Treatment Of Anaplastic Thyroid Cancer Research Articles

Knowledge mapping of anaplastic thyroid cancer treatments: a bibliometric analysis (2000-2023).

Anaplastic thyroid cancer (ATC) is a relatively rare and extensively malignant kind of thyroid carcinoma. The poor prognosis and high mortality rate of ATC can be attributed to its invasive features and undifferentiated phenotype. At present, there is a lack of efficacious therapeutic options. In light of the elevated fatality rate, it is vital to possess a comprehensive comprehension of the scientific terrain pertaining to ATC. To gather the perspectives of different researchers about the topic of ATC treatment, we did a bibliometric network analysis, which offers a comprehensive view of the scholarly literature. A systematic search was conducted on the WoSCC database to identify publications pertaining to ATC treatment between the years 2000 and 2023. In this bibliometric investigation, the tools VOSviewers, CiteSpace, and the R package "bibliometrix" were employed to investigate the general attributes, developmental framework, and academic frontiers of the subject matter. 1223 publications in total, written by 6937 scholars from 53 areas and 1402 institutions and published in 358 scholarly journals, were analyzed. There has been a gradual increase in the quantity of publications pertaining to ATC treatment. The United States and China emerged as the most prominent nations. The University of Texas MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Counseling Center are prominent research institutions in highly productive countries. The journal Thyroid holds a prominent position within its discipline, being widely recognized as both the most popular and highly co-cited publication. According to the available data, Maria Cabanillas has authored the highest number of published articles, while RC Smallridge has received the highest number of co-citations. It turned out that the prevailing keywords encompassed expression, therapy, apoptosis, survival, activation, proliferation, metastasis, and other related terms. Immunotherapy, targeted therapy, and prognostic factors are the emerging research hotspots and trends. This paper presents a complete overview of research trends and advancements in the treatment of ATC using bibliometric analysis. The acquisition of information will offer vital insights for funding and potential creative strategies in researching the treatment of ATC, which indicates the research frontiers as well as prevalent directions in recent years.

Selective inhibition of DNA ligase IV provides additional efficacy to the treatment of anaplastic thyroid cancer.

Although the incidence of anaplastic thyroid carcinoma (ATC) is low (2.5% of thyroid cancer cases), this cancer has a very poor prognosis (survival rates < 5 months) and accounts for 14-39% of deaths. Conventional therapies based on surgery in combination with radiotherapy or chemotherapy showed limited effectiveness primarily due to the robust and protective DNA damage response in thyroid cancer cells. We used single-cell transcriptomic data from patients with different subtypes of thyroid cancer to study expression of genes involved in homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. Then, we investigated the mechanisms of DNA damage and repair in anaplastic (C643 and Hth74) and papillary (TPC-1) thyroid cancer cell lines. The effect of caffeine (inhibitor of ATM and ATR) and UCN-01 (CHK1 inhibitor) was evaluated in cell cycle progression of thyroid cancer cells after γ-radiation or doxorubicin treatment. The DNA damage response was monitored after staining of phosphorylated γ-H2AX and 53BP1. Reporter plasmids were used to determine the efficacy of double-strand DNA breaks (DSBs) repair by HR and NHEJ in thyroid cancer cells. We evaluated the combination of selective inhibition of the DNA ligase IV by SCR7 and doxorubicin on cellular apoptosis and tumor growth in xenograft murine models of anaplastic thyroid cancer. Single-cell RNA-Seq showed that NHEJ- and HR-related genes are expressed in ATC and PTC patients. We showed that ATC cells undergo mitosis in the presence of unrepaired DNA damage caused by γ-radiation and doxorubicin treatment. To proliferate and survive, these cells efficiently repair DNA lesions using homologous recombination (HR) and non-homologous end joining (NHEJ). The combination of SCR7 with doxorubicin, significantly increased apoptosis and impaired ATC tumor growth in a xenograft mouse model compared to doxorubicin monotherapy. This study shows the therapeutic value of the combination of a DNA ligase IV inhibitor and DNA-damaging agents (doxorubicin and/or γ-radiation) for the treatment of anaplastic thyroid cancer.

