Treatment Of Medullary Thyroid Carcinoma Research Articles

Axonal neuropathy, long limbs and bumpy tongue: Think of MEN2B

Multiple endocrine neoplasia type 2 (MEN 2) is an uncommon autosomal dominant cancer syndrome which can be associated with nerve conduction abnormalities. A 14-year-old boy with a family history of consanguinity developed progressive gait clumsiness, pes cavus, hypotonia, and mucosal tumors of the lips and tongue since the age of 3 years. At age 11 years, he was diagnosed with an hereditary motor neuropathy (Charcot-Marie-Tooth syndrome). Physical examination revealed a Marfanoid habitus, mucocutaneous verrucous tumors, thyroid nodules, and cervical adenopathy. Genetic testing demonstrated the p.M918T mutation in the RET gene, and blood tests showed elevated levels of calcitonin. Clinical suspicion in MEN2 is crucial for early diagnosis and subsequent therapy. Mucosal neuroma and a Marfanoid habitus are especially useful. Other neurologic manifestations should not disguise the endocrine disorder, because early diagnosis and treatment of medullary thyroid carcinoma determines the prognosis.

Effects of vandetanib on body composition in patients with advanced medullary thyroid carcinomas: Results from a placebo-controlled study.

5569 Background: Muscle (MT) and adipose tissue (AT) share common intra cellular pathways with tumor, thus it is not surprising to observe metabolic consequences with targeted therapies. The aim of the study was to assess the effects of vandetanib, a tyrosine kinase inhibitor (TKI) which demonstrated efficacy for the treatment of advanced medullary thyroid carcinoma (MTC), on MT and AT. Methods: 33 patients (25 men and 8 women, mean age of 54 years) with metastatic MTC received vandetanib 300 mg/d (n=23) or placebo (n=10) in the setting of the ZETA study. Cross-sectional areas (cm2) of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and MT were assessed by computed tomography imaging at 3rd lumbar vertebra and were indexed for height (cm2/m2). Comparisons between treatment and placebo were made at 3 months, and long-term evolution was evaluated over 12 months. Results: At 3 months, compared to baseline, patients treated with vandetanib gained 1.5 kg, 1.3 cm2/m2 of MT, 5.1 cm2/m2 of VAT and 4.5 cm2/m2 of SAT. In contrast, patients under placebo lost 1.5 kg (p=0.02), 1.0 cm2/m2 of MT (p=0.009), 5.5 cm2/m2 of SAT (p=0.004) and gained significantly less VAT (0.6 cm2/m2) (p=0.02). At 12 months, compared to baseline, patients treated with vandetanib gained 2 kg (NS), lost 0.3 cm2/m2 MT (NS), gained 3.4 cm2/m2 of VAT (NS) and 8.7 cm2/m2 of SAT (95% CI, 1.1 to 16.2). A significant decrease of calcitonin (defined as ≤50% compared to baseline) was associated with higher weight (p=0.01), VAT (p=0.01), and total adipose tissue (p=0.02). Conclusions: Beyond its proved efficacy in MTC treatment, and despite common intracellular pathways, vandetanib is the only studied TKI to preserve MT and to restore AT. Further research is needed to explore whether the relationship between changes of VAT and vandetanib treatment results from a direct metabolic action of vandetanib or is a consequence of biochemical tumor control.

Medullary Thyroid Carcinoma Surgical Cytoreduction Induces an Increase in Serum Calcitonin and Carcinoembryonic Antigen Doubling Times

