine is a vascular disrupting agent, which is a type of drug that is designed to damage the vasculature (blood vessels) of cancer tumors, causing central necrosis. This drug showed activity against anaplastic thyroid cancer that was demonstrated in orthotopic xenograft models as well as in Phase I/II trials with or without carboplatin and paclitaxel combination therapy. In all of these studies, fosbretabulin was well tolerated.

Hypofractionated Radiation Therapy in the Treatment of Anaplastic Thyroid Cancer: Non-Squamous Cell Malignancies of the Head and Neck (thyroid, skin cancers, salivary gland and sinus cancers)

Hypofractionated Radiation Therapy in the Treatment of Anaplastic Thyroid Cancer: Non-Squamous Cell Malignancies of the Head and Neck (thyroid, skin cancers, salivary gland and sinus cancers)

Genomically driven precision medicine to improve outcomes in anaplastic thyroid cancer.

Thyroid cancer is an endocrine malignancy with an incidence rate that has been increasing steadily over the past 30 years. While well-differentiated subtypes have a favorable prognosis when treated with surgical resection and radioiodine, undifferentiated subtypes, such as anaplastic thyroid cancer (ATC), are far more aggressive and have a poor prognosis. Conventional therapies (surgical resection, radiation, chemotherapy, and radioiodine) have been utilized for treatment of ATC, yet these treatments have not significantly improved the overall mortality rate. As cancer is a genetic disease, genetic alterations such as mutations, fusions, activation of oncogenes, and silencing of tumor suppressors contribute to its aggressiveness. With the use of next-generation sequencing and the Cancer Genome Atlas, mutation-directed therapy is recognized as the upcoming standard of care. In this review, we highlight the known genetic landscape of ATC and the need for a comprehensive genetic characterization of this disease in order to identify additional therapeutic targets to improve patient outcomes.

MicroRNA Deregulation in Anaplastic Thyroid Cancer Biology.

Anaplastic thyroid cancer (ATC) is among the most lethal types of cancers, characterized as a fast-growing and highly invasive thyroid tumor that is unresponsive to surgery and radioiodine, blunting therapeutic efficacy. Classically, genetic alterations in tumor suppressor TP53 are frequent, and cumulative alterations in different signaling pathways, such as MAPK and PI3K, are detected in ATC. Recently, deregulation in microRNAs (miRNAs), a class of small endogenous RNAs that regulate protein expression, has been implicated in tumorigenesis and cancer progression. Deregulation of miRNA expression is detected in thyroid cancer. Upregulation of miRNAs, such as miR-146b, miR-221, and miR-222, is observed in ATC and also in differentiated thyroid cancer (papillary and follicular), indicating that these miRNAs' overexpression is essential in maintaining tumorigenesis. However, specific miRNAs are downregulated in ATC, such as those of the miR-200 and miR-30 families, which are important negative regulators of cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), processes that are overactivated in ATC. Therefore, molecular interference to restore the expression of tumor suppressor miRNAs, or to blunt overexpressed oncogenic miRNAs, is a promising therapeutic approach to ameliorate the treatment of ATC. In this review, we will explore the importance of miRNA deregulation for ATC cell biology.

Tolfenamic acid induces apoptosis and growth inhibition in anaplastic thyroid cancer: Involvement of nonsteroidal anti-inflammatory drug-activated gene-1 expression and intracellular reactive oxygen species generation

Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually used for the treatment of inflammatory diseases. However, certain NSAIDs also have antitumor activities in various cancers, including head and neck cancer, through cyclooxygenase-dependent or independent pathways. Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), a TGF-β superfamily protein, is induced by NSAIDs and has been shown to be induced by several antitumorigenic compounds and to exhibit proapoptotic and antitumorigenic activities. In this report, we demonstrate for the first time that tolfenamic acid (TA) transcriptionally induced the expression of NAG-1 during TA-induced apoptosis of anaplastic thyroid cancer (ATC) cells. TA reduced the viability of ATC cells in a dose-dependent manner and induced apoptosis, findings that were coincident with NAG-1 expression. Overexpression of the NAG-1 gene using cDNA enhanced the apoptotic effect of TA, whereas suppression of NAG-1 expression by small interfering RNA attenuated TA-induced apoptosis. Subsequently, we found that intracellular ROS generation plays an important role in activating the proapoptotic protein NAG-1. Then, we confirmed antitumorigenic effects of TA in a nude mouse orthotopic ATC model, and this result accompanied the augmentation of NAG-1 expression and ROS generation in tumor tissue. Taken together, these results demonstrate that TA induces apoptosis via NAG-1 expression and ROS generation in in vitro and in vivo ATC models, providing a novel mechanistic explanation and indicating a potential chemotherapeutic approach for treatment of ATC.

