Real-World Experience with Targeted Therapy for the Treatment of Anaplastic Thyroid Carcinoma

Iyer, Priyanka; Dadu, Ramona; Ferrarotto, Renata; Busaidy, Naifa L.; Habra, Mouhammed Amir; Zafereo, Mark; Gross, Neil D.; Hess, Kenneth R.; Gule-Monroe, Maria; Williams, Michelle D.; Cabanillas, Maria E.

doi:10.1089/thy.2017.0285

Cited by 100 publications

(86 citation statements)

References 26 publications

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“…However, while the initial response rate was impressive, the persistence of the response was limited by the development of drug resistance. 32,33 In this study, we dem- pathway, which was consistent with the previous studies that melatonin alone or combined with chemotherapeutic agents induced apoptosis in several cancers. 36,37 The main cause of death in ATC patients is related to its profound metastasis and invasion characteristics 38 chondrial DNA and regulation of DNA damage response.…”

Section: Discussionsupporting

confidence: 90%

Melatonin synergizes BRAF‐targeting agent dabrafenib for the treatment of anaplastic thyroid cancer by inhibiting AKT/hTERT signalling

Liao

Gao

Chang³

et al. 2020

J Cellular Molecular Medi

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As a selective inhibitor of BRAF kinase, dabrafenib has shown potent anti‐tumour activities in patients with BRAFV600E mutant anaplastic thyroid cancer. However, the resistance of thyroid cancer cells to dabrafenib limited its therapeutic effect. The effects of melatonin and dabrafenib as monotherapy or in combination on the proliferation, cell cycle arrest, apoptosis, migration and invasion of anaplastic thyroid cancer cells were examined. The molecular mechanism involved in drug combinations was also revealed. Melatonin enhanced dabrafenib‐mediated inhibition of cell proliferation, migration and invasion, and promoted dabrafenib‐induced apoptosis and cell cycle arrest in anaplastic thyroid cancer cells. Molecular mechanistic studies further uncovered that melatonin synergized with dabrafenib to inhibit AKT and EMT signalling pathways. Furthermore, melatonin and dabrafenib synergistically inhibited the expression of hTERT, and the inhibition of cell viability and the induction of cell cycle arrest mediated by the combination of these two drugs were reversed by hTERT overexpression. Taken together, our results demonstrated that melatonin synergized the anti‐tumour effect of dabrafenib in human anaplastic thyroid cancer cells by inhibiting multiple signalling pathways, and provided new insights in exploring the potential therapeutic targets for the treatment of anaplastic thyroid cancer.

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Section: Discussionsupporting

confidence: 90%

Melatonin synergizes BRAF‐targeting agent dabrafenib for the treatment of anaplastic thyroid cancer by inhibiting AKT/hTERT signalling

Liao

Gao

Chang³

et al. 2020

J Cellular Molecular Medi

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“…Crosstalk between these complex microenvironmental pathways has been increasingly recognized; common driver alterations in the MAPK and PI3K pathways have been shown to increase programs of angiogenesis and cell proliferation/survival, and increased VEGF secretion by both thyroid cancer cells and tumor‐infiltrating myeloid cells has been linked to impaired anti‐tumor immunity . Many of these alterations have become targetable with the advent of small molecule inhibitors and monoclonal antibodies …”

Section: Introductionmentioning

confidence: 99%

Anti‐PD‐1/PD‐L1 therapy augments lenvatinib's efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer

Gunda

Gigliotti

Ashry

et al. 2019

Intl Journal of Cancer

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Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite multimodal therapy with surgery and chemoradiation. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, as well as checkpoint inhibitors targeting the programmed cell death pathway, have proven effective in some patients with advanced thyroid cancer. Combination of these therapies is a potential means to boost effectiveness and minimize treatment resistance in ATC. We utilized our novel immunocompetent murine model of orthotopic ATC to demonstrate that lenvatinib led to significant tumor shrinkage and increased survival, while combination therapy led to dramatic improvements in both. Lenvatinib monotherapy increased tumorinfiltrating macrophages, CD8 + T-cells, regulatory T-cells, and most notably, polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs). While both combination therapies led to further increases in CD8 + T-cells, only the lenvatinib and anti-PD-1 combination decreased PMN-MDSCs. PMN-MDSC expansion was also seen in the blood of mice and one patient receiving lenvatinib therapy for ATC. RNA-Seq of the ATC cell line used in our mouse model demonstrated that lenvatinib has multifaceted effects on angiogenesis, response to hypoxia, the epithelial-to-mesenchymal transition, and on multiple pathways implicated in inflammation and host immunity. Combination of lenvatinib with anti-Gr-1 antibody ameliorated lenvatinib's expansion of MDSCs and significantly improved lenvatinib's anti-tumor effect. These data suggest that MDSCs play a negative role in ATC's response to lenvatinib and support future study of their role as a potential biomarker and treatment target.

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“…In clinical trials, BRAF V600E inhibitors have achieved preliminary success in the treatment of PTCs (Kim et al 2013, Dadu et al 2015, and the antitumor activity of vemurafenib with a partial response rate of 38.5% for patients with BRAF V600E -positive PTC was observed in a recent phase 2 clinical trial (Brose et al 2016). Molecularly targeted therapies also emerge as the standard of care for ATC patients either with metastatic or radiation-resistant diseases (Hanna et al 2018, Iyer et al 2018, Subbiah et al 2018. However, there is increasing evidence that thyroid cancer patients undergoing TKI treatment may ultimately escape the effects of therapy and then develop resistance (Kreissl et al 2019).…”

Section: Autophagy In Molecularly Targeted Therapy Of Thyroid Cancersmentioning

confidence: 99%

Targeting autophagy in thyroid cancers

Wei

Hardin

Luo

2019

Endocrine-Related Cancer

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Thyroid cancer is one of the most common endocrine malignancies. Although the prognosis for the majority of thyroid cancers is relatively good, patients with metastatic, radioiodine-refractory or anaplastic thyroid cancers have an unfavorable outcome. With the gradual understanding of the oncogenic events in thyroid cancers, molecularly targeted therapy using tyrosine kinase inhibitors (TKIs) is greatly changing the therapeutic landscape of radioiodine-refractory differentiated thyroid cancers (RR-DTCs), but intrinsic and acquired drug resistance, as well as adverse effects, may limit their clinical efficacy and use. In this setting, development of synergistic treatment options is of clinical significance, which may enhance the therapeutic effect of current TKIs and further overcome the resultant drug resistance. Autophagy is a critical cellular process involved not only in protecting cells and organisms from stressors but also in the maintenance and development of various kinds of cancers. Substantial studies have explored the complex role of autophagy in thyroid cancers. Specifically, autophagy plays important roles in mediating the drug resistance of small-molecular therapeutics, in regulating the dedifferentiation process of thyroid cancers and also in affecting the treatment outcome of radioiodine therapy. Exploring how autophagy intertwines in the development and dedifferentiation process of thyroid cancers is essential, which will enable a more profound understanding of the physiopathology of thyroid cancers. More importantly, these advances may fuel future development of autophagy-targeted therapeutic strategies for patients with thyroid cancers. Herein, we summarize the most recent evidence uncovering the role of autophagy in thyroid cancers and highlight future research perspectives in this regard. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10 2021-2035. (https://doi.

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Real-World Experience with Targeted Therapy for the Treatment of Anaplastic Thyroid Carcinoma

Abstract: Targeted therapies, lenvatinib, and dabrafenib plus trametinib (for BRAF mutants) may provide clinical benefit in ATC patients who are unable to participate in clinical trials, and toxicities are manageable.

Cited by 100 publications

References 26 publications

Melatonin synergizes BRAF‐targeting agent dabrafenib for the treatment of anaplastic thyroid cancer by inhibiting AKT/hTERT signalling

Melatonin synergizes BRAF‐targeting agent dabrafenib for the treatment of anaplastic thyroid cancer by inhibiting AKT/hTERT signalling

Anti‐PD‐1/PD‐L1 therapy augments lenvatinib's efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer

Targeting autophagy in thyroid cancers

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