Anaplastic thyroid cancer cells reduce CD71 levels to increase iron overload tolerance

BackgroundFollicular thyroid cancer (FTC) is a prevalent form of differentiated thyroid cancer, whereas anaplastic thyroid cancer (ATC) represents a rare, fast-growing, undifferentiated, and highly aggressive tumor, posing significant challenges for eradication. Ferroptosis, an iron-dependent cell death mechanism driven by the excessive production of reactive oxygen species and subsequent lipid peroxidation, emerges as a promising therapeutic strategy for cancer. It has been observed that many cancer cells exhibit sensitivity to ferroptosis, while some other histotypes appear to be resistant, by counteracting the metabolic changes and oxidative stress induced by iron overload.MethodsHere we used human biopsies and in vitro approaches to analyse the effects of iron-dependent cell death. We assessed cell proliferation and viability through MTT turnover, clonogenic assays, and cytofluorimetric-assisted analysis. Lipid peroxidation assay and western blot were used to analyse molecular mechanisms underlying ferroptosis modulation. Two distinct thyroid cancer cell lines, FTC-133 (follicular) and 8505C (anaplastic), were utilized. These cell lines were exposed to ferroptosis inducers, Erastin and RSL3, while simulating an iron overload condition using ferric ammonium citrate.ResultsOur evidence suggests that FTC-133 cell line, exposed to iron overload, reduced their viability and showed increased ferroptosis. In contrast, the 8505C cell line seems to better tolerate ferroptosis, responding by modulating CD71, which is involved in iron internalization and seems to have a role in resistance to iron overload and consequently in maintaining cell viability.ConclusionsThe differential tolerance to ferroptosis observed in our study may hold clinical implications, particularly in addressing the unmet therapeutic needs associated with ATC treatment, where resistance to ferroptosis appears more pronounced compared to FTC.

Beneficial Role of Multi-Disciplinary Treatment for Anaplastic Thyroid Cancer with Initial Distant Metastasis

Anaplastic thyroid cancer (ATC) is a rare, highly aggressive tumor, with median survival around 5 months. Approximately half of the ATC patients presents with distant metastases at diagnosis, showing even more devastating prognosis, yet no outcome analysis had been reported. In this study, we aim to evaluate the clinical outcome of M1 ATC patients, and to define the group of patients who would benefit from local treatment based on multi-disciplinary approach. A total of 133 histology-confirmed ATC patients underwent protocol-based multidisciplinary treatment including surgery and chemoradiotherapy (CRT) between May 2016 and January 2022. Patients received intensity-modulated radiotherapy of 30 fractions concurrently with paclitaxel on days 1, 8 and 15 every 4 weeks, and lenvatinib was added upon progression. After 18 fractions of CRT, interim response analysis using modified RECIST was conducted for adaptive treatment planning. We reviewed 58 patients with distant metastasis at diagnosis (stage IVC). Overall survival (OS) and progression-free survival (PFS) were measured from the day of diagnosis. Most common metastatic site was lung (91.4%), followed by bone (31.0%) and brain (5.2%). Lenvatinib was added for 35 patients after any sign of progression. Fourteen patients received upfront surgery (16 debulking and 5 total) followed by adjuvant CRT in 16 patients. Thirty-one patients received upfront CRT with 2 patients receiving total resection after sufficient down-staging. Six (10%) patients could not complete radiotherapy but continued receiving systemic treatment. The median follow-up was 5.9 months. The median and 1-year OS were 6.2 months and 20.5%, and PFS were 3.7 months and 3.5%. Total RT dose over 60 Gy significantly improved median OS (7.5 vs 4.1 months, p = 0.012) and median PFS (4.4 vs 3.0, p = 0.010). Patients with less than 10 initial metastatic tumors showed better median OS (9.1 vs 4.6 months, p = 0.002) but not PFS (5.1 vs 3.6, p = 0.485). At interim analysis, early response (CR, PR and SD) of primary tumor was not associated with survival, while progression of distant metastases showed significantly worse median OS (9.8 vs 4.6 months, p = 0.001). More than 10 metastatic tumors (HR 2.73, 95% CI 1.32-5.66) and stable metastasis at interim analysis (HR 2.39, 95% CI 1.04-5.48) remained as significant factor in the multivariable cox regression analysis. Median OS and PFS of patients with less than 10 metastases showing no progression at interim analysis were 9.1 months, and 5.1 months. Local treatment combined with chemotherapy for M1 ATC patients showed outcome comparable to those of non-metastatic ATC results. Active local treatment should be considered especially for patients with less than 10 metastases, and patients without distant progression in early response evaluation.

