Immunotherapy and ferroptosis regulation in thyroid cancer: Novel strategies and future perspectives.

Epidemiology of Thyroid Cancer.

PurposePathogenic fusion events involving neurotrophic receptor tyrosine kinase (NTRK) have been described in ~ 2% of differentiated thyroid cancer (DTC). The selective tropomyosin receptor kinase (TRK) inhibitors entrectinib and larotrectinib have been approved in a tumor agnostic manner based on phase 1/2 clinical trials. In a real-world setting at five referral centers, we aimed to describe the prevalence of NTRK gene fusions and the efficacy and safety of TRK inhibitor treatment for non-medullary, advanced thyroid cancer (TC).MethodsA total of 184 TC patients with testing for NTRK gene fusions were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan–Meier method in six patients with NTRK fusion-positive TC who underwent TRK inhibitor therapy.Results8/184 (4%) patients harbored NTRK gene fusions. Six patients with radioiodine (RAI)-refractory TC harboring NTRK1 (n = 4) and NTRK3 (n = 2) gene fusions were treated with larotrectinib. Five patients (83%) had received ≥ 1 prior systemic therapy and one patient did not receive prior systemic therapy. All patients had morphologically progressive disease before treatment initiation. Objective response rate was 83%, including two complete remissions. Median PFS from start of TRK inhibitor treatment was 23 months (95% confidence interval [CI], 0–57.4) and median OS was not reached (NR) (95% CI, NR). Adverse events were of grade 1–3.ConclusionThe prevalence of NTRK gene fusions in our cohort of RAI-refractory TC is slightly higher than reported for all TC patients. Larotrectinib is an effective treatment option in the majority of NTRK gene fusion-positive advanced TC patients after prior systemic treatment and has a favorable safety profile.

Simple SummaryThyroid cancer is the most common endocrine malignancy. Patients with advanced thyroid cancers have poor survival rates, largely because of limited therapeutic options to combat their aggressive nature, creating a compelling need to identify novel therapeutic targets. We and others have previously shown that Src is a clinically relevant target in thyroid cancer and that combined inhibition of Src and the MAP kinase pathway results in enhanced anti-tumor responses. The goals of this study were to identify the mechanism(s) mediating these anti-tumor effects and identify additional potential biomarkers of response to improve therapies for patients with advanced thyroid cancer.Patients with advanced thyroid cancer, including advanced papillary thyroid cancer and anaplastic thyroid cancer (ATC), have low survival rates because of the lack of efficient therapies available that can combat their aggressiveness. A total of 90% of thyroid cancers have identifiable driver mutations, which often are components of the MAPK pathway, including BRAF, RAS, and RET-fusions. In addition, Src is a non-receptor tyrosine kinase that is overexpressed and activated in thyroid cancer, which we and others have shown is a clinically relevant target. We have previously demonstrated that combined inhibition of Src with dasatinib and the MAPK pathway with trametinib synergistically inhibits growth and induces apoptosis in BRAF- and RAS-mutant thyroid cancer cells. Herein, we identified the pro-apoptotic protein BCL2L11 (BIM) as being a key mediator of sensitivity in response to combined dasatinib and trametinib treatment. Specifically, cells that are sensitive to combined dasatinib and trametinib treatment have inhibition of FAK/Src, MEK/ERK, and AKT, resulting in the dramatic upregulation of BIM, while cells that are resistant lack inhibition of AKT and have a dampened induction of BIM. Inhibition of AKT directly sensitizes resistant cells to combined dasatinib and trametinib but will not be clinically feasible. Importantly, targeting BCL-XL with the BH3-mimeitc ABT-263 is sufficient to overcome lack of BIM induction and sensitize resistant cells to combined dasatinib and trametinib treatment. This study provides evidence that combined Src and MEK1/2 inhibition is a promising therapeutic option for patients with advanced thyroid cancer and identifies BIM induction as a potential biomarker of response.

An open label, multicenter, phase II study of dovitinib in advanced thyroid cancer

