Mitogen-Activated Protein Kinase Pathway Inhibition for Redifferentiation of Radioiodine Refractory Differentiated Thyroid Cancer: An Evolving Protocol

Iravani, Amir; Solomon, Benjamin; Pattison, David A.; Jackson, Price; Kumar, Aravind Ravi; Kong, Grace; Hofman, Michael S; Akhurst, Tim; Hicks, Rodney J.

doi:10.1089/thy.2019.0143

Cited by 88 publications

(75 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…28 A new study suggested that MAPK pathway inhibition or BRAF inhibitor could inverse RAI-refractory TC. 29 On the other hand, the effect of RAI in poorly differentiated patients with PM might be explained by the well-differentiated variant of metastatic lesions, which need further study and more evidence. Furthermore, the dose of radioiodine could make difference.…”

Section: Discussionmentioning

confidence: 99%

Radioactive Iodine Therapy in Patients With Thyroid Carcinoma With Distant Metastases: A SEER-Based Study

2020

Cancer Control

View full text Add to dashboard Cite

Distant metastasis (DM) is the dominant negative prognosis for thyroid carcinoma. Radioactive iodine (RAI) therapy serves as an effective treatment for thyroid carcinoma. However, resistance to RAI occurs in patients with DMs. The present study aims to discriminate patients who may benefit from RAI. We extracted patients with thyroid cancer in the Surveillance, Epidemiology, and End Results program and analyzed thyroid cancer–specific survival after radiotherapy based on age and grade subgroups. A total of 1608 patients having DMs were eligible, including 521 (32.4%) cases with bone metastasis, 90 (5.6%) cases with brain metastasis, 158 (9.8%) cases with liver metastasis, 995 (61.9%) cases with lung metastasis, and 50 (3.1%) cases with other metastases. Advanced age, poor differentiation, follicular carcinoma, lymphatic metastasis, tumor size >10 mm, and extracapsular invasion are associated with pulmonary metastases. With respect to patients with DM, RAI therapy improved the survival in the age <45 years group and the well-/moderately differentiated group. For patients with pulmonary metastasis, RAI improved the survival in the higher grade group but did not have a strong effect in the better grade group. Our data indicate that the disparity of metastatic sites has different risk factors. Similarly, this finding indicates that RAI should be precisely applied to patients who undergo DM but are young and have well-/moderately differentiated tumors and may improve survival in pulmonary metastasis patients with poor grade tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Radioactive Iodine Therapy in Patients With Thyroid Carcinoma With Distant Metastases: A SEER-Based Study

2020

Cancer Control

View full text Add to dashboard Cite

show abstract

“…Patients with tumors harboring an NRAS mutations are treated with the MEK inhibitor trametinib, while those with tumors characterized by BRAF V600E mutation are treated with combination therapies, including BRAF inhibitors such as dabrafenib and vemurafenib and MEK inhibitors ( Figure 3 ). Preliminary data suggest high efficacy of such an approach with partial response to RAI therapy at three months’ follow-up observed in all patients who achieved sufficient restoration of RAI uptake [ 110 ]. A similar concept is being utilized in another ongoing multicentric prospective non-randomized phase II trial with two independent arms studying the use of trametinib for NRAS mutation-harboring tumors and dabrafenib for BRAF V600E -harboring tumors ( identifier NCT03244956) ( Table 2 ).…”

