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H H Milioli, S Alexandrou, E Lim, and C E Caldon

Cyclin E1 is one the most promising biomarkers in estrogen receptor positive (ER+) breast cancer for response to the new standard of care drug class, CDK4/6 inhibitors. Because of its strong predictive value, cyclin E1 expression may be used in the future to triage patients into potential responders and non-responders. Importantly, cyclin E1 is highly related to cyclin E2, and both cyclin E1 and cyclin E2 are estrogen target genes that can facilitate anti-estrogen resistance and can be highly expressed in breast cancer. However cyclin E1 and E2 are often expressed in different subsets of patients. This raises questions about whether the expression of cyclin E1 and cyclin E2 have different biological drivers, if high expressing subsets represent different clinical subtypes, and how to effectively develop a biomarker for E-cyclin expression. Finally, several pan-CDK inhibitors that target cyclin E-CDK2 activity have reached Phase II clinical trials. In this review, we outline the data identifying that different cohorts of patients have high expression of cyclins E1 and E2 in ER+ cancer and address the implications for biomarker and therapeutic development.

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Claudio Ricci, Stefano Partelli, Carlo Ingaldi, Valentina Andreasi, Davide Campana, Francesca Muffatti, Laura Alberici, Cecilia Giorgi, Riccardo Casadei, and Massimo Falconi

Overall survival (OS) is considered as the standard measure of outcome in oncology. However, considering that resectable pancreatic neuroendocrine neoplasms (Pan-NENs) usually have a long OS, the feasibility of prospective studies is questionable due to a long follow-up period needed. The primary endpoint was to validate the use of disease-free survival (DFS) as a surrogate measure of OS. The secondary endpoint was to calculate the gain in sample size using DFS instead of OS in hypothetical prospective studies with two parallel groups. A systematic review of studies reporting both OS and DFS in resected Pan-NENs was carried out. Multivariate linear regression analysis was used to evaluate if DFS predicts the OS in patients undergoing radical resection. Monte Carlo simulation was performed to estimate the gain in sample size, supposing the use of DFS instead of OS, to evaluate a hypothetical adjuvant treatment after surgery in a randomized trial. Six studies reporting data about seven cohorts of resected Pan-NENs were included, for a total of 1088 patients. The median OS and DFS were 144 (27–134) and 122 (50–267) months, respectively. There was a significant correlation between DFS and OS (R 2 = 0.988; P = 0.035). Monte Carlo simulations showed that the number of patients needed to demonstrate a significant reduction of probability of a ‘target event’ in a hypothetical two-arm group exploring the hypothetical role of adjuvant therapy was reduced using DFS instead OS. This finding supports the legitimacy of using DFS as an acceptable surrogate for OS in surgical clinical trials.

Open access

Johan O Paulsson, Na Wang, Jiwei Gao, Adam Stenman, Jan Zedenius, Ninni Mu, Weng-Onn Lui, Catharina Larsson, and C Christofer Juhlin

Mutations in the miRNA enzyme gene DICER1 have been reported in several endocrine malignancies and is associated with the rare tumour-predisposing DICER1 syndrome. DICER1 mutations have been reported in subsets of follicular thyroid carcinoma (FTC), but the role of DICER1 in follicular thyroid tumorigenesis has not been extensively studied. In this study, we investigate the role of DICER1 in 168 follicular thyroid tumours and in an FTC cell line. We found rare DICER1 mutations in paediatric FTC cases and a general DICER1 down-regulation in FTCs visualized both on mRNA and protein level, especially pronounced in Hürthle cell carcinoma (HuCC). The down-regulation was also evident in follicular thyroid adenomas (FTAs), suggesting a potential early step in tumorigenesis. The expression of DICER1 was lower in FTCs of older patients in which TERT promoter mutations are more frequent. In FTCs, DICER1 down-regulation was not caused by gene copy number loss but significantly correlated to expression of the transcription factor GABPA in clinical cases. GABPA was found to bind to the DICER1 promoter and regulate DICER1 expression in vitro, as GABPA depletion in FTC cell lines reduced DICER1 expression. This in turn stimulated cell proliferation and affected the miRNA machinery, evident by altered miRNA expression. To conclude, we show that GABPA directly regulates DICER1 in FTC, acting as a tumour suppressor and displaying down-regulation in clinical samples. We also show reduced expression of DICER1 in benign and malignant follicular thyroid tumours, suggesting a potentially early tumorigenic role of this gene aberrancy.