Serum calcitonin (Ct) and carcinoembryonic antigen (CEA) doubling times (DT) are considered to be strong prognostic markers in patients with medullary thyroid carcinoma (MTC). The Objective of this work is to study the effect of MTC debulking on Ct and CEA DTs. 4 patients with MTC are presented who after an initial neck operation had residual disease were followed-up with serial measurements of serum Ct and CEA for several years before and after a secondary incomplete removal of involved cervical lymph nodes. The patients received no other treatment for MTC. Ct and CEA DTs were determined after fitting the Ct or CEA values to an exponential growth equation. In patient A, Ct DT increased from 1.45 years (1.17-1.89, 95% CI) preoperatively, to 5.72 (3.22-25.77) postoperatively. In patient B, Ct DT was 1.63 years (1.36-2.02) preoperatively, and very long (serum Ct practically ceased increasing) postoperatively. In patient C, Ct DT was 4.03 years (2.22-21.58) before, and very long after the operation. In patient D, Ct DT from 1.16 years (0.82-1.99) before, increased to 4.21 years (3.04-6.86) after the operation. The changes in CEA DTs were similar to those of Ct DTs in 2 patients in whom the tumor was apparently producing the protein. In conclusion, surgical MTC cytoreduction in 4 patients caused an increase in the Ct and CEA DTs, and the patients could be reclassified in new Ct DT-based strata with better prognosis than before the operation. We hypothesize that such tumor burden reduction may slow the growth of any residual MTC and we discuss mechanisms that could be responsible for this phenomenon.

Efficacy and Tolerability of Pharmacotherapy Options for the Treatment of Medullary Thyroid Cancer

Metastatic and unresectable medullary thyroid carcinoma (MTC) is often difficult to treat as it is relatively unresponsive to radiation and conventional chemotherapy. This emphasizes the importance of the development of targeted therapies for advanced MTC. Vandetanib was approved by the US Food and Drug Administration for the treatment of symptomatic or progressive MTC in patients with advanced disease in April 2011. This therapy proved to be a breakthrough in the management of MTC. We review the efficacy and safety of this novel treatment and other treatments that are being evaluated in this disease.

The Treatment Outcomes of Medullary Thyroid Carcinoma

Received December 23, 2011 Revised February 16, 2012 Accepted February 21, 2012 Address for correspondence Kang Dae Lee, MD Department of OtolaryngologyHead and Neck Surgery, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea Tel +82-51-990-6248 Fax +82-51-245-8539 E-mail kosinent@yahoo.co.kr Background and ObjectivesZZThe aim of this study was to evaluate the treatment outcomes of medullary thyroid carcinoma (MTC) by retrospective data analysis. Subjects and MethodZZWe conducted a retrospective chart review of 17 cases of pathologically proven MTC patients who were treated from 1998 to 2010 at the department of Otolaryngology-Head and Neck Surgery, Kosin University College of Medicine. ResultsZZThe mean tumor size was 2.32 cm (0.5-3.4 cm). Seventy-one percent of patients were diagnosed with advanced stage (III or IV) of MTC. We performed RET genetic screening in 8 of 17 patients. Hereditary MTC was found in 3 of 17 patients (18%) and sporadic MTC was found in 14 of 17 (82%). The preoperative assessment of basal serum calcitonin (CT) level was performed in 15 of 17 patents. Eleven patients had elevated basal calcitonin levels (>13 pg/ mL). After the operation for MTC, the serum CT levels were elevated in 7 patients. Overall 5-year survival rate was 94%. Normalization of serum calcitonin level was accomplished more frequently in the absence of extra thyroidal invasion (p=0.034), multifocal tumor (p=0.02). ConclusionZZThe initial treatment of MTC is total thyroidectomy with central compartment neck dissection with or without lateral neck dissection. To detect recurrence or metastasis, regular checking of serum calcitonin is necessary. A better knowledge of prognostic factors could improve the management of MTC patients. Korean J Otorhinolaryngol-Head Neck Surg 2012;55:166-72

Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumor with lymph node metastasis: A case report

