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Open access

Tobias Hofving, Viktor Sandblom, Yvonne Arvidsson, Emman Shubbar, Gülay Altiparmak, John Swanpalmer, Bilal Almobarak, Anna-Karin Elf, Viktor Johanson, Erik Elias, Erik Kristiansson, Eva Forssell-Aronsson and Ola Nilsson

177Lu-octreotate is an FDA-approved radionuclide therapy for patients with gastroenteropancreatic neuroendocrine tumours (NETs) expressing somatostatin receptors. The 177Lu-octreotate therapy has shown promising results in clinical trials by prolonging progression-free survival, but complete responses are still uncommon. The aim of this study was to improve the 177Lu-octreotate therapy by means of combination therapy. To identify radiosensitising inhibitors, two cell lines, GOT1 and P-STS, derived from small intestinal neuroendocrine tumours (SINETs), were screened with 1224 inhibitors alone or in combination with external radiation. The screening revealed that inhibitors of Hsp90 can potentiate the tumour cell-killing effect of radiation in a synergistic fashion (GOT1; false discovery rate <3.2 × 10−11). The potential for Hsp90 inhibitor ganetespib to enhance the anti-tumour effect of 177Lu-octreotate in an in vivo setting was studied in the somatostatin receptor-expressing GOT1 xenograft model. The combination led to a larger decrease in tumour volume relative to monotherapies and the tumour-reducing effect was shown to be synergistic. Using patient-derived tumour cells from eight metastatic SINETs, we could show that ganetespib enhanced the effect of 177Lu-octreotate therapy for all investigated patient tumours. Levels of Hsp90 protein expression were evaluated in 767 SINETs from 379 patients. We found that Hsp90 expression was upregulated in tumour cells relative to tumour stroma in the vast majority of SINETs. We conclude that Hsp90 inhibitors enhance the tumour-killing effect of 177Lu-octreotate therapy synergistically in SINET tumour models and suggest that this potentially promising combination should be further evaluated.

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Ornella Affinito, Paolo Salerno, Alfonso D’Alessio, Mariella Cuomo, Ermanno Florio, Francesca Carlomagno, Agnese Proietti, Riccardo Giannini, Fulvio Basolo, Lorenzo Chiariotti, Sergio Cocozza and Massimo Santoro

Molecular differentiation between benign (follicular thyroid adenoma (FTA)) and malignant (follicular thyroid carcinoma (FTC)) thyroid neoplasms is challenging. Here, we explored the genome-wide DNA methylation profile of FTA (n.10) and FTC (n.11) compared to normal thyroid (NT) (n.7) tissues. FTC featured 3564 differentially methylated CpGs (DMCpG), most (84%) of them hypermethylated, with respect to normal controls. At the principal component analysis (PCA), the methylation profile of FTA occupied an intermediate position between FTC and normal tissue. A large fraction (n. 2385) of FTC-associated DMCpG was related (intragenic or within 1500 bp from the transcription start site) to annotated genes (n. 1786). FTC-hypermethylated genes were enriched for targets of the Polycomb transcriptional repressor complex and the specific histone H3 marks (H3K4me2/me3-H3K27me3) found in chromatin domains known as ‘bivalent’. Transcriptome profiling by RNAseq showed that 7.9% of the DMCpGs-associated genes were differentially expressed in FTC compared to NT, suggesting that altered DNA methylation may contribute to their altered expression. Overall, this study suggests that perturbed DNA methylation, in particular hypermethylation, is a component of the molecular mechanisms leading to the formation of FTC and that DNA methylation profiling may help differentiating FTCs from their benign counterpart.

Free access

Peder Rustøen Braadland and Alfonso Urbanucci

Tumor evolution is based on the ability to constantly mutate and activate different pathways under the selective pressure of targeted therapies. Epigenetic alterations including those of the chromatin structure are associated with tumor initiation, progression and drug resistance. Many cancers, including prostate cancer, present enlarged nuclei, and chromatin appears altered and irregular. These phenotypic changes are likely to result from epigenetic dysregulation. High-throughput sequencing applied to bulk samples and now to single cells has made it possible to study these processes in unprecedented detail. It is therefore timely to review the impact of chromatin relaxation and increased DNA accessibility on prostate cancer growth and drug resistance, and their effects on gene expression. In particular, we focus on the contribution of chromatin-associated proteins such as the bromodomain-containing proteins to chromatin relaxation. We discuss the consequence of this for androgen receptor transcriptional activity and briefly summarize wider gain-of-function effects on other oncogenic transcription factors and implications for more effective prostate cancer treatment.

