scholarly journals Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 709 ◽  
Author(s):  
Elena Tirrò ◽  
Federica Martorana ◽  
Chiara Romano ◽  
Silvia Rita Vitale ◽  
Gianmarco Motta ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Tumor Biology ◽  
Cancer Development ◽  
Disease Evolution ◽  
Molecular Alterations ◽  
Genomic Landscape ◽  
Thyroid Malignancies

Thyroid cancer comprises different clinical and histological entities. Whereas differentiated (DTCs) malignancies are sensitive to radioiodine therapy, anaplastic (ATCs) and medullary (MTCs) tumors do not uptake radioactive iodine and display aggressive features associated with a poor prognosis. Moreover, in a majority of DTCs, disease evolution leads to the progressive loss of iodine sensitivity. Hence, iodine-refractory DTCs, along with ATCs and MTCs, require alternative treatments reflective of their different tumor biology. In the last decade, the molecular mechanisms promoting thyroid cancer development and progression have been extensively studied. This has led to a better understanding of the genomic landscape, displayed by thyroid malignancies, and to the identification of novel therapeutic targets. Indeed, several pharmacological compounds have been developed for iodine-refractory tumors, with four multi-target tyrosine kinase inhibitors already available for DTCs (sorafenib and lenvatinib) and MTCs (cabozantib and vandetanib), and a plethora of drugs currently being evaluated in clinical trials. In this review, we will describe the genomic alterations and biological processes intertwined with thyroid cancer development, also providing a thorough overview of targeted drugs already tested or under investigation for these tumors. Furthermore, given the existing preclinical evidence, we will briefly discuss the potential role of immunotherapy as an additional therapeutic strategy for the treatment of thyroid cancer.

scholarly journals Wedding of Molecular Alterations and Immune Checkpoint Blockade: Genomics as a Matchmaker

2021 ◽  
Author(s):  
Elena Fountzilas ◽  
Razelle Kurzrock ◽  
Henry Hiep Vo ◽  
Apostolia-Maria Tsimberidou
Keyword(s):  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Beta Catenin ◽  
Molecular Alterations ◽  
Receptor Repertoire ◽  
Repair Deficiency ◽  
Tumor Mutational Burden

Abstract The development of checkpoint blockade immunotherapy has transformed the medical oncology armamentarium. But, despite its favorable impact on clinical outcomes, immunotherapy benefits only a subset of patients, and a substantial proportion of these individuals eventually manifest resistance. Serious immune-related adverse events and hyper-progression have also been reported. It is therefore essential to understand the molecular mechanisms and identify the drivers of therapeutic response and resistance. In this review, we provide an overview of the current and emerging clinically relevant genomic biomarkers implicated in checkpoint blockade outcome. U.S. Food and Drug Administration–approved molecular biomarkers of immunotherapy response include mismatch repair deficiency/microsatellite instability and tumor mutational burden ≥10 mutations/megabase. Investigational genomic-associated biomarkers for immunotherapy response include alterations of the following genes/associated pathways: chromatin remodeling (ARID1A, PBRM1, SMARCA4, SMARCB1, BAP1), major histocompatibility complex, specific (e.g., ultraviolet, APOBEC) mutational signatures, T-cell receptor repertoire, PDL1, POLE/POLD1, and neo-antigens produced by the mutanome; those potentially associated with resistance include β2-microglobulin, EGFR, Keap1, JAK1/JAK2/interferon-gamma signaling, MDM2, PTEN, STK11, and Wnt/Beta-catenin pathway alterations. Prospective clinical trials are needed to assess the role of a composite of these biomarkers in order to optimize the implementation of precision immunotherapy in patient care.

scholarly journals Autoregulatory control of microtubule binding in doublecortin-like kinase 1

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Regina L Agulto ◽  
Melissa M Rogers ◽  
Tracy C Tan ◽  
Amrita Ramkumar ◽  
Ashlyn M Downing ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Therapeutic Target ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Binding Domain ◽  
Cancer Development ◽  
Microtubule Binding ◽  
Microtubule Binding Domain

