Expression of angiogenic switch, cachexia and inflammation factors at the crossroad in undifferentiated thyroid carcinoma with BRAF

Husain, Amjad; Hu, Nina; Sadow, Peter M.; Nucera, Carmelo

doi:10.1016/j.canlet.2015.07.012

Cited by 11 publications

(12 citation statements)

References 65 publications

(88 reference statements)

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“…BRAF V600E could also be responsible for some clinical symptoms: in ATC the production and secretion of different angiogenic and pro-inflammatory key-factors (e.g. VEGFA, VEGFC, IL6) may contribute to the worsening of pathological features such as cachexia (the result of complex metabolic alterations which cause morbidity) 36 . Overall, these results highlight the complexity of tumor interaction with the microenvironment, and how this interplay can affect thyroid cancer progression and consequently patient prognosis.…”

Section: Genetic Alterations In Early Thyroid Tumorigenesismentioning

confidence: 99%

Coding Molecular Determinants of Thyroid Cancer Development and Progression

Valvo

Nucera

2019

Endocrinology and Metabolism Clinics of North America

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Thyroid cancer is the most common endocrine malignancy and its trends of incidence are the highest compared to other tumors. The characterization of the molecular pathways involved in thyroid cancer initiation and progression has made huge progress, underlining the essential role of determined signaling to promote specific features, including dedifferentiation, invasiveness, metastasis and drug resistance. The discovery of many genetic alterations that include point mutations, chromosome translocations, deletions, and copy-number gain has provided new exciting biological insights with translational/clinical applications. Furthermore, mechanisms of drug resistance involve role of pericytes and deregulation of pro-angiogenic molecules such as the tyrosine kinases (TKs) in the microenvironment. BRAF V600E-positive thyroid tumor growth is also influenced by the tumor microenvironment, which is in turn altered by the tumor itself, leading to abnormal extracellular matrix (ECM) deposition and activation of angiogenic pathways. Many of the processes involved in thyroid tumor growth and metastasis are mediated by signaling molecules downstream of BRAF V600E and activated TKs. Overall, understanding how molecular pathways interplay is one of the key-strategies to develop new therapeutic treatments and improve prognosis.

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Section: Genetic Alterations In Early Thyroid Tumorigenesismentioning

confidence: 99%

Coding Molecular Determinants of Thyroid Cancer Development and Progression

Valvo

Nucera

2019

Endocrinology and Metabolism Clinics of North America

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“…The mTORC1, which is a major signaling intermediary to stimulate anabolic processes, promotes skeletal muscle growth by increasing the adipogenesis and lipogenesis [ 53 ], and therefore inhibiting mTOR contributes to tumor cachexia. Cachexia is a result of complex metabolic alterations and causes morbidity and mortality in patients with advanced cancers such as undifferentiated (anaplastic) thyroid carcinoma [ 54 ]. It has been recently shown that the severe COVID-19 patients show cachexia like conditions but need more data to make conclusions.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin as a potential repurpose drug candidate for the treatment of COVID-19

Husain

Byrareddy

2020

Chemico-Biological Interactions

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The novel human coronavirus-2 (HCoV-2), called SARS-CoV-2, is the causative agent of Coronavirus Induced Disease (COVID-19) and has spread causing a global pandemic. Currently, there is no vaccine to prevent infection nor any approved drug for the treatment. The development of a new drug is time-consuming and cannot be relied on as a solution in combatting the immediate global challenge. In such a situation, the drug repurposing becomes an attractive solution to identify the potential of COVID-19 treatment by existing drugs, which are approved for other indications. Here, we review the potential use of rapamycin, an mTOR (Mammalian Target of Rapamycin) inhibitor that can be repurposed at low dosages for the treatment of COVID-19. Rapamycin inhibits protein synthesis, delays aging, reduces obesity in animal models, and inhibits activities or expression of pro-inflammatory cytokines such as IL-2, IL-6 and, IL-10. Overall, the use of rapamycin can help to control viral particle synthesis, cytokine storms and contributes to fight the disease by its anti-aging and anti-obesity effects. Since, rapamycin targets the host factors and not viral machinery, it represents a potent candidate for the treatment of COVID-19 than antiviral drugs as its efficacy is less likely to be dampened with high mutation rate of viral RNA. Additionally, the inhibitory effect of rapamycin on cell proliferation may aid in reducing viral replication. Therefore, by drug repurposing, low dosages of rapamycin can be tested for the potential treatment of COVID-19/SARS-CoV-2 infection.