Antitumor mechanism of Saikosaponin A in the Xiaoying Sanjie Decoction for treatment of anaplastic thyroid cancer by network pharmacology analysis and experiments in vitro and in vivo

Effective therapies for anaplastic thyroid cancer (ATC) are still limited due to its dedifferentiated phenotype and high invasiveness. Xiaoying Sanjie Decoction (XYSJD), a clinically empirical Chinese medicine compound, has shown positive effects for ATC treatment and recovery. However, the pharmacological mechanisms of effective active compound in XYSJD remain unclear. In this study, we aimed at elucidating the antitumor mechanism of the active compound and identifying the kernel molecular mechanisms of XYSJD against ATC. Firstly, the main chemical constituents of XYSJD were identified by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Then we used network pharmacology and ClusterONE algorithm to analyze the possible targets and pathways of the prescription and active compound Saikosaponin A (SSA). Seven core targets, including P2RY12, PDK1, PPP1CC, PPP2CA, TBK1, ITGB1 and ITGB6, which may be involved in the anti-tumor activity of XYSJD were screened. Finally, using cell biology, molecular biology and experimental zoology techniques, we investigated the mechanism of active compound SSA in the treatment of ATC. The results of qRT-PCR indicated that these seven nuclear targets might play an important role in SSA, the active compound of XYSJD. The combined data provide preliminary study of the pharmacological mechanisms of SSA in XYSJD. SSA may be a promising potential therapeutic and chemopreventive candidate for ATC.

Nanoclay Drug-Delivery System Loading Potassium Iodide Promotes Endocytosis and Targeted Therapy in Anaplastic Thyroid Cancer.

The rapid proliferative biological behavior of primary foci of anaplastic thyroid cancer (ATC) makes it a lethal tumor. According to the specific iodine uptake capacity of thyroid cells and enhanced endocytosis of ATC cells, we designed a kind of nanoclay drug-loading system and showed a promising treatment strategy for ATC. Introducing potassium iodide (KI) improves the homoaggregation of clay nanoparticles and then affects the distribution of nanoparticles in vivo, which makes KI@DOX-KaolinMeOH enriched almost exclusively in thyroid tissue. Simultaneously, the improvement of dispersibility of KI@DOX-KaolinMeOH changes the target uptake of ATC cells by improving the endocytosis and nanoparticle-induced autophagy, which regulate the production of autolysosomes and autophagy-enhanced chemotherapy, eventually contributing to a tumor inhibition rate of more than 90% in the primary foci of ATC. Therefore, this facile strategy to improve the homoaggregation of nanoclay by introducing KI has the potential to become an advanced drug delivery vehicle in ATC treatment.

Disparities in Presentation, Treatment, and Survival in Anaplastic Thyroid Cancer.

Disparities have been previously described in the presentation, management, and outcomes of other thyroid cancer subtypes; however, it is unclear whether such disparities exist in anaplastic thyroid cancer (ATC). We identified patients with ATC from the National Cancer Database (2004-2020). The primary outcomes were receipt of surgery, chemotherapy, and radiation. The secondary outcome was 1-year survival. Multivariable logistic and Cox proportional hazards regressions were used to assess the associations between sex, race/ethnicity, and the outcomes. Among 5359 patients included, 58% were female, and 80% were non-Hispanic white. Median tumor size was larger in males than females (6.5 vs. 6.0 cm; p < 0.001) and in patients with minority race/ethnicity than in white patients (6.5 vs. 6.0 cm; p < 0.001). After controlling for tumor size and metastatic disease, female patients were more likely to undergo surgical resection (odds ratio [OR]: 1.20; p = 0.016) but less likely to undergo chemotherapy (OR: 0.72; p < 0.001) and radiation (OR: 0.76; p < 0.001) compared with males. Additionally, patients from minority racial/ethnic backgrounds were less likely to undergo chemotherapy (OR: 0.69; p < 0.001) and radiation (OR: 0.71; p < 0.001) than white patients. Overall, unadjusted, 1-year survival was 23%, with differences in treatment receipt accounting for small but significant differences in survival between groups. There are disparities in the presentation and treatment of ATC by sex and race/ethnicity that likely reflect differences in access to care as well as patient and provider preferences. While survival is similarly poor across groups, the changing landscape of treatments for ATC warrants efforts to address the potential for exacerbation of disparities.

Autophagic blockade potentiates anlotinib-mediated ferroptosis in anaplastic thyroid cancer.

