Can pegylated interferon α 2a cause development of thyroid disorders in patients with chronic hepatitis B?

Introduction: Hepatitis B virus infection is treated with pegylated (Peg) IFNα and nucleos(t)ide analogues. The disadvantages of PegIFNα include thyroid disorders. In this single-center study, the type, incidence and consequences of thyroid dysfunction in patients receiving PegIFNα due to chronic hepatitis B (CHB) were analyzed.

Patients and methods: The analysis included 106 patients (80 males) with CHB, aged 20 – 58 years, treated with PegIFNα-2a at a dose of 180 μg/week subcutaneously for 48 weeks. The levels of thyroid-stimulating hormone (TSH) and thyroid antibodies (TAbs) that is anti-thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies were measured in all patients at baseline. Furthermore, TSH was measured every 3 months during treatment and for 12 months after completion of treatment. If the TSH level was abnormal, free thyroxine 4 levels and TAbs were measured.

Results: All patients started the therapy with normal TSH and TAb levels. In 99 patients, TSH levels remained normal throughout the therapy. Thyroid disorder occurred in seven patients (6.6%), six of whom developed hypothyroidism and one who developed hyperthyroidism. Thyroid dysfunction was diagnosed in six women and one man. TAbs (only TPOAbs) were found in two patients (1.88%).

Conclusions: Thyroid disorder is a rare, though possible not transient, complication of IFN therapy in CHB patients.     

The mTOR protein as a target in thyroid cancer

Introduction: The mammalian target of rapamycin (mTOR) protein is a downstream effector of the phosphatidilinositol-3 kinase (PI3K)/Akt pathway, which regulates not only cell proliferation and viability, but also iodide uptake in thyroid cells. Genetic alterations in the PI3K/Akt/mTOR pathway are common during thyroid cancer progression, and thus, these proteins are attractive targets for cancer therapy. So far, specific mTOR inhibitors, such as rapamycin analogs, have been developed and studied as anti-cancer agents.

Areas covered: This review discusses evidence that justifies the potential use of mTOR signaling pathway inhibitors as therapeutic agents for thyroid cancer.

Expert opinion: In the near future, mTOR-targeted drugs might represent a new approach for the therapy of thyroid cancer patients; rapamycin analogs have already been developed and are currently being clinically tested. Besides the antiproliferative action of mTOR inhibition, the stimulatory effect on thyroid iodide uptake can also be useful in the treatment of recurrent thyroid cancer. Therefore, if rapamycin analogs are able to increase iodide uptake in thyroid cancer, either alone or in combination with other agents, this will represent a new approach for the treatment of thyroid cancer, which may possibly improve the treatment of patients in which radioiodine therapy is not effective.     

Novel therapies for thyroid cancer

Introduction: New therapeutic options for both differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) have opened up during the past few years, as the key role of tyrosine kinases in the pathogenesis of thyroid carcinoma has been proved. Recently, two tyrosine kinase inhibitors (TKIs) targeting VEGFR vandetanib (Caprelsa) and cabozantinib (Cometriq) have been approved for advanced MTC, whereas, sorafenib (Nexavar) has been accepted to treat late-stage of DTC. Their efficacy was demonstrated in Phase III studies, compared to placebo; each of them significantly prolonged the progression-free survival.

Areas covered: Common adverse reactions related to VEGFR blockade are hypertension, proteinuria, impaired wound healing, hemorrhage and thrombosis, and congestive heart failure. Fatigue, different gastrointestinal disturbances with diarrhea, appetite decrease and weight loss are observed in the majority of patients. Another frequent TKI side effect is thyroid-stimulating hormone increase secondary to inhibition of MCT8-dependent T3 and T4 uptake in pituitary.

Expert opinion: So far, no direct comparison of both treatment outcomes and toxicity between particular drugs has been carried out. The evidence-based medicine guidelines are necessary to precisely indicate what drug to use: more effective or less toxic and when to start the treatment.     

Cardiovascular toxicity associated with small molecule tyrosine kinase inhibitors currently in clinical use

Introduction: Tyrosine kinase inhibitors (TKIs) have changed the concepts of systemic therapy for a variety of advanced solid and hematologic malignancies. However, their toxicity can be significant, and includes both cardiac and non-cardiac effects.

Areas covered: The authors evaluate comprehensively the adverse cardiovascular portfolio of small molecule TKIs, postulate their underlying mechanisms and offer recommendations regarding prevention and therapy of these toxicities.