IntroductionPapillary thyroid carcinoma and medullary thyroid carcinoma are two different thyroid neoplasia. The simultaneous occurrence of medullary thyroid carcinoma and papillary thyroid carcinoma as a collison tumor with metastases from both lesions in the regional lymph nodes is a rare phenomenon.Case presentationA 32-year-old Iranian man presented with a fixed anterior neck mass. Ultrasonography revealed two separate thyroid nodules as well as a suspicious neck mass that appeared to be a metastatic lesion. The results of thyroid function tests were normal, but the preoperative calcitonin serum value was elevated. Our patient underwent a total thyroidectomy with neck exploration. Two separate and ill-defined solid lesions grossly in the right lobe were noticed. Histological and immunohistochemical studies of these lesions suggested the presence of medullary thyroid carcinoma and papillary thyroid carcinoma. The lymph nodes isolated from a neck dissection specimen showed metastases from both lesions.ConclusionsThe concomitant occurrence of papillary thyroid carcinoma and medullary thyroid carcinoma and the exact diagnosis of this uncommon event are important. The treatment strategy should be reconsidered in such cases, and genetic screening to exclude multiple endocrine neoplasia 2 syndromes should be performed. For papillary thyroid carcinoma, radioiodine therapy and thyroid-stimulating hormone suppressive therapy are performed. However, the treatment of medullary thyroid carcinoma is mostly radical surgery with no effective adjuvant therapy.

Aurora kinases are expressed in medullary thyroid carcinoma (MTC) and their inhibition suppresses in vitro growth and tumorigenicity of the MTC derived cell line TT

BackgroundThe Aurora kinase family members, Aurora-A, -B and -C, are involved in the regulation of mitosis, and alterations in their expression are associated with cell malignant transformation. To date no information on the expression of these proteins in medullary thyroid carcinoma (MTC) are available. We here investigated the expression of the Aurora kinases in human MTC tissues and their potential use as therapeutic targets.MethodsThe expression of the Aurora kinases in 26 MTC tissues at different TNM stages was analyzed at the mRNA level by quantitative RT-PCR. We then evaluated the effects of the Aurora kinase inhibitor MK-0457 on the MTC derived TT cell line proliferation, apoptosis, soft agar colony formation, cell cycle and ploidy.ResultsThe results showed the absence of correlation between tumor tissue levels of any Aurora kinase and tumor stage indicating the lack of prognostic value for these proteins. Treatment with MK-0457 inhibited TT cell proliferation in a time- and dose-dependent manner with IC50 = 49.8 ± 6.6 nM, as well as Aurora kinases phosphorylation of substrates relevant to the mitotic progression. Time-lapse experiments demonstrated that MK-0457-treated cells entered mitosis but were unable to complete it. Cytofluorimetric analysis confirmed that MK-0457 induced accumulation of cells with ≥ 4N DNA content without inducing apoptosis. Finally, MK-0457 prevented the capability of the TT cells to form colonies in soft agar.ConclusionsWe demonstrate that Aurora kinases inhibition hampered growth and tumorigenicity of TT cells, suggesting its potential therapeutic value for MTC treatment.

Comparison of biological stability and metabolism of CCK2 receptor targeting peptides, a collaborative project under COST BM0607

Stability of radiolabelled cholecystokinin 2 (CCK2) receptor targeting peptides has been a major limitation in the use of such radiopharmaceuticals especially for targeted radionuclide therapy applications, e.g. for treatment of medullary thyroid carcinoma (MTC). The purpose of this study was to compare the in vitro stability of a series of peptides binding to the CCK2 receptor [selected as part of the COST Action on Targeted Radionuclide Therapy (BM0607)] and to identify major cleavage sites. Twelve different 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-minigastrin/CCK conjugates were provided within an European COST Action (BM0607) by different laboratories and radiolabelled with (177)Lu. Their in vitro stabilities were tested in fresh human serum. Radiochemical yields (RCY) and intact radioligands for half-life calculations were determined by radio-HPLC. Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) analysis of metabolites was performed to identify cleavage products using conjugates labelled with excess stable (nat)Lu, incubated in serum at 37°C. Urine metabolite analysis after injection in normal mice was performed by radio-HPLC analysis. Variable stability in human serum was found for the different peptides with calculated half-lives between 4.5 ± 0.1 h and 198 ± 0.1 h (n = 2). In urine of normal mice only metabolised peptide fragments were detected even at short times after injection for all peptides. MALDI-TOF MS revealed a major cleavage site of all minigastrin derivatives between Asp and Phe-NH(2) at the C-terminal end. Development of CCK2 receptor ligands especially for therapeutic purposes in patients with MTC or small cell lung cancer (SCLC) is still ongoing in different laboratories. This comparative study provided valuable insight into the importance of biological stability especially in the context of other results of this comparative trial within the COST Action BM0607.

