cabozantinib and Carcinoma--Medullary

Medullary thyroid carcinoma (MTC) represents 3-5% of thyroid cancers. 75% is sporadic and 25% is the dominant component of the hereditary multiple endocrine neoplasia (MEN) type 2 syndromes. Three different subtypes of MEN2, such as MEN2A, MEN2B, and Familial MTC (FMTC) have been defined, based on presence or absence of hyperparathyroidism, pheocromocytoma and characteristic clinical features. Mutations of the RET proto-oncogene are implicated in the pathogenesis of MTC, but there are many other mutational patterns involved. In MEN2A, Codon 634 in exon 11 (Cys634Arg), corresponding to a cysteine in the extracellular cysteine-rich domain, is the most commonly altered codon. Many other mutations include codons 611, 618, 620. In the genetical testing of RET mutations in MTCs, Next-Generation Sequencing (NGS) is taking an increasingly important role. One of the most important benefit is the comprehensive analysis of molecular alterations in MTC, which allows rapidly to select patients with different risk levels. There is a difference in miRNA expression pathway between sporadic and hereditary MTCs. Among sporadic cases, expression of miR-127 was significantly lower in those who harbor somatic RET mutations than those with wild-type RET. CDKN1B mutations are associated with many clinical pictures of cancers, such as MEN4. V109G polymorphism is associated with sporadic MTCs negative for RET mutations, and might influence the clinical course of the patients affected by MTC. Although surgery (i.e. total thyroidectomy with neck lymph node dissection) is the elective treatment for MTCs, about 80% of patients have distant metastases at diagnosis and in this cases surgery is not enough and an additional treatment is needed. Interesting results come from two large phase III clinical trials with two targeted tyrosine kinase inhibitors (TKIs), vandetanib and cabozantinib.. New genetical testings and therapeutical approaches open new perspectives in MTC management.

Topics: Anilides; Carcinoma, Medullary; Codon; Exons; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 2a; Mutation; Piperidines; Polymorphism, Genetic; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Thyroid Neoplasms; Thyroidectomy

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.. 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.. 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.

Topics: Anilides; Animals; Carcinoma, Medullary; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Humans; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyridines; Signal Transduction; Thyroid Neoplasms

Metastatic medullary thyroid cancer (MTC) is an incurable disease once metastasis becomes unresectable. Many therapeutic drugs and methods have been tried to circumvent this difficulty. We review currently published treatments and hope for future developments of more effective treatment methods.. Motesanib, vandetanib, axitinib (tyrosine kinase inhibitors), and XL184 (multikinase inhibitor) have been shown to achieve partial response or stable disease state of metastatic MTC. Sunitinib and sorafenib, currently available tyrosine kinase inhibitors, can also be tried for patients with MTC. However, these medications are not curative and do not improve survival rate. Only carcinoembryonic antigen-I-iodine-based radioimmunotherapy improved survival of a subset of patients with a very aggressive type of MTC. Drugs currently available for possible use of MTC treatment include bortezomib (proteasome inhibitor), valproic acid (histone deacetylase inhibitor), capecitabine (5-fluorouracil prodrug), and indomethacin (NSAID), although clinical studies have yet to be done. Cardiac natriuretic hormones and an extract of the plant Cautleya gracilis are new agents to be studied for MTC.. Kinase inhibitors are the first drugs showing some efficacy in MTC. To improve survival, unconventional drugs or other therapies with or without kinase inhibitors need to be considered.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Medullary; Humans; Neoplasm Metastasis; Pyridines; Therapies, Investigational; Thyroid Neoplasms

Primary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.. EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.. Minimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.. The secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib.. NCT00704730.

Topics: Aged; Anilides; Carcinoma, Medullary; Diagnostic Imaging; Double-Blind Method; Female; Follow-Up Studies; Humans; International Agencies; Male; Prognosis; Pyridines; Survival Rate; Thyroid Neoplasms

Topics: Anilides; Antineoplastic Agents; Carcinoma, Medullary; Drug Approval; Humans; Mutation; Phenylurea Compounds; Piperidines; Precision Medicine; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Pyrimidines; Quinazolines; Quinolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

Topics: Anilides; Animals; Apoptosis; Carcinoma, Medullary; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Mice; MicroRNAs; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Pyridines; Receptor Protein-Tyrosine Kinases; Thyroid Neoplasms

In Spain medullary thyroid carcinoma (MTC) would not exceed 80 new cases per year and less than half of them would be good candidates for systemic treatment with novel agents.. Relevant literature was reviewed, including PubMed searches supplemented with additional articles.. The consensus summarizes the clinical outcomes in terms of activity and toxicity of each of the available drugs. A brief summary of the minimum requirements in terms of follow up and genetic counseling around MTC is also included.. Only those patients with objective imaging progression in the last 12-14 months with large volume of disease are clear candidates to start systemic treatment. However, those patients with low disease volume should be considered for 'wait and see' strategy until symptoms of the disease appear. Multidisciplinary approach for the management of MTC patient is mandatory nowadays.

Topics: Anilides; Antineoplastic Agents; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Medullary; Combined Modality Therapy; Diagnostic Imaging; Disease Management; Doxorubicin; Genetic Association Studies; Humans; Neoplasm Metastasis; Prognosis; Proto-Oncogene Proteins c-ret; Pyridines; Radiotherapy; Thyroid Neoplasms

A limited number of approved therapeutic options are available to metastatic medullary thyroid cancer (MTC) patients, and the response to conventional chemotherapy and/or radiotherapy strategies is inadequate. Sporadic and inherited mutations in the tyrosine kinase RET result in oncogenic activation that is associated with the pathogenesis of MTC. Cabozantinib is a potent inhibitor of MET, RET, and vascular endothelial factor receptor 2 (VEGFR2), as well as other tyrosine kinases that have been implicated in tumor development and progression. The object of this study was to determine the in vitro biochemical and cellular inhibitory profile of cabozantinib against RET, and in vivo antitumor efficacy using a xenograft model of MTC.. Cabozantinib was evaluated in biochemical and cell-based assays that determined the potency of the compound against wild type and activating mutant forms of RET. Additionally, the pharmacodynamic modulation of RET and MET and in vivo antitumor activity of cabozantinib was examined in a MTC tumor model following subchronic oral administration.. In biochemical assays, cabozantinib inhibited multiple forms of oncogenic RET kinase activity, including M918T and Y791F mutants. Additionally, it inhibited proliferation of TT tumor cells that harbor a C634W activating mutation of RET that is most often associated with MEN2A and familial MTC. In these same cells grown as xenograft tumors in nude mice, oral administration of cabozantinib resulted in dose-dependent tumor growth inhibition that correlated with a reduction in circulating plasma calcitonin levels. Moreover, immunohistochemical analyses of tumors revealed that cabozantinib reduced levels of phosphorylated MET and RET, and decreased tumor cellularity, proliferation, and vascularization.. Cabozantinib is a potent inhibitor of RET and prevalent mutationally activated forms of RET known to be associated with MTC, and effectively inhibits the growth of a MTC tumor cell model in vitro and in vivo.

Topics: Anilides; Animals; Carcinoma, Medullary; Cell Line, Tumor; Cell Proliferation; Mice; Mice, Nude; Phosphorylation; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-ret; Pyridines; Receptor Protein-Tyrosine Kinases; Thyroid Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2