Expert opinion: For most pan-selective TKIs, there might not be a clear-cut relationship between specific patterns of TK inhibition and cardiovascular toxicity. Cardiovascular side effects are likely due to dysregulation of mulitple kinase regulated pathways. The cardiovascular effects of small molecule TKIs include peripheral edema and congestive heart failure, systemic and pulmonary hypertension, acute coronary syndromes and cardiac arrest due to QTc prolongation. Caution should be sought in patients with pre-existing cardiac dysfunction before initiating any of these agents. It is hoped that newer TKI generations will display minimal if any cardiovascular toxicity, while maintaining their anticancer efficacy. As of today, the high likelihood of morbidity without treatment mandates that cardiovascular toxicity of TKIs be carefully assessed and balanced with the known benefits of administering these agents.     

Treatment options for chronic myeloid leukemia

Introduction : The bcr-abl tyrosine kinase inhibitors (TKIs) are the cornerstone treatment for chronic myeloid leukemia (CML). However, there are many topics related to therapy that remain debated.

Areas covered : The aim of this paper is to give the reader a comprehensive review of how to treat CML at diagnosis, how to monitor the disease and a brief read of special populations and case scenarios. It describes the first-line (imatinib) and second-line (nilotinib and dasatinib) TKIs currently used for the treatment of CML, including landmark studies proving their efficacy, side effect profile, dosage and use in special populations. It also reviews the current guidelines regarding treatment and monitoring of the disease while on TKIs, along with an overview of treatment in advanced stages, the role of allogeneic stem cell transplantation and investigational drugs.

Expert opinion : Although imatinib represented a mayor therapeutic advancement over conventional chemotherapy, second-generation TKIs offer higher rates of optimal response and should be used as the frontline therapy. Patients with the T315I mutation carry a worse prognosis and should be offered allogeneic stem cell transplantation. The treatment in advanced stages of CML remains suboptimal and bench, translational and clinical research is encouraged.     

Hedgehog-mediated regulation of thyroid hormone action through iodothyronine deiodinases

Introduction: The three iodothyronine deiodinases catalyze the metabolic pathway that removes one iodine residue from the T4 molecule, thus producing either the active T3 or the inactive metabolite rT3. Hence, deiodination is a potent mechanism by which to modulate thyroid hormone (TH) action at cellular level, thereby allowing cells to customize their own T3 availability, both spatially and temporally, irrespective of TH serum concentrations. Sonic hedgehog (Hh) regulates patterning and growth of a remarkable variety of tissues throughout embryogenesis. Its constitutive activation is associated with cancer development.

Areas covered: Recent evidences from two independent systems implicate the Hh signaling pathway in regulation of TH action via modulation of deiodinase expression. Interestingly, many critical developmental events, for example, amphibian metamorphosis, are tightly regulated by the TH and Hh signaling pathways. This review provides an overview of recent data referring to the intricate regulation of deiodinase activity and intracellular TH action by the Hh pathway.

Expert opinion: This functional cross-talk provides a paradigm for interaction between two key signaling pathways critical during development and neoplastic transformation. This interaction may be relevant in other tissues and situations in which the two signaling pathways participate. Deciphering these mechanisms constitutes an exciting field for future research.     

Thyromimetics: a review of recent reports and patents (2004 – 2009)

Importance of the field: Thyroid hormones are produced by the thyroid gland and peripheral tissues, and control metabolic rate, including oxygen consumption, lipid metabolism and the cardiovascular system, mainly through binding to and activating thyroid hormone receptors (TRs). Abnormal elevation or lowering of circulating thyroid hormone induces various physiological disorders. As candidates for the treatment of such diseases, various thyromimetics, such as subtype- or tissue-selective TR agonists and antagonists, have been developed.

Areas covered in this review: This review focuses on recent reports and patents covering thyromimetics, especially those published in the last 6 years.

What the reader will gain: In this review, we classify thyromimetics based on structure. The structures of most thyromimetic compounds are based on those of endogenous thyroid hormones, which consist of a biaryl ether skeleton substituted with iodine, α-alanine moiety and hydroxyl group at two benzene rings. Many thyromimetics have been developed by replacement of the polar group, changing the bridging oxygen, or introduction of heterocycles. This review provides an overview of the structure–activity relationship.

Take home message: Some thyromimetics are subtype- or tissue-selective TR agonists and antagonists, and such compounds have the potential to become novel therapeutic agents, especially in the field of metabolic diseases.     

Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches

Introduction: Thyroid cancer is an emerging public health concern. In the USA, its incidence has doubled in the past decade, making it the eighth most commonly diagnosed neoplasm in 2010. Despite this alarming increase, most thyroid cancer patients benefit from conventional approaches (surgery, radioiodine, radiotherapy, TSH suppression with levothyroxine) and are often cured. Nevertheless, a minority have aggressive tumors resistant to cytotoxic and other historical therapies; these patients sorely need new treatment options.