The association of low socioeconomic status with advanced stage thyroid cancer

Simple SummaryRecently, selpercatinib, a highly selective inhibitor of RET receptor tyrosine kinase, has been used for RET-altered thyroid cancer. However, real-world data of its effectiveness and safety in various clinical situations are lacking. We present four cases of patients with advanced thyroid cancer who were treated with selpercatinib with variable clinical situations. Selpercatinib showed good efficacy in all four patients without significant side effects. Despite facing varying clinical obstacles of the real world, selpercatinib safely proved remarkable therapeutic efficacy, although drug safety and durability through long-term use should be further validated.Recently, selpercatinib, a highly selective inhibitor of RET receptor tyrosine kinase, has been used for RET-altered thyroid cancer. We present four cases of patients with advanced thyroid cancer who were treated with selpercatinib. The first patient was a 63-year-old male with advanced medullary thyroid cancer (MTC) treated with vandetanib. Six months ago, he had an intracranial hemorrhage and swallowing difficulty. He started selpercatinib with percutaneous endoscopic gastrostomy (PEG). For 11 months, a partial response (PR) was observed stably with PEG administration without any more cardiovascular events. The second patient was a 67-year-old female with advanced MTC treated with vandetatib. After selpercatinib treatment, a PR was observed for most metastatic sites, including choroidal metastasis. The third patient was a 32-year-old female with advanced papillary thyroid cancer (PTC) without history of systematic treatment. For six months, a PR was observed at her metastatic site with manageable adverse events. The last patient was a 59-year-old female with advanced PTC treated with lenvatinib. She suffered from a panic disorder and pleural pain due to metastasis during lenvatinib treatment. After selpercatinib treatment, her pain and panic symptoms were improved. Facing varying clinical obstacles of the real world, selpercatinib safely proved remarkable therapeutic efficacy regardless of previous treatment or metastatic site.

Frontiers in Thyroid Cancer: December 2009

BackgroundThere is a high unmet need for effective systemic treatment for patients with metastatic radioactive iodine refractory (RAI-R) differentiated thyroid cancer (DTC) and anaplastic thyroid cancer (ATC). Immunotherapy may be...

NKX2-1 is a homeodomain transcription factor, known as a master regulator of thyroid development. NKX2-1 is also crucial for lung epithelium differentiation, and the involvement of NKX2-1 in lung carcinogenesis and cancer progression has been intensely investigated. However, the role of NKX2-1 in thyroid cancer progression remains elusive. The Cancer Genome Atlas (TCGA) dataset analysis demonstrated that papillary thyroid cancer (PTC) patients with low NKX2-1 mRNA expression had significantly poorer prognosis than those with a combination of intermediate and high mRNA expression of NKX2-1. Lentivirus-transduced tetracycline (Tet)-inducible system was used to achieve NKX2-1 overexpression in advanced follicular thyroid cancer (FTC) cell lines, FTC-238 and WRO, and an anaplastic thyroid cancer (ATC) cell line 8305C, in which NKX2-1 expression is barely/not detected. All these thyroid cancer cell lines showed significant suppression of cell proliferation with NKX2-1 overexpression. In addition, NKX2-1 overexpression inhibited migration of FTC-238 cells. The levels of mRNA and protein expression of mesenchymal markers, matrix metalloproteinase-2 (MMP-2) and fibronectin, were decreased by NKX2-1 overexpression in FTC-238 cells, suggesting a possibility that NKX2-1 partially inhibits epithelial-mesenchymal transition (EMT). SNAIL and SLUG are essential EMT transcription factors involved in metastasis in cancer progression. NKX2-1 mRNA expression was significantly lower in high SNAI1 (encoding SNAIL) expressing PTC in TCGA database. Indeed, suppression of SNAIL protein expression was found upon overexpression of NKX2-1 in FTC-238 cells which naturally express high level of SNAIL. These findings suggest that NKX2-1 may inhibit the migration of advanced thyroid cancer cells through SNAIL-induced EMT. Similarly, suppression of SLUG protein expression by overexpression of NKX2-1 was observed in WRO and 8305C cells which express high level of SLUG protein. Whether NKX2-1 overexpression inhibits migration and invasion of WRO and 8305C cells through SLUG-induced EMT is currently under examination. The Tet-inducible NKX2-1 expressing thyroid cancer cells will be used for in vivo evaluation of their metastatic ability using an immunocompromised mouse model. The findings so far suggest that NKX2-1 exerts a tumor suppressive activity in advanced thyroid cancers through suppression of cell proliferation, and cell migration presumably via suppression of EMT transcription factors. Citation Format: Yo-Taro Shirai, Shioko Kimura. Tumor suppressive role of NKX2-1 in advanced thyroid cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 207.

The sharply increasing incidence of thyroid cancer has attracted considerable attention over the last few years. The combination of surgery, radioiodine ablation and thyroid-stimulating hormone suppression is usually efficient for the majority of thyroid tumors. However, advanced thyroid cancer that is recurrent, metastatic and 131I-refractory, or medullary thyroid cancer, pose a therapeutic challenge. Autophagy is a process that metabolizes damaged cytoplasmic organelles and long-lived proteins in order to recycle cellular materials and maintain homeostasis. It has been confirmed that autophagy plays a dual role during cancer development, progression and treatment, mainly depending on the type and stage of the tumor. Autophagy modulation has become a potential therapeutic target for diverse diseases. The mechanism of thyroid tumorigenesis and cancer progression was largely demonstrated to be correlated with the dysregulation of the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathways, as well as with abnormal epigenetic modifications. Those mechanisms are associated with autophagy regulation and may be beneficial for the treatment of advanced thyroid cancer. However, the number of available studies on the role of autophagy in thyroid cancer development, progression and treatment outcome, is currently limited. The aim of this review was to elaborate on the relevant knowledge and future prospectives of autophagy in the treatment of thyroid cancer.