Anlotinib-mediated angiogenic remodeling was delineated in various tumors. Meanwhile, we previously showed that anlotinib inhibited tumor angiogenesis in anaplastic thyroid cancer (ATC). However, the potential role of anlotinib on cell lethality in ATC remains an enigma. Herein, we found that anlotinib inhibited the viability, proliferation, and migration of KHM-5M, C643, and 8505C cells in a dose-dependently manner. Under anlotinib treatment, PANoptosis (pyroptosis, apoptosis, and necroptosis) markers were not changed; however, ferroptosis targets (transferrin, HO-1, FTH1, FTL, and GPX4) were significantly downregulated. ROS levels also increased in a concentration-dependent manner after anlotinib treatment in KHM-5M, C643, and 8505C cells. In addition, protective autophagy was activated in response to anlotinib, and autophagic blockade potentiated anlotinib-mediated ferroptosis and antitumor effects in vitro and in vivo. Our new discovery identified autophagy-ferroptosis signaling pathway which provides mechanistic insight into anlotinib-mediated cell death, and synergistic combination therapy may help develop new ATC treatment strategies.

What is the best treatment for Anaplastic Thyroid Cancer?

The LaryngoscopeEarly View Triological Society Best Practice What is the best treatment for Anaplastic Thyroid Cancer? Kareem Al-Mulki MD, Kareem Al-Mulki MD Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A.Search for more papers by this authorRichard V. Smith MD, Corresponding Author Richard V. Smith MD [email protected] orcid.org/0000-0002-5216-6374 Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A. Send correspondence to Richard V. Smith, MD, Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY. Email: [email protected]Search for more papers by this author Kareem Al-Mulki MD, Kareem Al-Mulki MD Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A.Search for more papers by this authorRichard V. Smith MD, Corresponding Author Richard V. Smith MD [email protected] orcid.org/0000-0002-5216-6374 Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A. Send correspondence to Richard V. Smith, MD, Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY. Email: [email protected]Search for more papers by this author First published: 03 May 2023 https://doi.org/10.1002/lary.30724 Editor's Note: This Manuscript was accepted for publication on April 15, 2023. The authors have no funding, financial relationships, or conflicts of interest to disclose. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. BIBLIOGRAPHY 1Bible KC, Kebebew E, Brierley J, et al. 2021 American Thyroid Association Guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2021; 31(3): 337- 386. 2Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018; 36(1): 7- 13. 3Hu S, Helman SN, Hanly E, Likhterov I. The role of surgery in anaplastic thyroid cancer: a systematic review. Am J Otolaryngol. 2017; 38(3): 337- 350. 4Kwon J, Kim BH, Jung HW, Besic N, Sugitani I, Wu HG. The prognostic impacts of postoperative radiotherapy in the patients with resected anaplastic thyroid carcinoma: a systematic review and meta-analysis. Eur J Cancer. 2016; 59: 34- 45. 5Baek SK, Lee MC, Hah JH, et al. Role of surgery in the management of anaplastic thyroid carcinoma: Korean nationwide multicenter study of 329 patients with anaplastic thyroid carcinoma, 2000 to 2012. Head Neck. 2017; 39(1): 133- 139. Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Modulation of EZH2 Activity Induces an Antitumoral Effect and Cell Redifferentiation in Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is a rare and lethal form of thyroid cancer that requires urgent investigation of new molecular targets involved in its aggressive biology. In this context, the overactivation of Polycomb Repressive Complex 2/EZH2, which induces chromatin compaction, is frequently observed in aggressive solid tumors, making the EZH2 methyltransferase a potential target for treatment. However, the deregulation of chromatin accessibility is yet not fully investigated in thyroid cancer. In this study, EZH2 expression was modulated by CRISPR/Cas9-mediated gene editing and pharmacologically inhibited with EZH2 inhibitor EPZ6438 alone or in combination with the MAPK inhibitor U0126. The results showed that CRISPR/Cas9-induced EZH2 gene editing reduced cell growth, migration and invasion in vitro and resulted in a 90% reduction in tumor growth when EZH2-edited cells were injected into an immunocompromised mouse model. Immunohistochemistry analysis of the tumors revealed reduced tumor cell proliferation and less recruitment of cancer-associated fibroblasts in the EZH2-edited tumors compared to the control tumors. Moreover, EZH2 inhibition induced thyroid-differentiation genes' expression and mesenchymal-to-epithelial transition (MET) in ATC cells. Thus, this study shows that targeting EZH2 could be a promising neoadjuvant treatment for ATC, as it promotes antitumoral effects in vitro and in vivo and induces cell differentiation.