Free access

Dannah R Miller, Matthew A Ingersoll and Ming-Fong Lin

Currently, prostate cancer (PCa) remains the most commonly diagnosed solid tumor and the second leading cause of cancer-related deaths in US men. Most of these deaths are attributed to the development of castration-resistant (CR) PCa. ErbB-2 and ErbB family members have been demonstrated to contribute to the progression of this lethal disease. In this review, we focus on updating the role of ErbB-2 in advanced PCa progression and its regulation, including its regulation via ligand activation, miRNAs and protein phosphorylation. We also discuss its downstream signaling pathways, including AKT, ERK1/2 and STATs, involved in advanced PCa progression. Additionally, we evaluate the potential of ErbB-2, focusing on its protein hyper-phosphorylation status, as a biomarker for aggressive PCa as well as the effectiveness of ErbB-2 as a target for the treatment of CR PCa via a multitude of approaches, including orally available inhibitors, intratumoral expression of cPAcP, vaccination and immunotherapy.

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Antonio M Lerario, Kazutaka Nanba, Amy R Blinder, Sachiko Suematsu, Masao Omura, Tetsuo Nishikawa, Thomas J Giordano, William E Rainey and Tobias Else

Somatic variants in genes that regulate intracellular ion homeostasis have been identified in aldosterone-producing adenomas (APAs). Although the mechanisms leading to increased aldosterone production in APA cells have been well studied, the molecular events that cause cell proliferation and tumor formation are poorly understood. In the present study, we have performed whole-exome sequencing (WES) to characterize the landscape of somatic alterations in a homogeneous series of APA with pathogenic KCNJ5 variants. In the WES analysis on 11 APAs, 84 exonic somatic events were called by 3 different somatic callers. Besides the KCNJ5 gene, only two genes (MED13 and ZNF669) harbored somatic variants in more than one APA. Unlike adrenocortical carcinomas, no chromosomal instability was observed by the somatic copy-number alteration and loss of heterozygosity analyses. The estimated tumor purity ranged from 0.35 to 0.67, suggesting a significant proportion of normal cell infiltration. Based on the results of PureCN analysis, the KCNJ5 variants appear to be clonal. In conclusion, in addition to KCNJ5 somatic pathogenic variants, no significant somatic event that would obviously explain proliferation or tumor growth was observed in our homogeneous cohort of KCNJ5-mutated APA. The molecular mechanisms causing APA growth and tumorigenesis remain to be elucidated.

Open access

James Yao, Abhishek Garg, David Chen, Jaume Capdevila, Paul Engstrom, Rodney Pommier, Eric Van Cutsem, Simron Singh, Nicola Fazio, Wei He, Markus Riester, Parul Patel, Maurizio Voi, Michael Morrissey, Marianne Pavel and Matthew Helmut Kulke

Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.

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Taymeyah Al-Toubah, Stefano Partelli, Mauro Cives, Valentina Andreasi, Franco Silvestris, Massimo Falconi, Daniel A Anaya and Jonathan Strosberg

New systemic treatments have improved the therapeutic landscape for patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). While drugs such as everolimus, sunitinib, temozolomide and 177Lutetium-dotatate are appropriate for patients with widespread disease progression, local treatment approaches may be more appropriate for patients with unifocal progression. Surgical resection, radiofrequency ablation (RFA), hepatic arterial embolization (HAE) or radiation, can control discrete sites of progression, allowing patients to continue their existing therapy and sparing them toxicities of a new systemic treatment. We identified 69 patients with metastatic GEP-NETs who underwent a local treatment for focal progression in the setting of widespread metastases. Twenty-six percent underwent resection, 27% RFA, 23% external beam radiation and 23% selective HAE. With a median follow-up of 25 months, 42 (61%) patients subsequently progressed to the point of requiring additional intervention (12 locoregional, 30 systemic) for disease control. Median time to new systemic treatment was 32 months (95% CI, 16.5–47.5 months). Median time to any additional intervention was 19 months (95% CI, 8.7–25.3 months). Control of local sites of progression enabled the majority of patients to remain on their existing systemic treatment and avoid potential toxicities associated with salvage systemic therapy.