Abstract 4547: Treatment of human medullary thyroid carcinoma (MTC) with either proteasome (Pr) or histone deacetylase (HDAC) inhibitors leads to a fall in RET mRNA levels and, in turn, a decrease in RET protein expression providing alternate strategies to reduce RET expression in a tyrosine-kinase driven disease

Abstract Medullary thyroid carcinoma (MTC), a neuro-endocrine cancer of parafollicular C-cells accounts for 4-10% of all thyroid cancers and has low response rates to “cytotoxic chemotherapy”. The RET proto-oncogene encodes the RET (Rearranged during Transfection) transmembrane tyrosine kinase (TK) receptor, a pivotal player and a logical target for treatment of MTC. While trials with vandetanib (V) a RET TK inhibitor (TKI) in patients with MTC have been promising, we recognized a TKI is unlikely to have maximum benefit administered alone. We sought to combine V + a drug with a broad activity profile and no overlapping toxicities. Recognizing the failure of traditional “cytotoxic” agents we investigated the proteasome (Pr) inhibitor, bortezomib (B) not yet explored clinically in MTC. Initial experiments using TT MTC cells with a mutant C634W RET, found V + B non-antagonistic in cytotoxicity assays, and V showed decreased phospho-RET expression in TT cells with 0.5 or 1 µM in 1.5h. But while V did not change RET protein levels, B decreased RET protein 7 fold and secondarily phospho-RET levels. That this was secondary to Pr inhibition and not unique to B was confirmed by treating TT cells 6h or 24h with three other Pr inhibitors – epoxomycin, lactacystin or MG132. We observed 5-9 fold decreases in RET protein, which followed a time course and a dose response, with greater reduction at 24h than at 6h. To assess if the decrease in RET protein was due to decreased RET mRNA levels, we assessed RET mRNA expression and were surprised to find a 4-9 fold decrease with Pr inhibitors. Since Pr inhibitors reduced RET by reducing mRNA levels, and reasoning this would provide an alternate strategy to impact RET function, we studied the effect of three HDAC inhibitors on RET mRNA and protein expression. Treatment of TT cells with vorinostat, belinostat, or romidepsin (R) decreased RET mRNA 3-4 fold at 24h and protein levels 4 and 7-14 fold, at 24 and 48h respectively. Furthermore B + R had greater impact than either drug separately, depressing RET protein in TT cells an additional 2-3 fold to levels 4-12 fold less than that in untreated cells, suggesting mechanisms whereby Pr and HDAC inhibitors reduce mRNA levels might differ. We have pursued the latter by examining mRNA and protein levels of 3 candidate transcription factors identified in a literature search. To date we have shown TTF1 and E2F1 mRNA levels are decreased 4-58 fold by both Pr and HDAC inhibitors whereas EGR1 levels only fall with Pr inhibitors. siRNA studies that modulate transcription factor levels will clarify their possible roles in the Pr and HDAC inhibitor drug effects and help elucidate whether these inhibitors, either alone or in combination, can prove useful in MTC therapy by reducing the crucial RET TK. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4547. doi:10.1158/1538-7445.AM2011-4547

