apatinib and Thyroid-Carcinoma--Anaplastic

Anaplastic thyroid carcinoma (ATC) is a rare and extremely aggressive type of thyroid cancer, and the potential mechanisms involved in ATC progression remains unclarified. In this study, we found that forkhead box K2 (FOXK2) was upregulated in ATC tissues, and the expression of FOXK2 was associated with tumor size. Evidenced by RNA-seq and Chromatin immunoprecipitation (ChIP)-seq assays, FOXK2 positively regulated VEGF and VEGFR signaling network, among which only VEGFA could be noticed in both RNA-seq and ChIP-seq results. ChIP, dual-luciferase reporter system and functional experiments further confirmed that FOXK2 promoted angiogenesis by inducing the transcription of VEGFA. On VEGFR2 blockage by specific targeting agent, such as Apatinib, FOXK2 could rapidly trigger therapeutic resistance. Mechanical analyses revealed that VEGFA transcriptionally induced by FOXK2 could bind to VEGFR1 as a compensation for VEGFR2 blockage, which promoted angiogenesis by activating ERK, PI3K/AKT and P38/MAPK signaling in human umbilical vein endothelial cells (HUVECs). Synergic effect on anti-angiogenesis could be observed when VEGFR1 suppressor AF321 was included in VEGFR2 inhibition system, which clarified the pivot role of FOXK2 in VEGFR2 targeting therapy resistance. More importantly, the binding of VEGFA to VEGFR1 could further promoter FOXK2-mediated VEGFA transcription, which consequently constituted a positive feedback loop. Therefore, the novel loop VEGFA/VEGFR1/FOXK2 functioned importantly in resistance to VEGFR2 targeting therapy in FOXK2

Topics: Animals; Chromatin Immunoprecipitation; Drug Resistance, Neoplasm; Female; Forkhead Transcription Factors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Neoplasm Transplantation; Pyridines; Sequence Analysis, RNA; Signal Transduction; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Transcriptional Activation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options. Current treatments of ATC include surgery, radiation, and chemotherapy, used in combination when possible. In the aspect of immunotherapy, the biomarker of TMB-H and MSI-H may suggest that patients benefit from pembrolizumab. Programmed cell death-ligand 1 (PD-L1) is highly expressed in ATC but has not been written into the guidelines or approved by the FDA as a biomarker for thyroid cancer immunotherapy.. A 55-year-old woman was admitted to our hospital because of a slight right-sided neck enlargement in November 2019.. The clinical diagnosis was ATC, pT3bN0M0, and stage IVB.. Oral administration of apatinib (250 mg 3 times daily) was initiated after surgery, but some unpleasant side effects emerged after 1 month of treatment. Next-generation sequencing revealed that the tumor harbored 2 mutations, HRAS p.Q61R and TP53 p.P278S, and PD-L1 staining was positive with a high expression. Thus, camrelizumab (programmed cell death protein 1 inhibitor) was combined with apatinib, and apatinib was changed to 250 mg once a day from March 2020.. No adverse reactions were observed after the treatment immunotherapy combined with antiangiogenic drugs. Currently, the survival time of patients is more than 11 months, and the quality of life is not affected.. This case suggests that immunotherapy in patients with ATC based upon PD-L1 evaluation provides a therapeutic option. Targeting programmed cell death protein 1/PD-L1 may provide a much-needed treatment option for patients with advanced ATC.

Topics: Administration, Oral; Antineoplastic Agents; B7-H1 Antigen; Biomarkers, Tumor; Female; Humans; Immunotherapy; Middle Aged; Pyridines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Anaplastic thyroid cancer is known to be the most lethal malignancy among endocrine tumors for its extremely limited survival rate after diagnosis. As a result of this poor survival prognosis, multimodal therapy is currently under investigation to address this global concern. In this reported case, the

Topics: Antineoplastic Agents; Brachytherapy; Combined Modality Therapy; Female; Humans; Iodine Radioisotopes; Middle Aged; Prognosis; Pyridines; Thyroid Carcinoma, Anaplastic; Thyroidectomy

Apatinib, an inhibitor of vascular endothelial growth factor receptor-2, has been shown to promote anti-cancer action across a wide range of malignancies, including gastric, lung, and breast cancers. Our previous study showed that apatinib increases apoptosis in anaplastic thyroid carcinoma (ATC), but the direct functional mechanism of tumor lethality mediated by apatinib is still unknown. In this study, we demonstrated that apatinib induced both autophagy and apoptosis in human ATC cells through downregulation of p-AKT and p-mTOR signals via the AKT/mTOR pathway. Moreover, inhibition of apatinib-induced autophagy increased apatinib-induced apoptosis in ATC cells, and additional tumor suppression was critically produced by the combination of apatinib and the autophagy inhibitor chloroquine in vivo and in vitro. These findings showed that both autophagy and AKT/mTOR signals were engaged in ATC cell death evoked by apatinib. ATC patients might benefit from the new anti-cancer drug, and molecular targeted treatment in combination with autophagy inhibitors shows promise as a treatment improvement.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Chloroquine; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridines; Signal Transduction; Thyroid Carcinoma, Anaplastic; TOR Serine-Threonine Kinases

Anaplastic thyroid carcinoma (ATC) is one of the most lethal human malignancies, and there is no efficient method to slow its process. Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma patients. However, the effects of Apatinib in ATC are still unknown.. In this study, we explored the effects and mechanisms of Apatinib on tumor growth and angiogenesis in vitro and in vitro in ATC cells. Angiogenesis antibodies array was utilized to detect the expression of angiogenesis-related genes after Apatinib treatment in ATC cells. In addition, we used Akt activator, Akt inhibitor and GSK3β inhibitor to further study the mechanism for how Apatinib suppressed angiogenesis.. Apatinib treatment could suppress the growth of ATC cells in a dose- and time-dependent manner via inducing apoptosis and blocking cell cycle progression at G0/G1 phase. Moreover, Apatinib treatment decreased the expression of angiogenin (ANG) and inhibited angiogenesis of ATC cells in vitro and in vitro. We further confirmed that recombinant human ANG (rhANG) significantly abrogated Apatinib-mediated anti-angiogenic ability in ATC cells. Additionally, Apatinib treatment decreased the level of p-Akt and p-GSK3β. Moreover, the Apatinib-mediated decrease of ANG and anti-angiogenic ability were partly reversed when an Akt activator, SC79, was administered. Furthermore, the anti-angiogenic ability of Apatinib can be enhanced in the presence of Akt inhibitor, and the inhibition of GSK3β attenuated the anti-angiogenic ability of Apatinib.. Our results demonstrated that Apatinib treatment inhibited tumor growth, and Apatinib-induced suppression of Akt/GSK3β/ANG signaling pathway may play an important role in the inhibition of angiogenesis in ATC, supporting a potential therapeutic approach for using Apatinib in the treatment of ATC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; G1 Phase Cell Cycle Checkpoints; Glycogen Synthase Kinase 3 beta; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Physiologic; Proto-Oncogene Proteins c-akt; Pyridines; Recombinant Proteins; Ribonuclease, Pancreatic; Signal Transduction; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Transplantation, Heterologous