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Kristen Wong, Francesca Di Cristofano, Michela Ranieri, Daniela De Martino and Antonio Di Cristofano

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. Despite its low incidence, it accounts for a disproportionate number of thyroid cancer-related deaths, because of its resistance to current therapeutic approaches. Novel actionable targets are urgently needed to prolong patient survival and increase their quality of life. Loss and mutation of the RB1 tumor suppressor are rare events in ATC, which suggests that therapies directed at inhibiting the cyclin D/CDK4complexes, responsible for RB phosphorylation and inactivation, might be effective in this tumor type. In fact, we found that the CDK4/6 inhibitor, palbociclib, strongly inhibits proliferation in all the RB1 wild-type ATC cell lines tested. Efficacy was also observed in vivo, in a xenograft model. However, ATC cells rapidly developed resistance to palbociclib. Resistance was associated with increased levels of cyclin D1 and D3. To counter cyclin D overexpression, we tested the effect of combining palbociclib with the PI3K/mTOR dual inhibitor, omipalisib. Combined treatment synergistically reduced cell proliferation, even in cell lines that do not carry PI3K-activating mutations. More importantly, low-dose combination was dramatically effective in inhibiting tumor growth in a xenograft model. Thus, combined PI3K/mTOR and CDK4/6 inhibition is a highly promising novel approach for the treatment of aggressive, therapy-resistant thyroid cancer.

Free access

Weijun Wei, Heather Hardin and Quan-Yong Luo

Thyroid cancer is one of the most common endocrine malignancies. Although the prognosis for the majority of thyroid cancers is relatively good, patients with metastatic, radioiodine-refractory or anaplastic thyroid cancers have an unfavorable outcome. With the gradual understanding of the oncogenic events in thyroid cancers, molecularly targeted therapy using tyrosine kinase inhibitors (TKIs) is greatly changing the therapeutic landscape of radioiodine-refractory differentiated thyroid cancers (RR-DTCs), but intrinsic and acquired drug resistance, as well as adverse effects, may limit their clinical efficacy and use. In this setting, development of synergistic treatment options is of clinical significance, which may enhance the therapeutic effect of current TKIs and further overcome the resultant drug resistance. Autophagy is a critical cellular process involved not only in protecting cells and organisms from stressors but also in the maintenance and development of various kinds of cancers. Substantial studies have explored the complex role of autophagy in thyroid cancers. Specifically, autophagy plays important roles in mediating the drug resistance of small-molecular therapeutics, in regulating the dedifferentiation process of thyroid cancers and also in affecting the treatment outcome of radioiodine therapy. Exploring how autophagy intertwines in the development and dedifferentiation process of thyroid cancers is essential, which will enable a more profound understanding of the physiopathology of thyroid cancers. More importantly, these advances may fuel future development of autophagy-targeted therapeutic strategies for patients with thyroid cancers. Herein, we summarize the most recent evidence uncovering the role of autophagy in thyroid cancers and highlight future research perspectives in this regard.

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Brendan M Finnerty, Maureen D Moore, Akanksha Verma, Anna Aronova, Shixia Huang, Dean P Edwards, Zhengming Chen, Marco Seandel, Theresa Scognamiglio, Yi-Chieh Nancy Du, Olivier Elemento, Rasa Zarnegar, Irene M Min and Thomas J Fahey III

Loss of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) expression by CpG promoter hypermethylation is associated with metastasis in gastroenteropancreatic neuroendocrine tumors; however, the mechanism of how UCHL1 loss contributes to metastatic potential remains unclear. In this study, we first confirmed that the loss of UCHL1 expression on immunohistochemistry was significantly associated with metastatic tumors in a translational pancreatic neuroendocrine tumor (PNET) cohort, with a sensitivity and specificity of 78% and 89%, respectively. To study the mechanism driving this aggressive phenotype, BON and QGP-1 metastatic PNET cell lines, which do not produce UCHL1, were stably transfected to re-express UCHL1. In vitro assays, RNA sequencing and reverse phase protein array (RPPA) analyses were performed comparing empty-vector negative controls and UCHL1-expressing cell lines. UCHL1 re-expression is associated with lower anchorage-independent colony growth in BON cells, lower colony formation in QGP cells and a higher percentage of cells in the G0/G1 cell-cycle phase in BON and QGP cells. On RPPA proteomic analysis, there was an upregulation of cell-cycle regulatory proteins CHK2 (1.2-fold change, P = 0.004) and P21 (1.2-fold change, P = 0.023) in BON cells expressing UCHL1; western blot confirmed upregulation of phosphorylated CHK2 and P21. There were no transcriptomic differences detected on RNA sequencing between empty-vector negative controls and UCHL1-expressing cell lines. In conclusion, UCHL1 loss correlates with metastatic potential in PNETs and its re-expression induces a less aggressive phenotype in vitro, in part by inducing cell-cycle arrest through posttranslational regulation of phosphorylated CHK2. UCHL1 expression should be considered as a functional biomarker in detecting PNETs capable of metastasis.