Thyroid cancer is the most common endocrine malignancy, with over 60,000 cases reported per year in the US alone. The incidence of thyroid cancer has increased in the last several years. Patients with metastatic differentiated thyroid cancer (DTC) generally have a good prognosis. Metastatic DTC can often be treated in a targeted manner with radioactive iodine, but the ability to accumulate iodine is lost with decreasing differentiation. Until recently, chemotherapy was the only treatment in patients with advanced thyroid cancer, which is no longer amenable to therapy with radioactive iodine. The modest efficacy and significant toxicity of chemotherapy necessitated the need for urgent advances in the medical field. New insights in thyroid cancer biology propelled the development of targeted therapies for this disease, including the tyrosine kinase inhibitor sorafenib as salvage treatment for DTC. In 2015, the US Food and Drug Administration approved a second tyrosine kinase inhibitor, lenvatinib, for the treatment of radioiodine-refractory thyroid cancer. Although associated with a significant progression-free survival improvement as compared to placebo in a large Phase III study (median progression-free survival 18.2 vs 3.6 months; hazard ratio 0.21; 99% confidence interval 0.14–0.31; P<0.001), the benefit of lenvatinib needs to be proved in the context of associated moderate to severe toxicities that require frequent dose reduction and delays. This article reviews the evidence supporting the use of lenvatinib as salvage therapy for radioactive iodine-refractory thyroid cancer, with a focus on the toxicity profile of this new therapy.

Thyroid cancer (TC) represents the most prevalent malignancy within the endocrine system. In recent years, there has been a marked global increase in the incidence of thyroid cancer, garnering substantial scientific interest. Comprehensive investigations into the pathogenesis of TC have identified a significant association with ferroptosis, a newly characterized form of cell death mediated by iron ions. Distinct from apoptosis, necrosis, and autophagy, ferroptosis is characterized by the accumulation of lipid peroxides and reactive oxygen species, culminating in cellular damage and death.Recent research has elucidated a connection between ferroptosis and the initiation, progression, and treatment of thyroid cancer. These findings underscore the significance of ferroptosis in thyroid cancer and offer valuable insights into the development of novel therapeutic strategies and precise predictive markers. The unique mechanisms of ferroptosis present opportunities for targeting treatment-resistant thyroid cancers. Consequently, the regulation of ferroptosis may emerge as a novel therapeutic target, potentially addressing the limitations of current treatments. Moreover, elucidating the molecular mechanisms underpinning ferroptosis in thyroid cancer may facilitate the identification of novel biomarkers for early detection and prognostication. This review endeavors to synthesize the extant knowledge regarding the role of ferroptosis in thyroid cancer, examine potential therapeutic implications, and propose future research trajectories to enhance the understanding and clinical application of ferroptosis.

Disclosure: D. Chen: None. M. Banerjee: None. T. Xu: None. F.P. Worden: None. M.R. Haymart: None. Background. Since 2011, the United States Food and Drug Administration (FDA) has approved eight small-molecule kinase inhibitors (SMKIs) for the treatment of advanced thyroid cancer (i.e., radioiodine-refractory metastatic differentiated thyroid cancer, metastatic medullary thyroid cancer, and anaplastic thyroid cancer). The National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend use of 15 SMKIs, of which eight are FDA-approved and seven are commercially available, for the treatment of advanced thyroid cancer. However, little is known about how these medications are used in the real-world setting for treatment of patients with advanced thyroid cancer. Methods. This descriptive study used data from Optum Clinformatics Data Mart, a de-identified commercial claims database of a large national health insurance provider. We identified patients with thyroid cancer who had prescription claims for at least one of the 15 SMKIs of interest (axitinib, cabozantinib, dabrafenib, entrectinib, everolimus, larotrectinib, lenvatinib, pazopanib, pralsetinib, selpercatinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib). Lines of therapy were defined by the date of SMKI claims. We describe changes in usage patterns over time with a focus on the demographics of patients who were newly initiated on treatment of advanced thyroid cancer, and on the medications used for each line of therapy. Results. Between 2013-2021, 886 patients were treated for advanced thyroid cancer with at least one of the 15 SMKIs of interest. Median age was 65.1 years. Most patients were female (54.6%), non-Hispanic White (62.1%), and had supplementary Medicare insurance (60.6%). Between 2013 and 2016, there was an increase in the proportion of Hispanic patients and a corresponding decrease in the proportion of non-Hispanic White patients treated for advanced thyroid cancer. Although most patients were initiated on an FDA-approved SMKI as first line therapy, 23.1% (N=205) were initiated on a commercially available SMKI. Sorafenib was the most prescribed first-line therapy in 2013 (24.4%) and 2014 (48.3%). Lenvatinib was the most prescribed first-line therapy between 2015-2021 when prescriptions for lenvatinib constituted 38.3-55.6% of all SMKIs prescribed for the treatment of advanced thyroid cancer. Between 2017-2021, a minority of patients were treated with up to a fifth line of therapy although the majority (81.8%) were treated with only a first line agent. Conclusions. Since 2015 when lenvatinib was approved by the FDA for treatment of advanced differentiated thyroid cancer, it has become the most commonly prescribed SMKI for treatment of advanced thyroid cancer. However, variation exists in which SMKIs are used to treat patients with advanced thyroid cancer, with almost one-quarter of patients initiated on commercially available SMKIs. Presentation Date: Saturday, June 17, 2023