Surgical treatment and prognosis analysis on medullary thyroid carcinoma

To study the clinical characteristics, the surgical treatments and the prognostic factors of medullary thyroid carcinoma. Eighty-two cases of medullary thyroid carcinoma undergoing surgeries between January 1999 and December 2004 were reviewed. There were 39 males and 43 females. Age ranged from 16 to 77 years old, with a median of 46 years old. The calcitonin, chromogranin A and neuron-specific enolase were analysed by immunohistochemistry in samples, and calcitonin was detected in 24 cases. Of them, 28 cases underwent lobectomy with isthmectomy, 24 for remained lobe dissection, 16 for total thyroidectomy, and 14 only for neck and upper mediastinal lymph node dissection. Of the 82 cases, 68 cases underwent trachea esophageal ditch dissection, 53 for unilateral neck dissection, 11 for bilateral neck dissection, 13 for upper mediastinal lymph node dissection through trans-cervical approach, and 5 for mediastinal lymph node dissection through inverted T-shaped incision. Immunohistochemical examination revealed that the expression rates of calcitonin, chromogranin A and neuron-specific enolase were 95.8%, 88.9% and 80.0% respectively. Total metastasis rate of neck lymph nodes was 68.8%, and the rates in level II, III, IV, V and VI were 27.3%, 47.7%, 59.1%, 11.4% and 52.3% respectively. The overall five-year survival rate was 87.8%. The recurrent rate of contralateral lobes was 5.8% and local recurrent rate was 7.3% respectively. Univariate analysis showed that gender, age and TNM stage were significant prognostic factors. Multivariate analysis revealed that distant metastasis was an independent prognostic factor. Standard radical surgery of the primary and metastatic lesion is key to the treatment of medullary thyroid carcinoma. Lobectomy with isthmectomy should be applied to sporadic medullary thyroid carcinoma, with regular postoperative follow-up, and total thyroidectomy to familial or bilateral medullary thyroid carcinoma. Therefore, detecting the calcitonin is very important for medullary thyroid carcinoma patients' prognosis.

XL184 (cabozantinib) for medullary thyroid carcinoma

Introduction: Intrathyroidal medullary thyroid carcinoma (MTC) can generally be cured by surgery, but distant metastases are often already present at diagnosis. Currently, there is no effective treatment for metastatic MTC. In these cases, consensus treatment guidelines explicitly recommend new experimental drugs. Several kinase inhibitors are now being tested for treatment of MTC in clinical trials and XL184, an oral, small-molecule multi-kinase inhibitor, seems to be one of the most promising of these compounds.Areas covered: We review preliminary data on the safety and efficacy of XL184 in metastatic MTC based on an extensive search of the literature, which included published articles, abstracts and website information. In particular, the review focuses on the rationale for using XL184 in advanced MTC. The compound has been specifically designed to target multiple signaling pathways, and this is expected to produce synergistic antitumor effects superior to those achieved by single-kinase inhibition. Preliminary results from the Phase I study of XL184 seem to support this hypothesis.Expert opinion: Multiple receptor tyrosine kinases (RTKs) are concomitantly activated in the same tumor. The blockade of a single RTK may engage compensatory signaling that maintains cell growth. Targeting multiple kinases might overcome both intrinsic and acquired resistance to antitumoral drugs.

Octreotide-Targeted Liposomes Loaded with CPT-11 Enhanced Cytotoxicity for the Treatment of Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a rare endocrine tumor that frequently metastasizes, but treatment with irinotecan (CPT-11) is limited because of side effects. MTC is known to overexpress the somatostatin receptor subtype 2 (SSTR2). Octreotide (Oct) is a somatostatin analogue that has a high binding affinity for SSTR and can be used as a tumor-targeting ligand. We prepared Oct-targeted liposomes loaded with CPT-11 using Oct-poly (ethylene glycol) (PEG)-lipid and evaluated Oct-mediated association and cytotoxicity of the liposomes with an MTC cell line TT. The association of higher concentrations of modified Oct-targeted liposomes with TT cells was significantly higher than PEGylated liposomes and was significantly inhibited by empty Oct-targeted liposomes but not by free Oct. With exposure for 96 h, the cytotoxicity of Oct-targeted liposomal CPT-11 (IC50: 1.05 ± 0.47 μM) was higher than free CPT-11 (IC50: 3.76 ± 0.61 μM) or PEGylated liposomal CPT-11 (IC50: 3.05 ± 0.28 μM). In addition, empty Oct-targeted liposomes showed significantly higher cytotoxicity than empty nontargeted liposomes at a concentration where free Oct did not show cytotoxicity, suggesting that Oct as a ligand showed cytotoxicity. Moreover, Oct-targeted liposomal CPT-11 led to significantly higher antitumor activity and prolonged the survival time compared with nontargeted liposomal and free CPT-11 at a one-third dose and lower administration times with free CPT-11. These findings indicated that Oct-targeted liposomes loaded with CPT-11 may offer considerable potential for MTC chemotherapy because cytotoxicity of both CPT-11 and Oct was enhanced by effective cellular uptake via SSTR2.