Synergy between high intensity focused ultrasound and ethanol injection in ablation of thyroid cancer cells

We have investigated the combination of high intensity focused ultrasound (HIFU) and ethanol injection for ablation treatment of anaplastic thyroid cancer, a highly aggressive form of thyroid cancer characterized by &amp;gt;80% mortality within months. The suspension of FB1 anaplastic thyroid cancer cells (100 μl, 2.7 million cells/ml) were placed in a 0.2 ml thin-wall PCR tube and then exposed to HIFU alone, ethanol alone, or ethanol + HIFU. The focused ultrasound signal was generated by a 1.1 MHz transducer with acoustic power ranged from 4.1 W to 12.0 W. Ethanol was diluted in the FB1 cell growth medium to the concentration of 2%, 4%, or 10% (v/v) and applied to the cells before HIFU exposure. The viability of the cells was measured by flow cytometry and trypan blue exclusion 2, 24, and 72 h post-treatment. The exposure of FB1 cells to HIFU alone greatly reduced the number of viable cells immediately after treatment; however, their proliferation rate remained high. On the other hand, both the viability and proliferation rate significantly decreased in the cells treated with both ethanol and HIFU. In conclusion, percutaneous ethanol injection (PEI) and HIFU have a synergistic effect on anaplastic thyroid cancer ablation.

Carboplatin synergistically triggers the efficacy of photodynamic therapy via caspase 3-, 8-, and 12-dependent pathways in human anaplastic thyroid cancer cells

Anaplastic thyroid cancer is one of the most aggressive forms of malignancies which grow very rapidly. Several conventional methods have been applied for the treatment of anaplastic thyroid cancer, but most of them were not successful in complete recovery of the patients. Therefore, a combination of two or more conventional modalities is being applied nowadays for the treatment of this type of cancer. In this present study, the combination of photodynamic therapy (PDT) and chemotherapy has been studied in anaplastic thyroid cancer. Human anaplastic thyroid cancer cells FRO were treated with a chemotherapy drug, carboplatin (cis-diammine-1,1-cyclobutanedicarboxyl-ateplatinum II (CBDCA)), and radachlorin-mediated PDT individually and in combination. Several parameters like cytotoxicity assay by MTT, apoptosis study by annexin V and propidium iodide, cell cycle analysis by flow cytometry, confocal microscopic study, and Western blot analysis for different apoptosis-related proteins like Bax, cytochrome c, caspases 3, 9, 8, and 12, etc. were studied to check the efficacy of the combination treatment as well as to find out the mechanism of this enhanced efficacy. Results showed that both PDT and CBDCA can induce apoptosis in FRO cells. However, a synergistic efficacy was observed when the cells were treated with CBDCA and PDT in combination. Changes in mitochondrial membrane potential and an increase in reactive oxygen species generation were observed in combination treatments. The enhanced expression of different apoptotic pathway-related proteins like Bax, cytochrome c, caspase 3, caspase 8, caspase 12, etc. also confirmed the higher efficacy of combination treatment. Therefore, with this combination treatment, not only a higher efficacy can be achieved but also the effective dose of the chemotherapy drug can be reduced, and hence, the adverse side effects of the chemotherapy drugs can also be controlled.