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Eyun Song, Dong Eun Song, Jonghwa Ahn, Tae Yong Kim, Won Bae Kim, Young Kee Shong, Min Ji Jeon, and Won Gu Kim

Major clinical challenges exist with differentiated thyroid cancers with distant metastases or rare but aggressive types, such as poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas. The precise characterization of the mutational profile in these advanced thyroid cancers is crucial. Samples were collected from primary tumors and distant metastases of 64 patients with distant metastases from differentiated thyroid cancer, poorly differentiated thyroid carcinoma, or anaplastic thyroid carcinoma. Targeted next-generation sequencing was performed with 50 known thyroid-cancer-related genes. Of the 82 tissues, 63 were from primary tumors and 19 from distant metastases. The most prevalent mutation observed from the primary tumors was TERT promoter mutation (56%), followed by BRAF (41%) and RAS (24%) mutations. TP3 was altered by 11%. Mutations in histone methyltransferases, SWI/SNF subunit–related genes, and PI3K/AKT/mTOR pathway-related genes were present in 42%, 12%, and 22%, respectively. When the mutational status was analyzed in 15 matched pairs of thyroid tumors and their matched distant metastases and one pair of distant metastases with two distinct sites, the concordance was high. A similar frequency of mutations in TERT promoter (58%) and BRAF (42%) as well as histone methyltransferases (37%), SWI/SNF subunits (10%), and PI3K/AKT/mTOR pathway (26%) were noted. The same main, early and late mutations were practically always present in individual primary tumor–metastasis pairs. Enrichment of TERT promoter, BRAF, and RAS mutations were detected in highly advanced thyroid cancers with distant metastasis. The genetic profiles of primary thyroid tumors and their corresponding distant metastases showed a high concordance.

Free access

Camille Buffet, Johanna Wassermann, Fabio Hecht, Laurence Leenhardt, Corinne Dupuy, Lionel Groussin, and Charlotte Lussey-Lepoutre

The management of radioiodine refractory thyroid cancers (RAIR TC) is challenging for the clinician. Tyrosine kinase inhibitors classically prescribed in this setting can fail due to primary or acquired resistance or the necessity of drug withdrawal because of serious or moderate but chronic and deleterious adverse effects. Thus, the concept of redifferentiation strategy, which involves treating patients with one or more drugs capable of restoring radioiodine sensitivity for RAIR TC, has emerged. The area of redifferentiation strategy leads to the creation of new definitions of RAIR TC including persistent non radioiodine-avid patients and ‘true’ RAIR TC patients. The latter group presents a restored or increased radioiodine uptake in metastatic lesions but with no radiological response on conventional imaging, that is, progression of a metastatic disease, thus proving that they are ‘truly’ resistant to the radiation delivered by radioiodine. Unlike these patients, metastatic TC patients with restored radioiodine uptake offer the hope of prolonged remission or even cure of the disease as for radioiodine-avid metastatic TC. Here, we review the different redifferentiation strategies based on the underlying molecular mechanism leading to the sodium iodide symporter (NIS) and radioiodine uptake reinduction, that is, by modulating signaling pathways, NIS transcription, NIS trafficking to the plasma membrane, NIS post-transcriptional regulation, by gene therapy and other potential strategies. We discuss clinical trials and promising preclinical data of potential future targets.

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Juliang Zhang, Huimin Meng, Mingkun Zhang, Cun Zhang, Meiling Huang, Changjiao Yan, Zhe Wang, Lan Hou, Liu Yang, and Rui Ling

Docetaxel (DTX)-based chemotherapy significantly eliminates rest cancerous cells and decreases the risk of death, thus remaining the mainstay of treatment for operable breast cancer (BCa). However, resistance or incomplete response to DTX occurs frequently, resulting in disease recurrence and poor prognosis. There is an urgent need to identify and understand the key factors and corresponding molecular bases driving this complicated pathogenesis. Herein, both data mining and profiling analysis using clinical BCa biopsies showed that expression levels of the nuclear receptor subfamily 2, group F, member 6 (NR2F6), a recently characterized central transcription factor for cancer immune surveillance, were significantly downregulated in DTX-resistant BCa. This downregulation, possibly regulated by leptin signaling, predicted a poor postoperative chemotherapy survival in DTX-resistant BCa. In both genetically engineered cell models and patient-derived xenograft models, we provided evidence that BCa cells with insufficient NR2F6 expression were less responsive to DTX treatment. Mechanistically, NR2F6 functioned as a potent corepressor of platelet-derived growth factor B receptor gene (PDGFRB) transcription by recruiting HDAC2 onto the PDGFRB promoter. Stable PDGFRB inhibition ameliorated NR2F6 deficiency-impaired response to DTX in BCa cells, indicating that NR2F6’s effect on DTX response is mediated, at least in part, through transcriptional repression of PDGFRB. Collectively, our findings define NR2F6 as an negative regulator of cell survival and DTX resistance, probably by serving as a convergent point linking leptin signaling and PDGF-B/PDGFRβ axis, in BCa cells.

Free access

Yu-Ling Tai, Chun-Jung Lin, Tsai-Kun Li, Tang-Long Shen, Jer-Tsong Hsieh, and Benjamin P C Chen

In mammalian cells, extracellular vesicles (EVs) derived from the endosomal system carry many different kinds of bioactive molecule to deliver to recipient cells in a paracrine or endocrine manner. EVs can mediate local and systemic intercellular communications, including reeducating stromal cells, remodeling the architecture of the tumor microenvironment, modulating cancer metabolism and metastases, or even conferring drug resistance. Because the molecular and functional characteristics of prostate cancer (PCa) evolve over time, the bioactive molecule profiles/signatures of tumor-derived EVs (TDEs) reflect the real-time status of cancer cells. TDEs appear to be valuable diagnostic and prognostic biomarkers as well as potential therapeutic vehicles, suggesting their essential role in precision medicine of disease management. We summarized critical aspects of TDEs in PCa and discussed their potential clinical applications.