Type 2 deiodinase is expressed in anaplastic thyroid carcinoma and its inhibition causes cell senescence.

Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedifferentiation of a well-differentiated papillary or follicular thyroid cancer. Type 2 deiodinase (D2), responsible for the activation of the thyroid hormone thyroxine into tri-iodothyronine (T3), is expressed in normal thyroid cells and its expression is strongly downregulated in papillary thyroid cancer. In skin cancer, D2 has been associated with cancer progression, dedifferentiation, and epithelial-mesenchymal transition. Here, we show that D2 is highly expressed in anaplastic compared to papillary thyroid cancer cell lines and that D2-derived T3 is required for ATC cell proliferation. D2 inhibition is associated with G1 growth arrest and induction of cell senescence, together with reduced cell migration and invasive potential. Finally, we found that mutated p5372R(R248W), frequently found in ATC, is able to induce D2 expression in transfected papillary thyroid cancer cells. Our results show that the action of D2 is crucial for ATC proliferation and invasiveness, providing a potential new therapeutic target for the treatment of ATC.

Targeting SHP2 reverses BRAF inhibitor tolerance in anaplastic thyroid carcinoma.

To explore the possibility of a combination of dabrafenib and SHP2 inhibitor in the treatment of anaplastic thyroid carcinoma and to provide a new therapeutic strategy for the treatment of anaplastic thyroid cancer. Firstly, a drug resistance model was established, and the expression levels of related RTK were detected by qPCR. Western blot was used to detect the protein expression levels of Akt and MAPK signaling pathways in the control group, single-drug group and two-drug combination group. The gene silencing of SHP2 was achieved by transfection of siRNA and verified by Western blot. CCK8 kit and clone formation assay were used to detect cell proliferation activity. In vivo model of mutant thyroid cancer cells was established by subcutaneous injection of mice and then divided into four groups. Tumor diameter was measured every two days. Immunohistochemistry was used to evaluate the expression of p-ERK, p-AKT and Ki67 in mouse tumors. In this study, dabrafenib-resistant ATC cells were first constructed, and the response of RTKs in drug-resistant cells was upregulated to activate Akt and MER/ERK pathways. The activation of Akt and MEK/ERK pathways in the combination group was significantly inhibited, and the proliferation ability of tumor cells was significantly reduced compared with Dabrafenib, SHP099 group and DMSO group. To verify that SHP099 was not off-target, we also silenced SHP2 expression by transfection with siRNA and obtained the same results. Finally, by building a mouse drug resistance model, we confirmed that dabrafenib and SHP099 can also play a powerful anti-cancer effect in vivo. The SHP2 inhibitor SHP099 can effectively reverse the drug resistance of dabrafenib through inhibiting the reactivated RAS signaling pathway in anaplastic thyroid cancer.The combination of dabrafenib with SHP2 inhibitor has shown significant tumor suppressive effects for dabrafenib-resistant cells and it may be a new therapeutic strategy with longer lasting therapeutic benefits.

TARGETED THERAPY OF ANAPLASTIC THYROID CANCER

Introduction. Anaplastic thyroid cancer is an aggressive disease with meager patient survival. The tumors are often unresectable and insensitive to standard treatment methods (chemotherapy and radioiodine therapy). In recent years, much attention has been paid to new therapeutic strategies, mainly targeted therapy. The purpose of our study was to summarize the data on targeted drugs used to treat anaplastic thyroid cancer and establish the main side effects associated with their use. Materials and methods. A scientific search was conducted in Pubmed, Scopus, and Web of Science databases. The following search terms were used: "anaplastic thyroid cancer," "targeted therapy," and "clinical trials." Results. A literature search was conducted regarding targeted drugs to treat anaplastic thyroid cancer. The results of clinical trials using BRAF/MEK, RET, NTRK, mTOR, and TKI inhibitors were analyzed. Several clinical trials have demonstrated that dabrafenib, combined with trametinib, has a sufficiently high therapeutic effect and can effectively treat anaplastic thyroid cancer. Other targeted drugs show limited clinical response, such as NTRK inhibitors, TKIs, and other BRAF/MEK inhibitors. Some drugs (e.g., lenvatinib) may only be effective with other anticancer agents. RETi and mTORi are believed to have some therapeutic potential, but more than several clinical trials are needed to evaluate their effectiveness. Discussion. The main reason for the relapse of the disease and the ineffectiveness of targeted drugs is the appearance of new mutations. The RAS mutation is responsible for resistance to the combination of dabrafenib and trametinib; the S100A4 protein is responsible for the ineffectiveness of vemurafenib. Developing new drugs capable of overcoming resistance mechanisms is necessary to solve this problem. Conclusions. Targeted therapy is a promising direction in the treatment of anaplastic thyroid cancer. Side effects are common but mostly manageable.