Genetic mutations in the treatment of anaplastic thyroid cancer: a systematic review

BackgroundAnaplastic thyroid cancer (ATC) is a rare, lethal disease associated with a median survival of 6 months despite the best multidisciplinary care. Surgical resection is not curative in ATC patients, being often a palliative procedure. Multidisciplinary care may include surgery, loco-regional radiotherapy, and systemic therapy. Besides conventional chemotherapy, multi kinase-targeted inhibitors are emerging as novel therapeutic tools. The numerous molecular alteration detected in ATC are targets for these inhibitors. The aim of this review is to determine the prevalence of the major genetic alterations occurring in ATC and place the results in the context of the emerging kinase-targeted therapies.MethodsThe study is based on published PubMed studies addressing the prevalence of BRAF, RAS, PTEN, PI3KCA and TP53 mutations and RET rearrangements in ATC.Results21 articles dealing with 652 genetic analyses of the selected genes were used. The overall prevalence determined were the following: RET/PTC, 4%; BRAF, 23%; RAS, 60%; PTEN, 16%; PI3KCA, 24%; TP53, 48%. Genetic alterations are sometimes overlapping.ConclusionsMutations of BRAF, PTEN and PI3KCA genes are common in ATC, with RAS and TP53 being the most frequent. Given ATC genetic complexity, effective therapies may benefit from individualized therapeutic regimens in a multidisciplinary approach.

Extensive Tracheal Necrosis After Treatment of Anaplastic Thyroid Cancer With Vascular Endothelial Growth Factor Inhibitors

Extensive Tracheal Necrosis After Treatment of Anaplastic Thyroid Cancer With Vascular Endothelial Growth Factor Inhibitors

Redifferentiation and induction of tumor suppressors miR-122 and miR-375 by the PAX8/PPARγ fusion protein inhibits anaplastic thyroid cancer: a novel therapeutic strategy

Anaplastic thyroid cancer (ATC) is an aggressive, fatal disease unresponsive to traditional therapies, generating a need to develop effective therapies. The PAX8/PPARγ fusion protein (PPFP) has been shown to favorably modulate tumor growth in follicular thyroid cancer, prompting our evaluation of its efficacy to inhibit ATC cell and tumor growth in vitro and in vivo. PPFP was constitutively expressed in five ATC cell lines: BHT-101, FRO, C-643, KTC-2 and KTC-3, and inhibited cell growth in four of five cell lines and xenograft tumor growth in four of four cell lines. PPFP-mediated growth inhibition involved multiple mechanisms, including upregulation of miR-122 and miR-375, associated with decreased angiogenesis and AKT pathway inactivation, respectively. Also, PPFP expression resulted in marked increase of thyroid-specific marker transcripts, including PAX8, thyroid peroxidase (TPO), sodium iodide symporter (NIS) and thyroglobulin, to varying degrees by activating their respective promoters, suggesting that PPFP induced cellular redifferentiation. Functional studies demonstrate that increased NIS messenger RNA is not associated with increased 125I uptake. However, ectopic expression of wild-type NIS-induced perchlorate-sensitive iodine uptake, suggesting that endogenous NIS in ATC cell lines is defective. As current treatment for ATC is only palliative, overexpression of PPFP may offer a novel therapeutic strategy for the treatment of ATC.

Recent Progress of Genome Study for Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) belongs to the most malignant and rapidly progressive human thyroid cancers and its prognosis is very poor. Also, it shows high resistance to cancer treatments, so that effective treatment for ATC has not been found to date, and virtually all patients terminate their life rapidly after diagnosis. Although targeted treatment of genetic alterations has emerged as an extremely promising approach to human cancers, such as BRAF in metastatic melanoma, it remains unclear that how commonly genomic alterations are influenced in ATC tumorigenesis. In recent years, genome wide approaches have been exploited to find genetic alterations associated with complex diseases, including cancer. Here, we reviewed the comprehensive genetic alterations in ATC and recent approaches in the context of identifying genomic alterations associated with ATC. Since surprisingly few reports have been published on the genome wide study of ATC, this review puts emphasis on the urgent needs of genomic research for the prevention and treatment of ATC.

Anaplastic thyroid cancer therapy: dream or reality?