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Isadora Pontes Cavalcante, Anna Vaczlavik, Ludivine Drougat, Claudimara Ferini Pacicco Lotfi, Karine Perlemoine, Christopher Ribes, Marthe Rizk-Rabin, Eric Clauser, Maria Candida Barisson Villares Fragoso, Jérôme Bertherat, and Bruno Ragazzon

ARMC5 (Armadillo repeat containing 5 gene) was identified as a new tumor suppressor gene responsible for hereditary adrenocortical tumors and meningiomas. ARMC5 is ubiquitously expressed and encodes a protein which contains a N-terminal Armadillo repeat domain and a C-terminal BTB (Bric-a-Brac, Tramtrack and Broad-complex) domain, both docking platforms for numerous proteins. At present, expression regulation and mechanisms of action of ARMC5 are almost unknown. In this study, we showed that ARMC5 interacts with CUL3 requiring its BTB domain. This interaction leads to ARMC5 ubiquitination and further degradation by the proteasome. ARMC5 alters cell cycle (G1/S phases and cyclin E accumulation) and this effect is blocked by CUL3. Moreover, missense mutants in the BTB domain of ARMC5, identified in patients with multiple adrenocortical tumors, are neither able to interact and be degraded by CUL3/proteasome nor alter cell cycle. These data show a new mechanism of regulation of the ARMC5 protein and open new perspectives in the understanding of its tumor suppressor activity.

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Hiroki Ide, Taichi Mizushima, Guiyang Jiang, Takuro Goto, Yujiro Nagata, Yuki Teramoto, Satoshi Inoue, Yi Li, Eiji Kashiwagi, Alexander S Baras, George J Netto, Takashi Kawahara, and Hiroshi Miyamoto

Androgen receptor (AR) and estrogen receptor-β (ERβ) have been implicated in urothelial tumor outgrowth as promoters, while underlying mechanisms remain poorly understood. Our transcription factor profiling previously performed identified FOXO1 as a potential downstream target of AR in bladder cancer cells. We here investigated the functional role of FOXO1 in the development and progression of urothelial cancer in relation to AR and ERβ signals. In non-neoplastic urothelial SVHUC cells or bladder cancer lines, AR/ERβ expression or dihydrotestosterone/estradiol treatment reduced the expression levels of FOXO1 gene and induced those of a phosphorylated inactive form of FOXO1 (p-FOXO1). In chemical carcinogen-induced models, FOXO1 knockdown via shRNA or inhibitor treatment resulted in considerable induction of the neoplastic transformation of urothelial cells or bladder cancer development in mice. Similarly, FOXO1 inhibition considerably induced the viability, migration, and invasion of bladder cancer cells. Importantly, in FOXO1 knockdown sublines, an anti-androgen hydroxyflutamide or an anti-estrogen tamoxifen did not significantly inhibit the neoplastic transformation of urothelial cells, while dihydrotestosterone or estradiol did not significantly promote the proliferation or migration of urothelial cancer cells. In addition, immunohistochemistry in surgical specimens showed that FOXO1 and p-FOXO1 expression was down-regulated and up-regulated, respectively, in bladder tumor tissues, which was further associated with worse patient outcomes. AR or ERβ activation is thus found to correlate with inactivation of FOXO1 which appears to be their key downstream effector. Moreover, FOXO1, as a tumor suppressor, is likely inactivated in bladder cancer, which contributes in turn to inducing urothelial carcinogenesis and cancer growth.

Open access

Emanuel Christ, Kwadwo Antwi, Melpomeni Fani, and Damian Wild

Receptors for the incretin glucagon-like peptide-1 (GLP-1R) have been found overexpressed in selected types of human tumors and may, therefore, play an increasingly important role in endocrine gastrointestinal tumor management. In particular, virtually all benign insulinomas express GLP-1R in high density. Targeting GLP-1R with indium-111, technetium-99m or gallium-68-labeled exendin-4 offers a new approach that permits the successful localization of small benign insulinomas. It is likely that this new non-invasive technique has the potential to replace the invasive localization of insulinomas by selective arterial stimulation and venous sampling. In contrast to benign insulinomas, malignant insulin-secreting neuroendocrine tumors express GLP-1R in only one-third of the cases, while they more often express the somatostatin subtype 2 receptors. Importantly, one of the two receptors appears to be always overexpressed. In special cases of endogenous hyperinsulinemic hypoglycemia (EHH), that is, in the context of MEN-1 or adult nesidioblastosis GLP-1R imaging is useful whereas in postprandial hypoglycemia in the context of bariatric surgery, GLP-1R imaging is probably not helpful. This review focuses on the potential use of GLP-1R imaging in the differential diagnosis of EHH.