Areas covered: Herein the biology and molecular characteristics of the common histological types of thyroid cancer are reviewed to provide context for subsequent discussion of recent developments and emerging therapeutics for advanced thyroid cancers.

Expert opinion: Several kinase inhibitors, especially those targeting VEGFR and/or RET, have already demonstrated promising activity in differentiated and medullary thyroid cancers (DTC, MTC). Although of minimal benefit in DTC and MTC, cytotoxic chemotherapy with anti-microtubule agents and/or anthracyclines in combination with intensity-modulated radiation therapy appears to extend survival for patients with locoregionally confined anaplastic thyroid cancer (ATC), but to have only modest benefit in metastatic ATC. Further discovery and development of novel agents and combinations of agents will be critical to further progress in treating advanced thyroid cancers of all histotypes.     

Targeting the thyrotropin receptor in thyroid disease

Introduction: The thyrotropin receptor (TSHR) is essential for thyroid growth and for the production of thyroid hormones. It is unique among the glycoprotein hormone receptors, in that some of the TSHRs undergo cleavage and shedding of the alpha subunit.

Areas covered: This review discusses the structure and function of the TSHR, followed by an evaluation of its role in thyroid disease. Possible limitations of the TSHR as a therapeutic target are also discussed.

Expert opinion: The TSHR is involved in a number of hereditary and acquired disorders of the thyroid making it of potential importance as a therapeutic target in thyroid disease. Expression of the TSHR in several non-thyroidal tissues and the development of systemic manifestations of thyroid disease suggest that the TSHR is also of interest as a therapeutic target outside the thyroid.     

An overview of tyrosine kinase inhibitors for the treatment of epithelial ovarian cancer

Introduction: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and the fifth most common cause of cancer-related deaths in women. Initial treatment with surgery and chemotherapy has improved survival significantly. However, the disease progresses or recurs in most patients. Thus, there is an urgent need to develop more effective treatment strategies.

Areas covered: This article provides an overview of tyrosine kinase inhibitors (TKIs) for the treatment of EOC, which is based on English peer-reviewed articles on MEDLINE and related abstracts presented at major conferences. The authors highlight the data from the published clinical trials in EOC patients who were treated with TKIs or TKI-based regimens.

Expert opinion: EOC is responsive to most chemotherapeutic drugs and/or biological agents and represents an ideal disease model for investigating novel anti-cancer agents. Numerous small-molecule TKIs targeting the VEGFR, PARP, PI3K-AKT-mTOR, MAPK, Src, PKC, Wee1 and HER1/2 signaling pathways are currently being tested in clinical trials. Research is needed for devising regimens combining TKIs with other agents in an optimal timing schedule and for identifying potential biomarkers predictive of response and survival.     

Tyrosine kinase inhibitors in the treatment of unresectable or metastatic gastrointestinal stromal tumors

Introduction: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. Proliferation of GIST is driven by activating mutations in the KIT or PDGFRA genes that found in most sporadic GISTs. Surgery is the main remedial measure for primary GIST, and imatinib is the principal therapeutic of choice for unresectable or metastatic GIST. Imatinib revolutionized treatment for unresectable or metastatic GISTs; however, resistance to imatinib has inevitably developed for most GIST patients.

Areas covered: PubMed was searched to find biological studies of GIST and clinical trials of molecularly targeted agents on unresectable or metastatic GISTs, and the key papers found have been reviewed. In this paper, the standard therapy which includes imatinib, sunitinib and regorafenib for unresectable or metastatic GIST has been reviewed and molecular mechanisms of resistance for tyrosine kinase inhibitors (TKIs) have been postulated and discussed. Treatment measures for resistant GIST and therapeutic choices after the standard therapy have also been described.

Expert opinion: The standard therapy for unresectable or metastatic GISTs is first-line imatinib, second-line sunitinib and third-line regorafenib. After standard therapy, best supportive care or clinical trials is recommended in the guidelines. However, patients may benefit from continuation of TKIs beyond disease progression and from rechallenge of TKIs used previously.     

Current concerns of undertreatment and overtreatment in chronic myeloid leukemia based on European LeukemiaNet 2013 recommendations

Introduction: The aim of this paper is to indicate optimal tyrosine kinase inhibitor (TKI) administration practices based on European LeukemiaNet (ELN) 2013 recommendations for chronic myeloid leukemia (CML). Likewise, current concerns of undertreatment and overtreatment with TKIs during the long-term clinical course of CML will be outlined.