6020 Background: There are few effective treatments for locally advanced or metastatic thyroid cancers that are refractory to radioactive iodine (RaI). The epidermal growth factor receptor (EGFR) is highly expressed on normal and malignant thyroid tissue, and has been associated with a worse prognosis in well-differentiated thyroid cancer. The EGFR tyrosine kinase inhibitor gefitinib is effective in inhibiting the growth of thyroid cancer cells in vitro. This study sought to determine the efficacy and tolerability of gefitinib in patients with advanced thyroid cancer. Methods: In this open-label phase II trial, patients with RaI-refractory, locally advanced or metastatic thyroid cancer received 250mg of daily gefitinib. Anaplastic and medullary thyroid carcinoma were considered RaI refractory based on histology. The primary endpoint was overall response rate. Secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), and tumor marker responses. Tumor markers consisted of serum thyroglobulin (Tg) in the differentiated cancers and serum calcitonin and carcinoembryonic antigen in medullary thyroid cancer. Results: A total of 27 patients were enrolled. 59% were male and the median age was 65. Histologic subtypes included papillary (41%), follicular (22%), anaplastic (19%), medullary (15%), and Hürthle cell carcinoma (4%). There were no objective tumor responses among the 25 patients evaluated, at which point the trial was halted. However, 32% of patients had objective reductions in tumor volume that did not meet criteria for PR. 48%, 24%, and 12% of patients had stable disease (SD) after 3, 6, and 12 months of treatment. Median PFS and OS were 3.7 [95% CI; 1.8, 5.7] and 17.5 months [9.2, not yet reached]. Five patients with SD had a decrease in Tg to &lt;90% of baseline level that was maintained for at least 3 months. Gefitinib was well tolerated, with 11% of patients experiencing grade 3 toxicity. Conclusions: Gefitinib therapy did not result in any objective tumor responses. However, reductions in tumor volume, falling Tg levels, and prolonged SD in a subset of patients may indicate biologic activity. The OS of 17.5 months was superior to historical rates in this population. However, the significance of this is difficult to interpret in the absence of a randomized comparison group. No significant financial relationships to disclose.

Thyroid cancer is the most common endocrine neoplasia and represents approximately 1.5% to 2.1% of all cancers diagnosed annually worldwide. Iodine Refractory Differentiated Thyroid Carcinoma (RR-DTC) and advanced/metastatic medullary thyroid carcinoma are relatively uncommon yet prognostically significant thyroid cancers. Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers, including thyroid cancer. Many Multi-Kinase Inhibitors (MKIs) which are now FDA-/EMA approved for thyroid cancer have shown clinical benefit in patients with advanced cancer. Treatment related toxicities occur frequently with these drugs and can be severe or life-threatening. This review summarizes the role of targeted therapy with MKIs in the management of RRDTC and advanced/metastatic MTC patients, focusing on side-effect profiles of these drugs, with a presentation of several recent patents published in this field. We review the scientific literature on advanced thyroid cancer and analyze the International Pharmacovigilance database (FAERS, Eudravigilance, and WHO Vigibase) for adverse drug reactions. This systematic analysis highlights the difference in the safety profile of the recent drugs used in the treatment of advanced thyroid cancer and the recent discoveries for diagnosis or treatment of the thyroid cancer. It is essential to investigate the safety profile of recent anticancer drugs for advanced thyroid cancer to allow health professionals to make the best choice for each patient by conducting risk/benefit assessment.