scholarly journals How to Treat a Signal? Current Basis for RET-Genotype-Oriented Choice of Kinase Inhibitors for the Treatment of Medullary Thyroid Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Hugo Prazeres ◽  
Joana Torres ◽  
Fernando Rodrigues ◽  
Joana P. Couto ◽  
João Vinagre ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tyrosine Kinase ◽  
Intracellular Signaling ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Age Of Onset ◽  
Point Mutations ◽  
Tyrosine Kinase Receptor ◽  
Intracellular Signaling Pathways ◽  
Activating Mutation

The significance ofRETin thyroid cancer comes from solid evidence that, when inherited, anRETactivating mutation primes C-cells to transform into medullary carcinomas. Moreover, environmental exposure to radiation also induces rearranged transforming RET “isoforms” that are found in papillary thyroid cancer. TheRETgene codes for a tyrosine kinase receptor that targets a diverse set of intracellular signaling pathways. The nature ofRETpoint mutations predicts differences in the mechanisms by which the receptor becomes activated and correlates with different forms of clinical presentation, age of onset, and biological aggressiveness. A number of RET-targeting Tyrosine Kinase Inhibitors (TKIs) are currently undergoing clinical trials to evaluate their effectiveness in the treatment of thyroid cancer, and it is conceivable that the RET genotype may also influence response to these compounds. The question that now emerges is whether, in the future, the rational for treatment of refractory thyroid cancer will be based on the management of an abnormal RET signal. In this paper we address the RET-targeting TKIs and review studies about the signaling properties of distinct RET mutants as a means to predict response and design combinatorial therapies for the soon to be available TKIs.

scholarly journals Increased therapeutic effect on medullary thyroid cancer using a combination of radiation and tyrosine kinase inhibitors

PLoS ONE ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. e0233720
Author(s):  
Viktor Sandblom ◽  
Johan Spetz ◽  
Emman Shubbar ◽  
Mikael Montelius ◽  
Ingun Ståhl ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Therapeutic Effect ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Medullary Thyroid

First Line Sorafenib Treatment for Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis

2018 ◽  
Vol 127 (04) ◽  
pp. 240-246 ◽  
Author(s):  
Judit Kocsis ◽  
Éva Szekanecz ◽  
Ali Bassam ◽  
Andrea Uhlyarik ◽  
Zsuzsanna Pápai ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tyrosine Kinase ◽  
Disease Control ◽  
Tyrosine Kinase Inhibitors ◽  
Phase Ii ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Efficacy And Safety ◽  
First Line ◽  
Medullary Thyroid

Abstract Background Medullary thyroid cancer (MTC) is a rare disease, the prognosis of advanced and metastatic disease is poor and few therapeutic options are available in this setting. Based on the results of phase II and III studies with sorafenib in differentiated thyroid cancer and the lack of availability of registered tyrosine kinase inhibitors, vandetabin and cabozantinib in Hungary, we designed a uncontrolled, prospective efficacy and safety study of patients with metastatic MTC treated with first-line sorafenib in five Hungarian oncology centers. Methods Ten consecutive patients with progressive or symptomatic metastatic MTC were included and started sorafenib 400  mg twice a day between June 2012 and March 2016. The primary end point was median progression-free survival (mPFS). Secondary endpoints included disease control rate, biochemical response, symptomatic response and toxicity. Results Four patients achieved partial remission (40%) according to RECIST 1.1 evaluation. Five patients had stable disease beyond 12 months (50%) and one patient had progressive disease (10%). Median PFS was 19.1 months. The disease control rate was 90%. Association between radiologic response and biochemical or symptomatic response was inconsistent. Most common side effects were Grade 1-2 fatigue (60%), palmar-plantar erythrodysesthesia, rash/dermatitis 50-50%, alopecia 40%. Conclusions In our prospective case series in patients with MTC first-line sorafenib showed at least similar efficacy as in other small phase II trials and case reports. Based on comparable efficacy with registered tyrosine kinase inhibitors and it’s manageable toxicity profile, we believe that sorafenib has role in the sequential treatment of MTC.

scholarly journals Pathological processes and therapeutic advances in radioiodide refractory thyroid cancer

2017 ◽  
Vol 59 (4) ◽  
pp. R141-R154 ◽  
Author(s):  
Marika H Tesselaar ◽  
Johannes W Smit ◽  
James Nagarajah ◽  
Romana T Netea-Maier ◽  
Theo S Plantinga
Keyword(s):  
Thyroid Cancer ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Medullary Thyroid Cancer ◽  
Disease Remission ◽  
Intracellular Signaling Pathways ◽  
Oncogenic Mutations ◽  
Diagnostics And Therapy ◽  
Disease Present