Molecular features of aggressive thyroid cancer.

Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have a worse prognosis with respect to well differentiated TC, and the loss of the capability of up-taking 131I is one of the main features characterizing aggressive TC. The knowledge of the genomic landscape of TC can help clinicians to discover the responsible alterations underlying more advance diseases and to address more tailored therapy. In fact, to date, the antiangiogenic multi-targeted kinase inhibitor (aaMKIs) sorafenib, lenvatinib, and cabozantinib, have been approved for the therapy of aggressive radioiodine (RAI)-resistant papillary TC (PTC) or follicular TC (FTC). Several other compounds, including immunotherapies, have been introduced and, in part, approved for the treatment of TC harboring specific mutations. For example, selpercatinib and pralsetinib inhibit mutant RET in medullary thyroid cancer but they can also block the RET fusion proteins-mediated signaling found in PTC. Entrectinib and larotrectinib, can be used in patients with progressive RAI-resistant TC harboring TRK fusion proteins. In addition FDA authorized the association of dabrafenib (BRAFV600E inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAFV600E-mutated ATC. These drugs not only can limit the cancer spread, but in some circumstance they are able to induce the re-differentiation of aggressive tumors, which can be again submitted to new attempts of RAI therapy. In this review we explore the current knowledge on the genetic landscape of TC and its implication on the development of new precise therapeutic strategies.

PSAT385 Single Center Experience with the Combination of Lenvatinib and Pembrolizumab for the Treatment of Anaplastic Thyroid Cancer

Abstract Introduction Anaplastic thyroid cancer (ATC) is rare with a poor prognosis. There are no approved treatments for non-BRAF-mutated ATCs, leading to an unmet need. Phase II studies of single-agent lenvatinib or immunotherapy showed minimal benefit (lenvatinib: overall response rate (ORR) 2.9%, progression free survival (PFS) 2.6 months, overall survival (OS) 3.2 months; spartalizumab: ORR 19%, PFS 1.7 months, OS 5.9 months). Synergism between lenvatinib and pembrolizumab (L/P) has been reported. We sought to assess the efficacy and safety of L/P in ATC. Methods Thisis a retrospective, single-center study of ATC patients treated with L/P, between 1/2015-10/2021. L/P had to be started before first restaging. Those with pembrolizumab added at the time of progression on lenvatinib alone were excluded. The endpoints were ORR and PFS (primary) and OS and safety (secondary). Response evaluation was assessed by a single radiologist using RECIST v1.1. Treatment start date was the date of either lenvatinib or pembrolizumab initiation. Results 18 patients were included: 61% men; median age 64; initial stage: IVA (17%), IVB (11%), IVC (72%); common distant metastases: lung (83%), mediastinum (39%), bone (22%). Previous therapies: surgery (78%), chemoradiation (39%), cytotoxic chemotherapy (11%), palliative neck radiation (17%), BRAF-targeted therapy (6%), and immunotherapy (6%). All patients had mutation testing, and the common included TP53 (67%), PTEN (50%), TERTp (39%), NF1 (28%), RAS (22%), PIK3CA (17%), BRAF-V600E (6%). 11/12 tested tumors had a PDL-1 score &amp;gt;1%. Lenvatinib was started at 14-24 mg daily. With respect to lenvatinib, pembrolizumab was started from -14 to +49 days (median +6 days) at a fixed dose of 200 mg every 3 weeks. ORR was evaluable in 12 patients (outside hospital restaging scans unavailable in 6 patients): 1/12 (8%) confirmed complete response, 7/12 (58%) partial response (3 confirmed), 2/12 (17%) stable disease, and 2/12 (17%) progressive disease. The median PFS was 4.1 months (95% CI, 2.2 to NA), with treatment durations ranging from 0.5-33.5 months. The median OS of the 18 patients was 6.2 months (95% CI, 4.6 to NA). Respective 12-month PFS and OS rates were 25% and 22%. Grade III/IV toxicities were fatigue (22%); anorexia, weakness, arthralgia, dry mouth, pneumonitis (6%, each). AEs leading to death were pulmonary hemorrhage (17%), gastrointestinal bleed, pulmonary embolism (6%, each). Lenvatinib dose reduction, interruption, and discontinuation rates were 28%, 6%, and 28%, respectively. Pembrolizumab dose interruption and discontinuation rates were 6% and 11%, respectively. Conclusions The combination L/P had an ORR of 66%. Although most responses were short-lived, a quarter of patients benefited for more than 1 year. The ORR, PFS, and OS were better than lenvatinib alone. The toxicity profile was as expected. Our results represent the largest single-institution experience thus far with L/P in ATC and warrant further investigation (NCT04171622). Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