Anaplastic thyroid cancer (ATC) is a rare thyroid malignancy representing 2 % of thyroid tumors. Usually, ATC is a lethal tumor with an overall median survival time \6 months from the diagnosis. Anecdotic cases of long-term survivors have been reported mainly in subjects with intrathyroid tumors at the time of surgical treatment [1]. The ATC management is very challenging because patients usually present with both extensive local disease and progressive distant metastases. A wide range of conventional therapeutic approaches including thyroidectomy, radiotherapy, chemotherapy, or varying combinations of these modalities have been proposed over the years, but the outcome does not appear to be significantly modified by these strategies which are indeed largely ineffective. This overall failure of all known methods of treating ATC is the main reason of the continuing search for novel treatment strategies. Recently, a very interesting study on the effectiveness of a combined treatment with bortezomib, a drug specifically targeting the ubiquitin–proteasome system, and MLN8054, which specifically inhibits Aurora kinases, has been reported [2]. The authors demonstrated that this combination was able to determine an antitumoral activity in 3 ATC cell lines, especially by reducing the cell growth rate and inducing cells apoptosis. The ubiquitin–proteasome pathway is likely the most important system for the degradation of the intracellular proteins. Recently, a novel class of antitumor agents has been identified in the proteasome inhibitors which have been demonstrated to be very active against both hematological and solid tumors. Bortezomib (Velcade) has been officially approved by the Food and Drug Administration for the treatment of multiple myeloma and it is intensively studied in other human malignant tumors. The effect of bortezomib has been evaluated in a series of carcinoma cell lines and a proapoptotic activity on both medullary and ATC cells has been demonstrated [3]. Aurora kinases are proteins which are implicated in the regulation of multiple aspects of chromosome segregation during the mitotic phase of the cell cycle. They are overexpressed in many human thyroid tissues and their degradation at the end of the mitosis is determined by the ubiquitin–proteasome pathway. Previous studies showed that MLN8054 alone, as well as other Aurora kinase inhibitors, such as VX-680 [4] or AZD1152 [5], had proapoptotic and antiproliferative effects in ATC cell lines. These findings strongly suggest the possibility that Aurora kinase inhibitors could be used in the treatment of ATC, and, likely, in other thyroid cancer not responsive to conventional therapies. The innovative aspect of the paper of Hoffmann and co-authors [2] recently published on this journal, is the demonstration of a synergistic effect of the combination of these two drugs which are directed against two different targets both very important for the inhibition of the cell cycle progression. The greatest interest of this study is the putative therapeutic role and clinical application. Several other studies have been previously published with the aim to find innovative therapeutic strategies for the treatment of ATC patients. Recently, it has been reported that the antitumor and antivascular activity of CLM94, a new cyclic amide drug, was very promising when tested on ATC cells [6]. Although with different mechanisms with respect to those exerted by bortezomib and MLN8054, also CLM94 determined a significant reduction of growth proliferation and a simultaneous increase of cell apoptosis. In R. Elisei (&) Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy e-mail: rossella.elisei@med.unipi.it

Preclinical efficacy of the oncolytic measles virus expressing the sodium iodide symporter in iodine non-avid anaplastic thyroid cancer: a novel therapeutic agent allowing noninvasive imaging and radioiodine therapy

Anaplastic thyroid cancer is an extremely aggressive disease resistant to radioiodine treatment because of loss of sodium iodide symporter (NIS) expression. To enhance prognosis of this fatal cancer, we validated the preclinical efficacy of measles virus (MV)-NIS, the vaccine strain of the oncolytic MV (MV-Edm), modified to include the NIS gene. Western blotting analysis confirmed that a panel of eight anaplastic thyroid cancer (ATC)-derived cell lines do not express NIS protein, but do express CD46, the MV receptor. In vitro cell death assays and in vivo xenograft studies demonstrate the oncolytic efficacy of MV-NIS in BHT-101 and KTC-3, ATC-derived cell lines. Radioactive iodine uptake along with single-photon emission computed tomography (SPECT)-computed tomography imaging of KTC-3 xenografts after (99)Tc(m) administration confirmed NIS expression in vitro and in vivo, respectively, after virus treatment. Adjuvant administration of RAI, to MV-NIS-treated KTC-3 tumors showed a trend for increased tumor cell killing. As current treatment for ATC is only palliative, and MV-NIS is currently Food and Drug Administration approved for human clinical trials in myeloma, our data indicate that targeting ATC with MV-NIS could prove to be a novel therapeutic strategy for effective treatment of iodine-resistant ATC and will expedite its testing in clinical trials for this aggressive disease.

