New Therapies for Dedifferentiated Papillary Thyroid Cancer

Fallahi, Poupak; Mazzi, Valeria; Vita, Roberto; Ferrari, Silvia; Materazzi, Gabriele; Galleri, David; Benvenga, Salvatore; Miccoli, Paolo; Antonelli, Alessandro

doi:10.3390/ijms16036153

Cited by 48 publications

(61 citation statements)

References 173 publications

(212 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, for cases in which these treatments are not effective, targeted drugs might be considered. Kinase inhibitors, such as sorafenib and lenvatinib, are now used as targeted drugs [9,10]. Less frequent genetic alterations, such as rearrangements of ALK [11] and ETV6 [12], identified in sPTC, but not yet investigated in fPTC, also represent new therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma

Caria

Cantara

Frau

et al. 2016

IJMS

View full text Add to dashboard Cite

Extensive research is dedicated to understanding if sporadic and familial papillary thyroid carcinoma are distinct biological entities. We have previously demonstrated that familial papillary thyroid cancer (fPTC) cells exhibit short relative telomere length (RTL) in both blood and tissues and that these features may be associated with chromosome instability. Here, we investigated the frequency of HER2 (Human Epidermal Growth Factor Receptor 2) amplification, and other recently reported genetic alterations in sporadic PTC (sPTC) and fPTC, and assessed correlations with RTL and BRAF mutational status. We analyzed HER2 gene amplification and the integrity of ALK, ETV6, RET, and BRAF genes by fluorescence in situ hybridization in isolated nuclei and paraffin-embedded formalin-fixed sections of 13 fPTC and 18 sPTC patients. We analyzed BRAFV600E mutation and RTL by qRT-PCR. Significant HER2 amplification (p = 0.0076), which was restricted to scattered groups of cells, was found in fPTC samples. HER2 amplification in fPTCs was invariably associated with BRAFV600E mutation. RTL was shorter in fPTCs than sPTCs (p < 0.001). No rearrangements of other tested genes were observed. These findings suggest that the association of HER2 amplification with BRAFV600E mutation and telomere shortening may represent a marker of tumor aggressiveness, and, in refractory thyroid cancer, may warrant exploration as a site for targeted therapy.

show abstract

Section: Introductionmentioning

confidence: 99%

Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma

Caria

Cantara

Frau

et al. 2016

IJMS

View full text Add to dashboard Cite

show abstract

“…Also, recurrences and distant metastases were the main causes of the failure of differentiated thyroid cancer therapy [24, 25]. To examine the synergistic effect of BKM120 and Prima-1 Met on cell migration and invasion, wound-healing assay and transwell assay were performed in THJ-29T and FTC-133 cells.…”

Section: Resultsmentioning

confidence: 99%

Synergistic Antitumor Effect of BKM120 with Prima-1Met Via Inhibiting PI3K/AKT/mTOR and CPSF4/hTERT Signaling and Reactivating Mutant P53

Xu²,

Li³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: PI3KCA and mutant p53 are associated with tumorigenesis and the development of cancers. NVP-BKM120, a selective pan-PI3K inhibitor, exerts the antitumor activity by suppressing the PI3K signaling pathway. Prima-1^Met, a low molecular weight compound, can rescue the gain-of-function of mutant p53 by restoring its transcriptional function. In this study, we investigated whether PI3K inhibition combined with mutant p53 reactivation could enhance the antitumor effect in thyroid cancer cells. Methods: The effects of BKM120 and Prima-1^Met on the proliferation, apoptosis, migration and invasion of thyroid cancer cells were measured by MTT, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Thyroid differentiation was assessed by detecting the expression levels of specific markers using RT-PCR and Western blot. The in vivo antitumor efficacy was analyzed in a mouse xenograft model. Results: The combinational treatment of BKM120 and Prima-1^Met significantly enhanced the inhibitions of cell viability, colony formation, migration and invasion, and the induction of apoptosis in thyroid cell lines, and synergistically suppressed tumor xenograft growth by inhibiting the PI3K/Akt/mTOR and EMT signaling pathways, up-regulating p53 targeted genes, and triggering the release of cytochrome c. Moreover, the combination of BKM120 and Prima-1^Met suppressed the stemlike traits of thyroid cancer cells and promoted their differentiation by upregulating the expression of thyroid-specific differentiation markers and repressing the expression of cancer stem cell markers. Furthermore, the mechanism study demonstrated that the combinational treatment synergistically abrogated the binding of CPSF4 at the promoter of hTERT and thus suppressed hTERT expression. Consistently, overexpression of hTERT rescued the inhibitions of cell viability, invasion and stem-like traits mediated by the combination of BKM120 and Prima-1^Met. Conclusion: Our results showed that the combination of BKM120 with Prima-1^Met synergistically suppressed the growth of thyroid cancer cells and tumor xenografts via inhibiting PI3K/Akt/mTOR and CPSF4/hTERT signaling and reactivating mutant p53.

show abstract

“…Notably, thyroidectomy and thyroid hormone suppression therapy with or without thyroid cancer remnant and metastasis ablation by radioiodine treatment are widely accepted as routine therapies for WDTC (2). However, during these treatment, around 30% of WDTC may progress to dedifferentiated thyroid cancer (DeTC), a state occupying an intermediate position in both morphology and behavior between WDTC and anaplastic thyroid cancer (ATC) (5,6). DeTC was characterized by aggressive growth, distant metastasis, recurrence, in particularly, resistance to radioiodide therapy and finally resulted in powerless in DeTC treatment.…”

Section: Introductionmentioning

confidence: 99%

“…The sodium/iodide symporter (SLC5A5, also named as NIS) is a key cytomembrane glycoprotein that mediates active transport of iodide in the thyroid, which plays a central role in the treatment of DeTC (9)(10)(11). The mechanisms of resistance to radioiodine are based on decreased expression of NIS, diminished plasma membrane localization of NIS, or both, which are caused by key genetic and epigenetic alterations and dysregulated signaling pathways (6,(11)(12)(13)(14)(15). Many of mutations possibly resulting in thyroid cell dedifferentiation, lead to the activation of two major signaling pathways: phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways (2,16,17).…”

Section: Introductionmentioning

confidence: 99%

Nevirapine Increases Sodium/Iodide Symporter-Mediated Radioiodide Uptake by Activation of TSHR/cAMP/CREB/PAX8 Signaling Pathway in Dedifferentiated Thyroid Cancer

Shang

Zhao

Yao³

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

New Therapies for Dedifferentiated Papillary Thyroid Cancer

Cited by 48 publications

References 173 publications

Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma

Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma

Synergistic Antitumor Effect of BKM120 with Prima-1Met Via Inhibiting PI3K/AKT/mTOR and CPSF4/hTERT Signaling and Reactivating Mutant P53

Nevirapine Increases Sodium/Iodide Symporter-Mediated Radioiodide Uptake by Activation of TSHR/cAMP/CREB/PAX8 Signaling Pathway in Dedifferentiated Thyroid Cancer

Contact Info

Product

Resources

About