162 (PB042) - The effects of Aurora Kinase inhibition on thyroid cancer growth and sensitivity to MAPK-directed therapies

Background: Advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) are the leading causes of endocrine cancer death. Mutations in the MAP kinase (MAPK) pathway are common in PTC and ATC. Recently, the combination of dabrafenib (BRAFi) and trametinib (MEKi) was approved for treatment of BRAF-mutant ATC. However, combined BRAF/ MEK inhibition is rarely curative for ATC patients and has had limited responses in PTC. Here, we identify an induction of Aurora Kinase B (AURKB) in response to MEKi in cells that are resistant to combined BRAF/MEK inhibition.

MiR-200c regulates invasion, proliferation and EMT of anaplastic thyroid cancer cells by targeting parathyroid hormone like hormone

This study aimed to explore the specific effect of miR-200c in anaplastic thyroid cancer (ATC). Hth74 and ARO cell lines were used. Proliferation, invasion, and colony formation activities of Hth74 and ARO cell lines affected by miR-200c were studied. Expression of epithelial-to-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin, Slug, and Snail) in the Hth74 and ARO cell lines were validated by western blot and qRT-PCR. In addition, the regulation of the parathyroid hormone-like hormone (PTHLH) by miR-200c was assessed. Overexpression of miR-200c inhibited the invasion, proliferation, and colony formation of the ATC cell lines, whereas its downregulation achieved the opposite results. PTHLH was found to be regulated negatively by miR-200c through a miR-200c binding site within the 3′-UTR of PTHLH. miR-200c repressed the proliferation, invasion, and EMT process of cells in ATC cell lines by targeting PTHLH post-transcriptionally, which indicates that miR-200c may be a potential target for the treatment of ATC.

A Pilot Study of Durvalumab (MEDI4736) with Tremelimumab in Combination with Image-Guided Stereotactic Body Radiotherapy in the Treatment of Metastatic Anaplastic Thyroid Cancer.

Background: Metastatic anaplastic thyroid cancer (ATC) has a poor prognosis. This pilot study aims to evaluate tremelimumab plus durvalumab with stereotactic body radiotherapy (SBRT) to improve overall survival (OS). Methods: Eligible patients received up to 4 doses tremelimumab (75 mg) given q4 weeks and up to 1 year of durvalumab (1500 mg) given q4 weeks. SBRT at 9 Gy × 3 fractions was given within the first 2 weeks of the start of treatment. Paired biopsies (pretreatment and between 3 and 10 weeks after the first dose of the drug treatment) were done in the medically qualified patients. Major inclusion criteria are metastatic ATC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, no prior immunotherapy, and last anticancer treatment >7 days before starting the study. The primary endpoint was 1 year OS with the combination of durvalumab, tremelimumab, and SBRT in metastatic ATC patients with a target of 1 year OS in ≥2 out of 12 patients. Results: A total of 13 patients signed consent but only 12 patients ultimately participated in this trial. One patient who consented to the protocol became ineligible for this study due to continued decline in performance status. Patient characteristics were as follows: male (n = 6) with a median age of 71 years (range: 49-82), and ECOG = 1. Nine patients had prior neck radiation and nine patients had prior chemotherapy. Next-generation sequencing and PD-L1 staining were done in the nine patients where tissue was available. High microsatellite instability (MSI) corresponding to mismatch repair defect was noted in two patients. There were zero confirmed responses and only one patient had stable disease and was treated with ≥4 cycles of study drugs. The median time that the patients were under treatment was 11 weeks (1-28 weeks). MSI status did not affect treatment response. High MSI patients were on treatment for 8-14 weeks before disease progression. The median OS was 14.5 weeks with only 1 patient alive beyond 1 year. The presence of a BRAF or p53 mutation did not appear to affect treatment outcome. Conclusions: Tremelimumab and durvalumab with SBRT did not improve OS for ATC. Future research is needed to examine other novel immunotherapy combinations with or without radiotherapy in the treatment of ATC. Clinical Trial Registration: NCT03122496.

