NTRK and RET fusion–directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake

Lee, Young Ah; Lee, Hyunjung; Im, Sangjun; Song, Young Shin; Oh, Do Youn; Kang, Hyoung Jin; Won, Jae Kyung; Jung, Kyeong Cheon; Kwon, Do Young; Chung, Eun Jae; Hah, J. Hun; Paeng, Jin Chul; Kim, Ji Hoon; Choi, Jaeyong; Kim, Ok Hee; Oh, Ji Min; Ahn, Byeong‐Cheol; Wirth, Lori J.; Shin, Choong Ho; Kim, Jong‐Il; Park, Young Joo

doi:10.1172/jci144847

Cited by 84 publications

(79 citation statements)

References 32 publications

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“…Analysis of animal models and human transcriptome databases suggests that ACE2 expression in the lower lung is relatively limited to type II alveolar cells , but is higher in the upper bronchial epithelia and much higher in the nasal epithelium, especially in the ciliated cells 71 – 76 . This difference in ACE2 expression level in the respiratory tract is mirrored by the SARS-CoV-2 infection gradient, with nasal ciliated cells being primary targets for SARS-CoV-2 replication in the early stage of infection 71 , 75 . Despite the respiratory route being dominant in SARS-CoV-2 infection, the highest levels of ACE2 expression are found in the small intestine, testis, kidney, heart muscle, colon and thyroid gland 73 , 77 .…”

Section: Sars-cov-2 Receptor Ace2mentioning

confidence: 99%

“…Two groups identified neuropilin 1 (NRP1) as a host factor for SARS-CoV-2 (refs 122 , 123 ). Although NRP1 is expressed in olfactory and respiratory epithelial cells 122 , its expression is low in ciliated cells, the primary target cells for SARS-CoV-2 in the airway, while it is high in goblet cells , which are not susceptible to SARS-CoV-2 (refs 71 , 75 ). Nonetheless, NRP1 was shown to enhance TMPRSS2-mediated entry (see the next section) of wild-type SARS-CoV-2 but not that of mutant virus that lacks the multibasic furin-cleavage site 122 .…”

Section: Additional Host Entry Factorsmentioning

confidence: 99%

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Mechanisms of SARS-CoV-2 entry into cells

Jackson

Farzan

Chen

et al. 2021

Nat Rev Mol Cell Biol

2,183

1,841

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The unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response. Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion. We define the roles of furin-like proteases, transmembrane protease, serine 2 (TMPRSS2) and cathepsin L in these processes, and delineate the features of ACE2 orthologues in reservoir animal species and S protein adaptations that facilitate efficient human transmission. We also examine the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. Finally, we present key outstanding questions associated with this critical process.

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Section: Sars-cov-2 Receptor Ace2mentioning

confidence: 99%

Section: Additional Host Entry Factorsmentioning

confidence: 99%

Mechanisms of SARS-CoV-2 entry into cells

Jackson

Farzan

Chen

et al. 2021

Nat Rev Mol Cell Biol

2,183

1,841

View full text Add to dashboard Cite

show abstract

“…In addition, it is unclear how the data presented relates to pediatric patients, as the TCGA dataset does not cover patients <18 years. It is likely that the majority of pediatric PTC patients with high-risk tumors have a high genetic component and therefore druggable targets (63,64).…”

Section: Discussionmentioning

confidence: 99%

Targeted Therapy of Papillary Thyroid Cancer: A Comprehensive Genomic Analysis

et al. 2021

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BackgroundA limited number of targeted therapy options exist for papillary thyroid cancer (PTC) to date. Based on genetic alterations reported by the “The Cancer Genome Atlas (TCGA)”, we explored whether PTC shows alterations that may be targetable by drugs approved by the FDA for other solid cancers.MethodsDatabases of the National Cancer Institute and MyCancerGenome were screened to identify FDA-approved drugs for targeted therapy. Target genes were identified using Drugbank. Genetic alterations were classified into conferring drug sensitivity or resistance using MyCancerGenome, CiViC, TARGET, and OncoKB. Genomic data for PTC were extracted from TCGA and mined for alterations predicting drug response.ResultsA total of 129 FDA-approved drugs with 128 targetable genes were identified. One hundred ninety-six (70%) of 282 classic, 21 (25%) of 84 follicular, and all 30 tall-cell variant PTCs harbored druggable alterations: 259 occurred in 29, 39 in 19, and 31 in 2 targetable genes, respectively. The BRAF V600 mutation was seen in 68% of classic, 16% of follicular variant, and 93% of tall-cell variant PTCs. The RET gene fusion was seen in 8% of classic PTCs, NTRK1 and 3 gene fusions in 3%, and other alterations in <2% of classic variant PTCs. Ninety-nine of 128 (77%) FDA-approved targetable genes did not show any genetic alteration in PTC. Beside selective and non-selective BRAF-inhibitors, no other FDA-approved drug showed any frequent predicted drug sensitivity (<10%).ConclusionTreatment strategies need to focus on resistance mechanisms to BRAF inhibition and on genetic alteration–independent alternatives rather than on current targeted drugs.

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“…A phase I study recruitment of patients with PTC (STARTRK-1, NCT02097810) was completed in June 2021 and a phase II trial (STARTRK-2, NCT02568267) is still recruiting. Another TRK inhibitor, larotrectinib, was found to restore radioiodine avidity in PTC-pediatric patients, leading to inhibition of tumor growth [ 140 ].…”

Section: Currently Used and Investigated Targeted Therapies In Tcsmentioning

confidence: 99%

“…The common activating RET alterations in PTC cases encouraged researchers to use RET kinase inhibitors for PTC therapy. The results of selpercatinib treatment in two independent case reports of patients with RET -altered PTC ( NCOA4-RET and CCDC6-RET fusions) showed restored radioiodine avidity and a re-differentiation effect suppressing Tg after six months of treatment [ 140 , 141 ].…”

Section: Currently Used and Investigated Targeted Therapies In Tcsmentioning

confidence: 99%

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

Ratajczak

Gawel

Godlewska

2021

IJMS

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Thyroid cancers (TCs) are the most common tumors of the endocrine system and a constant rise in the number of TC cases has been observed for the past few decades. TCs are one of the most frequent tumors in younger adults, especially in women, therefore early diagnosis and effective therapy are especially important. Ultrasonography examination followed by fine needle biopsy have become the gold standard for diagnosis of TCs, as these strategies allow for early-stage detection and aid accurate qualification for further procedures, including surgical treatment. Despite all the advancements in detection and treatment of TCs, constant mortality levels are still observed. Therefore, a novel generation line of targeted treatment strategies is being developed, including personalized therapies with kinase inhibitors. Recent molecular studies on TCs demonstrate that kinase inhibitor-based therapies might be considered as the most promising. In the past decade, new kinase inhibitors with different mechanisms of action have been reported and approved for clinical trials. This review presents an up-to-date picture of new approaches and challenges of inhibitor-based therapies in treatment of TCs, focusing on the latest findings reported over the past two years.

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NTRK and RET fusion–directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake

Cited by 84 publications

References 32 publications

Mechanisms of SARS-CoV-2 entry into cells

Mechanisms of SARS-CoV-2 entry into cells

Targeted Therapy of Papillary Thyroid Cancer: A Comprehensive Genomic Analysis

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

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