While in most patients with non-medullary thyroid cancer (TC), disease remission is achieved by thyroidectomy and ablation of tumor remnants by radioactive iodide (RAI), a substantial subgroup of patients with metastatic disease present tumor lesions that have acquired RAI resistance as a result of dedifferentiation. Although oncogenic mutations inBRAF,TERTpromoter andTP53are associated with an increased propensity for induction of dedifferentiation, the role of genetic and epigenetic aberrations and their effects on important intracellular signaling pathways is not yet fully elucidated. Also immune, metabolic, stemness and microRNA pathways have emerged as important determinants of TC dedifferentiation and RAI resistance. These signaling pathways have major clinical implications since their targeting could inhibit TC progression and could enable redifferentiation to restore RAI sensitivity. In this review, we discuss the current insights into the pathological processes conferring dedifferentiation and RAI resistance in TC and elaborate on novel advances in diagnostics and therapy to improve the clinical outcome of RAI-refractory TC patients.

Antineoplastic activity of the multitarget tyrosine kinase inhibitors CLM3 and CLM94 in medullary thyroid cancer in vitro

Surgery ◽  
2014 ◽  
Vol 156 (5) ◽  
pp. 1167-1176 ◽  
Author(s):  
Silvia Martina Ferrari ◽  
Poupak Fallahi ◽  
Concettina La Motta ◽  
Guido Bocci ◽  
Alda Corrado ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Antineoplastic Activity ◽  
Medullary Thyroid

Statin Treatment Inhibits FLT3 Signaling by Preventing Glycosylation of the Mature Receptor and Leads to Cell Death In Mutant FLT3 Expressing Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 779-779
Author(s):  
Allen Williams ◽  
Bao Nguyen ◽  
Li Li ◽  
Patrick Brown ◽  
Mark J. Levis ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Alternative Pathway ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Receptor ◽  
Flt3 Ligand ◽  
Hematopoietic Stem

Abstract Abstract 779 FLT3 is a tyrosine kinase receptor expressed on the surface of hematopoietic stem cells/progenitors and contributes to leukemogenesis as evidenced by its frequent mutation in acute myeloid leukemia (AML). FLT3 normally undergoes N-linked glycosylation to produce an immature 130 Kd protein in the endoplasmic reticulum followed by further processing in the Golgi to form the final 160 Kd mature glycoprotein that translocates to the surface. At the surface, FLT3 binds to FLT3 ligand (FL) resulting in phosphorylation and activation of multiple signaling cascades. FLT3 activating mutations primarily occur as internal tandem duplications (ITD) within the juxtamembrane domain or as point mutations in the kinase domain and have become the target of numerous small molecule tyrosine kinase inhibitors (TKI), several of which have entered clinical trials for AML. However, clinical trials to date have shown limited success due to a variety of reasons including the emergence of resistance mediated by alternative pathway activation, the acquisition of point mutations, expression of increased FLT3 ligand levels and poor inhibition of FLT3 kinase activity for a number of reasons. Statins are a well-defined class of drugs that have been safely used for treatment of hypercholesterolemia. Here, we show for the first time that statins can inhibit constitutive activation of both kinase domain and ITD mutants. Western blotting demonstrates that fluvastatin inhibits FLT3 phosphorylation by preventing receptor glycosylation, initially leading to loss of the mature receptor followed by instability of the receptor and subsequent degradation of FLT3 protein and ultimately, cell death. MTT analysis indicates that BaF3 cells transfected with FLT3/ITD are killed in a dose-dependent fashion by fluvastatin with an IC50 of <1 uM, a level which has been achieved in clinical trials. Annexin V binding confirms that BaF3/ITD cells undergo apoptosis when treated with Fluvastatin. Fluvastatin treatment causes a reduction in surface FLT3 expression as measured by flow cytometry that parallels induction of apoptosis. This finding is consistent with results obtained by immunofluoresence microsopy showing increased intracellular retention of FLT3/ITD. Additionally, fluvastatin eliminates the 2–3 fold shift in the dose-response to TKI seen when FLT3/ITD expressing cells are stimulated by FL. Also, a number of mutations that confer high level resistance to TKI are overcome by fluvastatin. These results demonstrate that statins, a class of drugs already clinically approved, might be useful in the management of AML cases in which FLT3 is over expressed, mutated or resistant to other clinically available inhibitors, either alone or more likely in combination with FLT3 TKI. Disclosures: Levis: Ambit Biosciences, Inc: Consultancy.

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