The microtubule-associated protein, doublecortin-like kinase 1 (DCLK1), is highly expressed in a range of cancers and is a prominent therapeutic target for kinase inhibitors. The physiological roles of DCLK1 kinase activity and how it is regulated remain elusive. Here, we analyze the role of mammalian DCLK1 kinase activity in regulating microtubule binding. We find that DCLK1 autophosphorylates a residue within its C-terminal tail to restrict its kinase activity and prevent aberrant hyperphosphorylation within its microtubule-binding domain. Removal of the C-terminal tail or mutation of this residue causes an increase in phosphorylation within the doublecortin domains, which abolishes microtubule binding. Therefore, autophosphorylation at specific sites within DCLK1 have diametric effects on the molecule's association with microtubules. Our results suggest a mechanism by which DCLK1 modulates its kinase activity to tune its microtubule-binding affinity. These results provide molecular insights for future therapeutic efforts related to DCLK1's role in cancer development and progression.

scholarly journals Recent Advances in Molecular Diagnosis of Thyroid Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Ioannis Legakis ◽  
Konstantinos Syrigos
Keyword(s):  
Thyroid Cancer ◽  
Tumor Development ◽  
Disease Process ◽  
Genetic Alterations ◽  
Aberrant Methylation ◽  
Novel Treatments ◽  
Molecular Alterations ◽  
Molecular Events ◽  
Diagnosis Of Thyroid Cancer

Recent molecular studies have described a number of abnormalities associated with the progression and dedifferentiation of thyroid carcinoma. These distinct molecular events are often associated with specific stages of tumor development. In particular, remarkable advances have occurred in several major biological areas of thyroid cancer, including the molecular alterations for the loss of radioiodine avidity of thyroid cancer, the pathogenic role of the MAP kinase and PI3K/Akt pathways and their related genetic alterations, and the aberrant methylation of functionally important genes in thyroid tumorigenesis and pathogenesis. Recognition of these features is crucial to the management of patients with thyroid cancer. Novel treatments are being designed based on our enhanced understanding of this disease process.

Thyroid Cancer—Risks and Causes

2014 ◽  
Vol 10 (02) ◽  
pp. 144
Author(s):  
Simon Bonnefond ◽  
Terry F Davies ◽  
◽  
Keyword(s):  
Thyroid Cancer ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Significant Proportion ◽  
Precipitating Factors ◽  
Local Tumor ◽  
Cancer Risks ◽  
The Us ◽  
Different Types ◽  
Metastatic Thyroid Cancer

The incidence of thyroid cancer has almost doubled in recent years and over 60,000 people will be diagnosed in the US in 2015. While the prognosis for most such patients is excellent, a significant proportion die of thyroid cancer from local tumor progression and above all from metastases. Here we review the different types of thyroid cancers and their molecular changes with a special emphasis on the currently known susceptibility and precipitating factors. With the recent clinical introduction of tyrosine kinase inhibitors for the treatment of metastatic thyroid cancer it is clear that a simple cure is not at hand and further understanding of the molecular mechanisms of these tumors is urgently needed.

scholarly journals Role of acidic tumor microenvironment in tumor pathogenesis and targeting

2020 ◽  
pp. 34-40
Author(s):  
Vishal Sharma ◽  
Chhaya Bawa ◽  
Kuldeep Chand Vatsyan
Keyword(s):  
Cell Growth ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Physiological State ◽  
Therapeutic Interventions ◽  
Cancer Cell Growth ◽  
Molecular Alterations ◽  
Cancer Pathogenesis

Extensive efforts are going on to understand the molecular mechanisms behind tumor initiation, progression, and invasion and find novel targets for cancer treatment. The physiological state of the tumor microenvironment (TME) is crucial to every step of tumor cell growth and angiogenesis. Cancer cells are rarely in contact with each other. The intervening medium between the cancer cells, immune cells, and other cells become acidic, which significantly affects cancer pathogenesis. It could be a novel targeting marker and may help treat tumors. Even after extensive research in this area, the nature of molecular alterations and the basic mechanisms in the tumor microenvironment remains unclear. Based on recent studies of TME, this mini-review bids a more inclusive overview of the role of TME in cancer cell growth. Also, it helps to understand the potential of TME for therapeutic interventions.

scholarly journals Telomeres and Cancer

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1405
Author(s):  
Hueng-Chuen Fan ◽  
Fung-Wei Chang ◽  
Jeng-Dau Tsai ◽  
Kao-Min Lin ◽  
Chuan-Mu Chen ◽  
...  
Keyword(s):  
Telomere Length ◽  
Molecular Mechanisms ◽  
Telomere Maintenance ◽  
Cancer Development ◽  
Telomere Elongation ◽  
Metabolism Pathway ◽  
Length Regulation ◽  
Telomere Length Regulation ◽  
Genome Protection

Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.

scholarly journals The Role of Altered Mitochondrial Metabolism in Thyroid Cancer Development and Mitochondria-Targeted Thyroid Cancer Treatment

2021 ◽  
Vol 23 (1) ◽  
pp. 460
Author(s):  
Siarhei A. Dabravolski ◽  
Nikita G. Nikiforov ◽  
Alexander D. Zhuravlev ◽  
Nikolay A. Orekhov ◽  
Liudmila M. Mikhaleva ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Energy Production ◽  
Recent Progress ◽  
Molecular Mechanisms ◽  
Reactive Oxygen Species Generation ◽  
Common Type ◽  
Mitochondrial Metabolism ◽  
Oxygen Species ◽  
Tumour Formation

Thyroid cancer (TC) is the most common type of endocrine malignancy. Tumour formation, progression, and metastasis greatly depend on the efficacy of mitochondria—primarily, the regulation of mitochondria-mediated apoptosis, Ca2+ homeostasis, dynamics, energy production, and associated reactive oxygen species generation. Recent studies have successfully confirmed the mitochondrial aetiology of thyroid carcinogenesis. In this review, we focus on the recent progress in understanding the molecular mechanisms of thyroid cancer relating to altered mitochondrial metabolism. We also discuss the repurposing of known drugs and the induction of mitochondria-mediated apoptosis as a new trend in the development of anti-TC therapy.

scholarly journals Tyrosine Kinase Receptors in Oncology

2020 ◽  
Vol 21 (22) ◽  
pp. 8529
Author(s):  
Jorge Esteban-Villarrubia ◽  
Juan José Soto-Castillo ◽  
Javier Pozas ◽  
María San Román-Gil ◽  
Inmaculada Orejana-Martín ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Essential Role ◽  
Kinase Inhibitors ◽  
Genetic Alterations ◽  
Cancer Development ◽  
Tyrosine Kinase Receptors ◽  
Precision Oncology ◽  
Comprehensive Review ◽  
Molecular Alterations ◽  
Tumor Types

Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.

scholarly journals The Genomics of Myelodysplastic Syndromes: Origins of Disease Evolution, Biological Pathways, and Prognostic Implications

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2512
Author(s):  
Hassan Awada ◽  
Bicky Thapa ◽  
Valeria Visconte
Keyword(s):  
Experimental Studies ◽  
Gene Mutations ◽  
High Rate ◽  
Murine Models ◽  
Disease Evolution ◽  
Molecular Alterations ◽  
Disease Phenotypes ◽  
Prognostic Implications ◽  
Made In

The molecular pathogenesis of myelodysplastic syndrome (MDS) is complex due to the high rate of genomic heterogeneity. Significant advances have been made in the last decade which elucidated the landscape of molecular alterations (cytogenetic abnormalities, gene mutations) in MDS. Seminal experimental studies have clarified the role of diverse gene mutations in the context of disease phenotypes, but the lack of faithful murine models and/or cell lines spontaneously carrying certain gene mutations have hampered the knowledge on how and why specific pathways are associated with MDS pathogenesis. Here, we summarize the genomics of MDS and provide an overview on the deregulation of pathways and the latest molecular targeted therapeutics.

scholarly journals Immunotherapy Strategies for Gastrointestinal Stromal Tumor

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3525
Author(s):  
Junaid Arshad ◽  
Philippos A. Costa ◽  
Priscila Barreto-Coelho ◽  
Brianna Nicole Valdes ◽  
Jonathan C. Trent
Keyword(s):  
Monoclonal Antibodies ◽  
Soft Tissue ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Soft Tissue Sarcomas ◽  
Standard Of Care ◽  
Current Standard ◽  
Molecular Alterations

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. The management of locally advanced or metastatic unresectable GIST involves detecting KIT, PDGFR, or other molecular alterations targeted by imatinib and other tyrosine kinase inhibitors. The role of immunotherapy in soft tissue sarcomas is growing fast due to multiple clinical and pre-clinical studies with no current standard of care. The potential therapies include cytokine-based therapy, immune checkpoint inhibitors, anti-KIT monoclonal antibodies, bi-specific monoclonal antibodies, and cell-based therapies. Here we provide a comprehensive review of the immunotherapeutic strategies for GIST.

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