Imatinib Enhances Docetaxel-Induced Apoptosis Through Inhibition of Nuclear Factor-κB Activation in Anaplastic Thyroid Carcinoma Cells

We previously reported the partial effectiveness of imatinib (also known as STI571, Glivec, or Gleevec) on anaplastic thyroid cancer (ATC) cells. Imatinib is a selective tyrosine kinase inhibitor that has been used for various types of cancer treatments. Recently, several reports have demonstrated that imatinib enhanced the sensitivity of cancer cells to other anticancer drugs. In this study, therefore, we investigated whether imatinib enhances the antitumor activity of docetaxel in ATC cells. Two ATC cell lines, FRO and KTC-2, were treated with imatinib and/or docetaxel. Cell survival assay and flow cytometry for annexin V were used to assess the induction of apoptosis. Changes of pro- and antiapoptotic factors were determined by Western blot. Nuclear factor-κB (NF-κB) activity was measured by DNA-binding assay. Tumor growth was also investigated in vivo. The combined treatment significantly enhanced apoptosis compared with single treatment. ATC cells themselves expressed high levels of antiapoptotic factors, X-linked inhibitor of apoptosis (XIAP), and survivin. The treatment with docetaxel alone further increased their expressions; however, the combined treatment blocked the inductions. Although imatinib alone had no effect on NF-κB background levels, combined treatment significantly suppressed the docetaxel-induced NF-κB activation. Further, the combined administration of the drugs also showed significantly greater inhibitory effect on tumor growth in mice xenograft model. Imatinib enhanced antitumor activity of docetaxel in ATC cells. Docetaxel seemed to induce both pro- and antiapoptotic signaling pathways in ATC cells, and imatinib blocked the antiapoptotic signal. Thus, docetaxel combined with imatinib emerges as an attractive strategy for the treatment of ATC.

Clinical Response with Sunitinib Therapy in the Treatment of Anaplastic Thyroid Cancer

Background: Anaplastic thyroid cancer (ATC), while rare, carries a uniformly poor prognosis. Current treatment includes surgery when possible, radiotherapy, and chemotherapy. Multiple chemotherapeutic agents are in the process of clinical testing, and promising agents include those in the tyrosine kinase inhibitor family. Our patient represents a novel case of ATC treated with sunitinib, one such tyrosine kinase inhibitor. Methods/Results: We utilized the experimental sunitinib in conjunction with radiation therapy to treat a patient with aggressive ATC in whom curative resection was unable to be achieved due to carotid sheath and tracheal involvement. The patient had marked clinical response and sustained stable disease for 8 months, which coincides with reported data regarding sunitinib to treat other thyroid malignancies. Conclusion: Our case illustrates the efficacy of sunitinib therapy as a possible adjunct in the treatment of ATC.

Stimulation of Cultured H9 Human Embryonic Stem Cells with Thyroid Stimulating Hormone Does Not Lead to Formation of Thyroid-Like Cells

The sodium-iodine symporter (NIS) is expressed on the cell membrane of many thyroid cancer cells, and is responsible for the radioactive iodine accumulation. However, treatment of anaplastic thyroid cancer is ineffective due to the low expression of NIS on cell membranes of these tumor cells. Human embryonic stem cells (ESCs) provide a potential vehicle to study the mechanisms of NIS expression regulation during differentiation. Human ESCs were maintained on feeder-independent culture conditions. RT-qPCR and immunocytochemistry were used to study differentiation marker expression, 125I uptake to study NIS function. We designed a two-step protocol for human ESC differentiation into thyroid-like cells, as was previously done for mouse embryonic stem cells. First, we obtained definitive endoderm from human ESCs. Second, we directed differentiation of definitive endoderm cells into thyroid-like cells using various factors, with thyroid stimulating hormone (TSH) as the main differentiating factor. Expression of pluripotency, endoderm and thyroid markers and 125I uptake were monitored throughout the differentiation steps. These approaches did not result in efficient induction of thyroid-like cells. We conclude that differentiation of human ESCs into thyroid cells cannot be induced by TSH media supplementation alone and most likely involves complicated developmental patterns that are yet to be understood.