Areas covered: Currently available TKIs for the management of CML are reviewed. The survival benefit of TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) for the CML is excellent. The CML and TKI literature search was made in PubMed with particular focus on the clinical trials, recommendations, guidelines and expert opinions, as well as the ELN CML 2013 recommendations.

Expert opinion: Initial TKI treatment for low-risk chronic phase CML is imatinib 400 mg; high-Sokal risk and/or CML patients with complex karyotypic abnormalities would require more powerful second-generation TKIs (dasatinib 100 mg or nilotinib 600 mg). Absence of early molecular response after 6 months, complete cytogenetic response after 12 months and major molecular response after 18 months may require a more powerful TKI switch. If one of the two second-generation TKIs (nilotinib or dasatinib) was used as first-line therapy and failed, the other (dasatinib or nilotinib) could be administered.     

Analysis of the protective effects of γ-aminobutyric acid during fluoride-induced hypothyroidism in male Kunming mice

Context: Compounds to treat hypothyroidism in the absence of cardiac side effects are urgently required. In this regard, γ-aminobutyric acid (GABA) has gained interest due to its anti-anxiolytic, antihypertensive and antioxidant properties, and reported benefits to the thyroid system.

Objective: We investigated the ability of GABA to ameliorate fluoride-induced thyroid injury in mice, and investigated the mechanism(s) associated with GABA-induced protection.

Materials and methods: Adult male Kumning mice (N?=?90) were exposed to NaF (50?mg/kg) for 30?days as a model of hypothyroidism. To evaluate the effects of GABA administration, fluoride-exposed mice received either thyroid tablets, or low (25?mg/kg), medium (50?mg/kg) or high (75?mg/kg) concentrations of pure GABA orally for 14?days groups (N?=?10 each). The effects of low (50?mg/kg); medium (75?mg/kg) and high (100?mg/kg) concentrations of laboratory-separated GABA were assessed for comparison. Effects on thyroid hormone production, oxidative stress, thyroid function-associated genes, and side-effects during therapy were measured.

Results: GABA supplementation in fluoride-exposed mice significantly increased the expression of thyroid TG, TPO, and NIS (P?P?Discussion and conclusion: Our findings support the assertion that GABA exerts therapeutic potential in hypothyroidism. The design and use of human GABA trials to improve therapeutic outcomes in hypothyroidism are now warranted.     

Tyrosine kinase inhibitors in the treatment of prostate cancer: taking the next step in clinical development

Introduction: Prostate cancer (PCa) is the most frequently diagnosed, non-cutaneous malignancy in Western countries. Until recently, few therapeutic options were available for patients with advanced PCa. Although these treatments may delay progression of disease, none are curative. Therefore, research continues to investigate other treatments for advanced PCa. Tyrosine kinase inhibitors (TKIs) have been extensively studied as a treatment for multiple malignancies and may represent an additional strategy. In addition to limiting cellular proliferation and metastasis, there is also growing interest in using these treatments to impact the bone microenvironment and reduce associated morbidity from PCa.

Areas covered: Several TKIs have been evaluated in the preclinical setting in advanced PCa. Targets reviewed include the epidermal growth factor family, VEGF receptor, c-Src family kinases, platelet-derived growth factor and c-Met.

Expert opinion: Despite strong biological rationale for the use of TKIs therapy for the treatment of PCa, Phase III clinical trials have produced disappointing results. As TKI strategies move forward, the failures of past trials need to be better understood. New approaches with these treatments will also have to take into account modern anti-androgens and a treatment landscape that now includes immunotherapy.     

Investigational drugs in early stage clinical trials for thyrotoxicosis with hyperthyroidism

ABSTRACT

Introduction: Thyrotoxicosis with hyperthyroidism is treated with these classical approaches (i) antithyroid drugs to blockade thyroid hormone release and normalize thyroid hormone production and (ii) destruction of the thyroid using radioiodine or surgical removal of the thyroid. The optimal medical therapy, especially for Graves´ disease, remains a subject of debate and there has been little progress in Graves’ disease therapeutics over the last decade.

Areas covered: Novel treatments of thyrotoxicosis with hyperthyroidism. This includes (i) small molecules such as synthetic thyroid hormone receptor antagonists and environmental molecules and (ii) molecules with interaction between thyroid stimulating hormone (TSH) receptor and TSH receptor antibodies such as M22, ANTAG3, org274179-0, 5C9, and K1-70. Other approaches to Graves´ disease treatment includes immunosuppressive treatment, glucocorticosteroids, rituximab, and intrathyroid injection of dexamethasone. Optimal iodine and selenium supplementation can also be considered.