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“…The most common AEs included rash, fatigue, weight loss, anorexia, dysgeusia, and alopecia [ 76 , 77 ]. Preclinical studies showed that Vemurafenib downregulates angiogenic/cachectic and pro-inflammatory/immune response factors (IL-6, VEGFA, and VEGFC) that mediate microenvironment interactions between endothelial and ATC cells, thus inhibiting in vitro angiogenesis and lymphangiogenesis in ATC cells cultures [ 78 ]. Vemurafenib demonstrated also to be able to reduce ATC xenografts and metastasis growth in mice models [ 79 ].…”

Section: Main Textmentioning

confidence: 99%

Recent advances in the management of anaplastic thyroid cancer

2020

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Anaplastic thyroid cancer (ATC) is undoubtedly the thyroid cancer histotype with the poorest prognosis. The conventional treatment includes surgery, radiotherapy, and conventional chemotherapy. Surgery should be as complete as possible, securing the airway and ensuring access for nutritional support; the current standard of care of radiotherapy is the intensity-modulated radiation therapy; chemotherapy includes the use of doxorubicin or taxanes (paclitaxel or docetaxel) generally with platin (cisplatin or carboplatin). However, frequently, these treatments are not sufficient and a systemic treatment with kinase inhibitors is necessary. These include multitarget tyrosine kinase inhibitors (Lenvatinib, Sorafenib, Sunitinib, Vandetanib, Axitinib, Pazopanib, Pyrazolo-pyrimidine compounds), single target tyrosine kinase inhibitors (Dabrafenib plus Trametinib and Vemurafenib against BRAF, Gefitinib against EGFR, PPARγ ligands (e.g. Efatutazone), Everolimus against mTOR, vascular disruptors (e.g. Fosbretabulin), and immunotherapy (e.g. Spartalizumab and Pembrolizumab, which are anti PD-1/PD-L1 molecules). Therapy should be tailored to the patients and to the tumor genetic profile. A BRAF mutation analysis is mandatory, but a wider evaluation of tumor mutational status (e.g. by next-generation sequencing) is desirable. When a BRAFV600E mutation is detected, treatment with Dabrafenib and Trametinib should be preferred: this combination has been approved by the Food and Drug Administration for the treatment of patients with locally advanced or metastatic ATC with BRAFV600E mutation and with no satisfactory locoregional treatment options. Alternatively, Lenvatinib, regardless of mutational status, reported good results and was approved in Japan for treating unresectable tumors. Other single target mutation agents with fair results are Everolimus when a mutation involving the PI3K/mTOR pathway is detected, Imatinib in case of PDGF-receptors overexpression, and Spartalizumab in case of PD-L1 positive tumors. Several trials are currently evaluating the possible beneficial role of a combinatorial therapy in ATC. Since in this tumor several genetic alterations are usually found, the aim is to inhibit or disrupt several pathways: these combination strategies use therapy targeting angiogenesis, survival, proliferation, and may act against both MAPK and PI3K pathways. Investigating new treatment options is eagerly awaited since, to date, even the molecules with the best radiological results have not been able to provide a durable disease control.

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Expression of angiogenic switch, cachexia and inflammation factors at the crossroad in undifferentiated thyroid carcinoma with BRAF

Cited by 11 publications

References 65 publications

Coding Molecular Determinants of Thyroid Cancer Development and Progression

Coding Molecular Determinants of Thyroid Cancer Development and Progression

Rapamycin as a potential repurpose drug candidate for the treatment of COVID-19

Recent advances in the management of anaplastic thyroid cancer

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