Medullary Thyroid Cancer: A Promising Model for Targeted Therapy

In recent years, the clinical validation of molecular targeted therapies inhibiting the action of pathogenic tyrosine kinase (TK) has been one of the most exciting developments in cancer research. In this context, medullary thyroid carcinoma (MTC) represents a promising model. It is well known that in MTC, the RET receptor TK and its signal transduction pathways, lead to subsequent neoplastic transformation. Several strategies aimed at blocking the activation and signaling of RET have been preclinically tested. The most advanced results have been obtained by competitive inhibition of RET-TK activity by tyrosine kinases inhibitors (TKI). However, although the inhibition of the RET pathway is actually one of the most studied for therapeutic purposes, other signal transduction pathways have been recognized to contribute to the growth and functional activity of MTC and are considered attractive therapeutic targets. To date, surgery represents the only curative treatment of MTC. Despite promising initial results, studies on targeted agents are in early stages and several issues regarding preclinical evaluations and clinical trials of new targeted agents in MTC are still unresolved. Now, available mouse models bearing mutations of RET or other genes, which spontaneously develop MTC, promise to improve preclinical evaluation of activity of targeted compounds. Furthermore, the rarity of the disease and the number of patients available for enrollment may lessen the relevance of clinical trials. A major effort needs to be made by endocrinologists and oncologists to refer their patients for multi-institutional trials in order to optimize them, perform translational studies and expedite the availability of novel beneficial selective therapies.

The Use of Preoperative Routine Measurement of Basal Serum Thyrocalcitonin in Candidates for Thyroidectomy due to Nodular Thyroid Disorders: Results from 2733 Consecutive Patients

The preoperative routine measurement of basal serum thyrocalcitonin (CT) in candidates for thyroidectomy due to thyroid nodules is currently a subject of debate. The objective of this study was to evaluate the role of systematic basal serum CT measurement in improving the diagnosis and surgical treatment of medullary thyroid carcinoma (MTC) in patients undergoing thyroidectomy for nodular thyroid disorders, regardless of preoperative CT levels. We determined basal serum CT levels in 2733 consecutive patients before thyroid surgery and performed a pentagastrin test in patients with hypercalcitoninemia. We correlated basal and stimulated CT levels with intraoperative and definitive histopathological findings, and we analyzed the impact of these results on surgical procedures. Twelve MTCs were found among the 43 patients with basal serum CT level of 10 pg/ml or greater. Two MTCs were present among the 2690 patients with normal CT levels. MTC was always present in patients with a basal CT of 60 pg/ml or greater. For CT levels ranging from 10 to 59 pg/ml, MTC was diagnosed in 11% of patients. When preoperative hypercalcitoninemia was present, total thyroidectomy associated with comprehensive intraoperative histopathological analysis allowed the intraoperative diagnosis of five latent, subclinical MTCs. The pentagastrin test gave no additional diagnostic information for the management of patients with elevated preoperative basal serum CT level. Routine measurement of CT in the preoperative work-up of nodular thyroid disorders is useful. This procedure improves intraoperative diagnosis of MTC and enables adapted initial surgery, the most determinant factor of treatment success.

Medullary Thyroid Carcinoma: Management of Lymph Node Metastases

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy of the thyroid C cells. Metastatic spread commonly occurs to cervical and mediastinal lymph nodes. MTC cells do not concentrate radioactive iodine and are not sensitive to hormonal manipulation. Surgery is currently the only therapy that can reliably lead to cure, reduction in tumor burden, or effective palliation. In patients with hereditary MTC, central lymph node dissection should be considered in preventative operations if the calcitonin level is elevated. Systematic surgical removal of at-risk or involved lymph node basins (compartmental dissection) should be performed in all patients with palpable primary tumors and recurrent disease. A "berry-picking" approach is discouraged. Although data are limited, standard chemotherapy and radiation therapy have not been shown to be effective in the treatment of MTC. Newer targeted drug therapies are promising and are being examined in therapeutic clinical trials.

Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis

Medullary thyroid carcinoma (MTC) is a rare endocrine tumor that frequently metastasizes, and treatment with irinotecan (CPT-11) is limited because of side effects. Mutations in the Rearranged during transfection (RET) proto-oncogene are considered the causative event of MTC. The objective of this study was to examine whether small interfering RNA (siRNA) and its combined treatment with CPT-11 could inhibit MTC cell growth in vitro and in vivo. The transfection of RET siRNA suppressed RET expression, reduced proliferation, and increased caspase-3/7 activity via the down-regulation of Bcl-2 expression. Combined treatments with CPT-11 or SN-38 significantly increased caspase 3/7 activity compared with RET siRNA, CPT-11 or SN-38 treatment alone. Importantly, intratumoral injection of RET siRNA along with intravenous injection of CPT-11 significantly inhibited the tumor growth of MTC xenografts via an increased apoptotic effect. These findings that RET siRNA enhanced sensitivity for CPT-11 will provide a novel strategy for the treatment of MTC with RET mutation.

Medullary Thyroid Cancer: New Targeted Molecular Therapies

Medullary thyroid carcinoma (MTC) is a rare tumor arising from neural crest-derived parafollicular C cells. Metastatic MTC patients are incurable because the cancer does not respond to radiotherapy or chemotherapy. The elucidation over the past two decades of multiple genetic abnormalities in MTC has provided specific targets for therapy. The identification of activating mutations of the RET tyrosine kinase receptor (TKR) in both hereditary and sporadic MTC makes this malignancy an excellent model to examine the effect of a group of small organic molecule tyrosine kinase inhibitors (TKIs) for treatment of metastatic MTC. Clinical trials with several TKIs targeting RET and other TKRs have shown positive results with generally tolerable toxicity. Approximately one-third to one-half of MTC patients have a reduction in tumor size up to 50%, with the longest treatment duration of approximately four years. The most common treatment-related toxicities are rash, nausea and diarrhea. Despite promising initial results these studies are in their early stages; however, the possibility of testing the sensitivity of primary MTC cells from each subject to different TKIs could increase the effectiveness of the treatment. A brief outline on current patents that are the focus on the treatment of Thyroid Cancer has also been provided in this review.

Medullary thyroid carcinoma and biomarkers: past, present and future

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

Beyond RET: potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation. Activating mutations of RET are associated with the pathogenesis of MTC and have been demonstrated in nearly all hereditary and in 30-50% of sporadic MTC cases, making this receptor an excellent target for small-molecule inhibitors for this tumour. Clinical trials of small organic inhibitors of tyrosine kinase receptors (TKIs) targeting the RET receptor have shown efficacy for treatment of metastatic MTC with 30-50% of patients responding to these agents. Despite the importance of the RET receptor in MTC, it is clear that other signal transduction pathways, tyrosine kinase receptors, and tumour suppressor genes are involved in MTC tumourigenesis and progression. A better understanding of molecular cross-talk between these signal pathways and the RET receptor may lead to combinatorial therapy that will improve outcomes beyond what is currently possible with RET-directed TKIs. Finally, there is evidence that immunological-based therapy using dendritic cell vaccination strategies have been effective for reducing tumour mass in a small number of patients. The identification of additional MTC-specific tumour antigens and a better understanding of specific epitopes in these tumour antigens may lead to improvement of response rates.

Diagnostic and surgical dilemmas in hereditary medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a rare malignancy arising from the parafollicular C cells within the thyroid gland. The majority of cases are sporadic, but at least 30% are hereditary in nature. Inherited forms of MTC occur as familial MTC or as a manifestation of multiple endocrine neoplasia type 2. Early diagnosis and aggressive surgical management, including prophylactic thyroidectomy, improve the prognosis of patients with hereditary MTC. Several issues regarding the diagnosis and treatment of MTC remain controversial. Genetic penetrance and virulence are variable. We present an index case of familial MTC to illustrate common difficulties in the initial diagnosis and dilemmas in the surgical approach, followed by a review of current literature relevant to the management of hereditary MTC.