Expert opinion: Clinical trials results suggest that novel thyroid treatments involving small molecule therapy, may predict a good future in Graves’ disease treatment; however, a greater understanding of these antagonists is needed. Other treatments comprising immunosuppressives have demonstrated a significant reduction of relapse of the disease, but are not recommended by international guidelines.     

Protein kinase inhibitors against malignant lymphoma

Introduction: Tyrosine kinases (TKs) are intimately involved in multiple signal transduction pathways regulating survival, activation, proliferation and differentiation of lymphoid cells. Deregulation or overexpression of specific oncogenic TKs is implicated in maintaining the malignant phenotype in B-lineage lymphoid malignancies. Several novel targeted TK inhibitors (TKIs) have recently emerged as active in the treatment of relapsed or refractory B-cell lymphomas that inhibit critical signaling pathways, promote apoptotic mechanisms or modulate the tumor microenvironment.

Areas covered: In this review, the authors summarize the clinical outcomes of newer TKIs in various B-cell lymphomas from published and ongoing clinical studies and abstracts from major cancer and hematology conferences.

Expert opinion: Multiple clinical trials have demonstrated that robust antitumor activity can be obtained with TKIs directed toward specific oncogenic TKs that are genetically deregulated in various subtypes of B-cell lymphomas. Clinical success of targeting TKIs is dependent upon on identifying reliable molecular and clinical markers associated with select cohorts of patients. Further understanding of the signaling pathways should stimulate the identification of novel molecular targets and expand the development of new therapeutic options and individualized therapies.     

Progress and contrasts of the development of tivozanib for therapy of kidney cancer

Introduction: Targets for drug development for the treatment of kidney cancer (renal cell carcinoma; RCC) include vascular endothelial growth factor (VEGF) and its receptors and mammalian target of rapamycin. Currently available oral multitargeted VEGF tyrosine kinase inhibitors (TKIs) that have been approved by the US Food and Drug Administration for advanced RCC, include sunitinib, sorafenib and pazopanib. Off-target TKI inhibition can potentially preclude full-dose combination with other targeted and chemotherapeutic agents. There is a need to develop more potent and selective targeted agents for RCC therapy, which are more effective and have minimal off-target effects.

Areas covered: This drug evaluation review addresses the ongoing development for the treatment of RCC with tivozanib: a potent, selective and long-half-life VEGF TKI. The testing for clinical efficacy alone or in combination with other therapies for RCC and for other tumor types, and the clinical and market relevance of introducing another RCC therapy are discussed.

Expert opinion: Tivozanib is distinguished by its high potency, selectivity, long-half-life and its potential to be effectively combined with other agents in RCC. This may offer more effective, yet well-tolerated treatment options. The relative clinical and market relevance remain to be seen, both for RCC therapy and other tumor types.     

Thyroid hormone analogs for the treatment of dyslipidemia: past,present, and future

Objective: Treatment of dyslipidemia is a major burden for public health. Thyroid hormone regulates lipid metabolism by binding the thyroid hormone receptor (TR), but the use of thyroid hormone to treat dyslipidemia is not indicated due to its deleterious effects on heart, bone, and muscle. Thyroid hormone analogs have been conceived to selectively activate TR in the liver, thus reducing potential side-effects.

Methods: The authors searched the PubMed database to review TR and the action of thyromimetics in vitro and in animal models. Then, all double-blind, placebo controlled trials that analyzed the use of thyroid hormone analog for the treatment of dyslipidemia in humans were included. Finally, the ongoing research on the use of TR agonists was searched, searching the US National Institutes of Health Registry and the WHO International Clinical Trial Registry Platform (ICTRP).

Results: Thyromimetics were tested in humans for the treatment of dyslipidemia, as a single therapeutic agent or as an add-on therapy to the traditional lipid-lowering drugs. In most trials, thyromimetics lowered total cholesterol, low-density lipoprotein cholesterol, and triglycerides, but their use has been associated with adverse side-effects, both in pre-clinical studies and in humans.

Conclusions: The use of thyromimetics for the treatment of dyslipidemia is not presently recommended. Future possible clinical applications might include their use to promote weight reduction. Thyromimetics might also represent an interesting alternative, both for the treatment of non-alcoholic steatohepatitis, and type 2 diabetes due to their positive effects on insulin sensitivity. Finally, additional experimental and clinical studies are needed for a better comprehension of the effect(s) of a long-term therapy.