Section: Targeted Therapies For Thyroid Cancermentioning

confidence: 99%

Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

Al-Jundi

Thakur

Gubbi

et al. 2020

Cancers

View full text Add to dashboard Cite

The knowledge on thyroid cancer biology has grown over the past decade. Thus, diagnostic and therapeutic strategies to manage thyroid cancer are rapidly evolving. With new insights into tumor biology and cancer genetics, several novel therapies have been approved for the treatment of thyroid cancer. Tyrosine kinase inhibitors (TKIs), such as lenvatinib and sorafenib, have been successfully utilized for the treatment of radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC). In addition, pretreatment with mitogen-activated protein kinase (MAPK) inhibitors (trametinib and selumetinib) has been shown to restore RAI avidity in previously RAI-refractory DTCs. Local therapies, such as external beam radiation and radiofrequency/ethanol ablation, have also been employed for treatment of DTC. Vandetanib and cabozantinib are the two TKIs currently approved by the Food and Drug Administration (FDA) for the treatment of medullary thyroid cancer (MTC). Other novel therapies, such as peptide receptor radionuclide therapy and carcinoembryonic antigen (CEA) vaccine, have also been utilized in treating MTC. Ongoing trials on selective rearranged-during-transfection (RET) protooncogene inhibitors, such as LOXO-292 and BLU-667, have demonstrated promising results in the treatment of metastatic MTC resistant to non-selective TKIs. The FDA-approved BRAF/MEK inhibitor combination of dabrafenib and trametinib has revolutionized treatment of BRAFV600E mutation positive anaplastic thyroid cancer. Several other emerging classes of medications, such as gene fusion inhibitors and immune checkpoint inhibitors, are being actively investigated in several clinical trials. In this review, we describe the molecular landscape of thyroid cancer and novel targeted therapies and treatment combinations available for the treatment of metastatic thyroid cancer.

show abstract

“…Based on these in vitro and in vivo data, pilot studies and phase 2 trials demonstrated that two selective BRAF inhibitors, namely Vemurafenib and Dabrafenib, are able to stimulate radioiodine uptake in patients with metastatic BRAF V600E -mutant RAI-R DTCs [11][12][13][14][15][16]. In addition, attempts of reverse RAI refractoriness in TC patients restoring radioiodine uptake, have been conducted with MEK inhibitors, tested as single agent [17] or, more recently, in combination with BRAF inhibitors [18,19].…”

Section: Introductionmentioning

confidence: 99%

The molecular and gene/miRNA expression profiles of radioiodine resistant papillary thyroid cancer

Colombo

Minna

Gargiuli

et al. 2020

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Papillary thyroid cancer (PTC) is the most frequent endocrine tumor. Radioiodine (RAI) treatment is highly effective in these tumors, but up to 60% of metastatic cases become RAI-refractory. Scanty data are available on either the molecular pattern of radioiodine refractory papillary thyroid cancers (PTC) or the mechanisms responsible for RAI resistance. Methods We analyzed the molecular profile and gene/miRNA expression in primary PTCs, synchronous and RAI-refractory lymph node metastases (LNMs) in correlation to RAI avidity or refractoriness. We classified patients as RAI+/D+ (RAI uptake/disease persistence), RAI−/D+ (absent RAI uptake/disease persistence), and RAI+/D- (RAI uptake/disease remission), and analyzed the molecular and gene/miRNA profiles, and the expression of thyroid differentiation (TD) related genes. Results A different molecular profile according to the RAI class was observed: BRAFV600E cases were more frequent in RAI−/D+ (P = 0.032), and fusion genes in RAI+/D+ cases. RAI+/D- patients were less frequently pTERT mutations positive, and more frequently wild type for the tested mutations/fusions. Expression profiles clearly distinguished PTC from normal thyroid. On the other hand, in refractory cases (RAI+/D+ and RAI−/D+) no distinctive PTC expression patterns were associated with either tissue type, or RAI uptake, but with the driving lesion and BRAF−/RAS-like subtype. Primary tumors and RAI-refractory LNMs with BRAFV600E mutation display transcriptome similarity suggesting that RAI minimally affects the expression profiles of RAI-refractory metastases. Molecular profiles associated with the expression of TPO, SLC26A4 and TD genes, that were found more downregulated in BRAFV600E than in gene fusions tumors. Conclusions The present data indicate a different molecular profile in RAI-avid and RAI-refractory metastatic PTCs. Moreover, BRAFV600E tumors displayed reduced differentiation and intrinsic RAI refractoriness, while PTCs with fusion oncogenes are RAI-avid but persistent, suggesting different oncogene-driven mechanisms leading to RAI refractoriness.

show abstract

Mitogen-Activated Protein Kinase Pathway Inhibition for Redifferentiation of Radioiodine Refractory Differentiated Thyroid Cancer: An Evolving Protocol

Cited by 88 publications

References 43 publications

Radioactive Iodine Therapy in Patients With Thyroid Carcinoma With Distant Metastases: A SEER-Based Study

Radioactive Iodine Therapy in Patients With Thyroid Carcinoma With Distant Metastases: A SEER-Based Study

Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

The molecular and gene/miRNA expression profiles of radioiodine resistant papillary thyroid cancer

Contact Info

Product

Resources

About