A pilot study of trametinib in combination with paclitaxel in the treatment of anaplastic thyroid cancer.

6088 Background: Anaplastic Thyroid Cancer (ATC) is a rare and highly aggressive tumor with extremely poor prognosis. Outside of the recent approval of dabrafenib/trametinib for BRAF mutant tumors, there are no other standard treatment available for metastatic ATC. The majority of ATC is driven through the MAPK pathway. Data in lung cancer suggested synergy with trametinib, a MEK inhibitor, and taxanes. Methods: In this pilot study we used Trametinib (2 mg) daily with Paclitaxel (80 mg/m2) administered weekly for the first 3 weeks out the 4 week-cycle. Restaging imaging was performed every 6-8 weeks (1.5-2 cycles). Eligible patients had ATC with baseline ECOG performance status ≤ 1 and were enrolled at Memorial Sloan Kettering Cancer Center. Prior treatment allowed. Prior brain metastases were allowed if treated and stable off of steroids. Primary objective was PFS at 6 months with the target of &gt; 2 subjects out of 12 at the time point. Results: 12 patients (6 men and 6 women) were enrolled between 11/2017 and 10/2021. Seven (58%) had prior radiation to the neck; 4 (33%) had prior treatment (not including with radiation) for ATC; 1 (8%) had prior brain metastases. Three (25%) partial responses were reported, and five (41.67%) reported stable disease. Subjects with partial responses had a BRAF V600E mutation (1), BRAF fusion gene (1), and a RAS mutation (1). Median time on treatment was 10.5 weeks (3-47+ weeks). Median overall survival was 26 weeks (3-59+). Six-month progression free survival (PFS) was achieved in 3 patient (25%), one of whom remains on study. 2 patients discontinued treatment due to unacceptable toxicity. The most frequent adverse events observed (all grades) were anemia (75%), increased AST, diarrhea and leukopenia (all 50%). Grade 3/4 AEs included neutropenia (25%), with anemia, AST increased, febrile neutropenia, and lymphopenia, all 16.67%. Grade 4 reactions included lymphopenia (n = 2) and leukopenia (n = 1). Conclusions: Our target progression-free survival (PFS) at 6 months was observed on this study. The combination of trametinib and paclitaxel should be evaluated in a larger cohort of patients in the future. Clinical trial information: NCT03085056.

NEDD9 links anaplastic thyroid cancer stemness to chromosomal instability through integrated centrosome asymmetry and DNA sensing regulation.

Stemness and chromosomal instability (CIN) are two common contributors to intratumor heterogeneity and therapy relapse in advanced cancer, but their interplays are poorly defined. Here, in anaplastic thyroid cancer (ATC), we show that ALDH+ stem-like cancer cells possess increased CIN-tolerance owing to transcriptional upregulation of the scaffolding protein NEDD9. Thyroid patient tissues and transcriptomic data reveals NEDD9/ALDH1A3 to be co-expressed and co-upregulated in ATC. Compared to bulk ALDH- cells, ALDH+ cells were highly efficient at propagating CIN due to their intrinsic tolerance of both centrosome amplification and micronuclei. ALDH+ cells mitigated the fitness-impairing effects of centrosome amplification by partially inactivating supernumerary centrosomes. Meanwhile, ALDH+ cells also mitigated cell death caused by micronuclei-mediated type 1 interferon secretion by suppressing the expression of the DNA-sensor protein STING. Both mechanisms of CIN-tolerance were lost upon RNAi-mediated NEDD9 silencing. Both in vitro and in vivo, NEDD9-depletion attenuated stemness, CIN, cell/tumor growth, while enhancing paclitaxel effectiveness. Collectively, these findings reveal that ATC progression can involve an ALDH1A3/NEDD9-regulated program linking their stemness to CIN-tolerance that could be leveraged for ATC treatment.