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Martin K Bakht, Iulian Derecichei, Yinan Li, Rosa-Maria Ferraiuolo, Mark Dunning, So Won Oh, Abdulkadir Hussein, Hyewon Youn, Keith F Stringer, Chang Wook Jeong, Gi Jeong Cheon, Cheol Kwak, Keon Wook Kang, Alastair D Lamb, Yuzhuo Wang, Xuesen Dong and Lisa A Porter

Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate adenocarcinoma (AdPC) cells and acts as a target for molecular imaging. However, some case reports indicate that PSMA-targeted imaging could be ineffectual for delineation of neuroendocrine (NE) prostate cancer (NEPC) lesions due to the suppression of the PSMA gene (FOLH1). These same reports suggest that targeting somatostatin receptor type 2 (SSTR2) could be an alternative diagnostic target for NEPC patients. This study evaluates the correlation between expression of FOLH1, NEPC marker genes and SSTR2. We evaluated the transcript abundance for FOLH1 and SSTR2 genes as well as NE markers across 909 tumors. A significant suppression of FOLH1 in NEPC patient samples and AdPC samples with high expression of NE marker genes was observed. We also investigated protein alterations of PSMA and SSTR2 in an NE-induced cell line derived by hormone depletion and lineage plasticity by loss of p53. PSMA is suppressed following NE induction and cellular plasticity in p53-deficient NEPC model. The PSMA-suppressed cells have more colony formation ability and resistance to enzalutamide treatment. Conversely, SSTR2 was only elevated following hormone depletion. In 18 NEPC patient-derived xenograft (PDX) models we find a significant suppression of FOLH1 and amplification of SSTR2 expression. Due to the observed FOLH1-supressed signature of NEPC, this study cautions on the reliability of using PMSA as a target for molecular imaging of NEPC. The observed elevation of SSTR2 in NEPC supports the possible ability of SSTR2-targeted imaging for follow-up imaging of low PSMA patients and monitoring for NEPC development.

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KeeMing Chia, Heloisa Milioli, Neil Portman, Geraldine Laven-Law, Rhiannon Coulson, Aliza Yong, Davendra Segara, Andrew Parker, Catherine E Caldon, Niantao Deng, Alexander Swarbrick, Wayne D Tilley, Theresa E Hickey and Elgene Lim

The role of androgen receptor (AR) in endocrine-resistant breast cancer is controversial and clinical trials targeting AR with an AR antagonist (e.g., enzalutamide) have been initiated. Here, we investigated the consequence of AR antagonism using in vitro and in vivo models of endocrine resistance. AR antagonism in MCF7-derived tamoxifen-resistant (TamR) and long-term estrogen-deprived breast cancer cell lines were achieved using siRNA-mediated knockdown or pharmacological inhibition with enzalutamide. The efficacy of enzalutamide was further assessed in vivo in an estrogen-independent endocrine-resistant patient-derived xenograft (PDX) model. Knockdown of AR inhibited the growth of the endocrine-resistant cell line models. Microarray gene expression profiling of the TamR cells following AR knockdown revealed perturbations in proliferative signaling pathways upregulated in endocrine resistance. AR loss also increased some canonical ER signaling events and restored sensitivity of TamR cells to tamoxifen. In contrast, enzalutamide did not recapitulate the effect of AR knockdown in vitro, even though it inhibited canonical AR signaling, which suggests that it is the non-canonical AR activity that facilitated endocrine resistance. Enzalutamide had demonstrable efficacy in inhibiting AR activity in vivo but did not affect the growth of the endocrine-resistant PDX model. Our findings implicate non-canonical AR activity in facilitating an endocrine-resistant phenotype in breast cancer. Unlike canonical AR signaling which is inhibited by enzalutamide, non-canonical AR activity is not effectively antagonized by enzalutamide, and this has important implications in the design of future AR-targeted clinical trials in endocrine-resistant breast cancer.

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Esben Andreas Carlsen, Nicola Fazio, Dan Granberg, Simona Grozinsky-Glasberg, Hojjat Ahmadzadehfar, Chiara Maria Grana, Wouter T Zandee, Jaroslaw Cwikla, Martin A Walter, Peter Sandor Oturai, Anja Rinke, Andrew Weaver, Andrea Frilling, Sara Gritti, Anne Kirstine Arveschoug, Amichay Meirovitz, Ulrich Knigge and Halfdan Sorbye

Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1–2 (G1–G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21–54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3–4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

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Priscilla A Furth

Peroxisome proliferator-activated receptor gamma agonists have been proposed as breast cancer preventives. Individuals who carry a mutated copy of BRCA1, DNA repair-associated gene, are at increased risk for development of breast cancer. Published data in the field suggest there could be interactions between peroxisome proliferator-activated receptor gamma and BRCA1 that could influence the activity of peroxisome proliferator-activated receptor gamma agonists for prevention. This review explores these possible interactions between peroxisome proliferator-activated receptor gamma, peroxisome proliferator-activated receptor gamma agonists and BRCA1 and discusses feasible experimental directions to provide more definitive information on the potential connections.

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Xiang Zhang, Ya Hu, Mengyi Wang, Ronghua Zhang, PeiPei Wang, Ming Cui, Zhe Su, Xiang Gao, Quan Liao and Yupei Zhao

Parathyroid carcinoma (PCa) is a rare endocrine neoplasia that typically has unfavourable outcomes. The contribution of long non-coding RNAs (lncRNAs) to the development of malignant and benign parathyroid tumours remains largely unknown. In this study, we explored transcriptomic profiling of lncRNA and mRNA expression in 6 PCa, 6 parathyroid adenoma (PAd) and 4 normal parathyroid (PaN) tissues. In total, 2641 lncRNA transcripts and 2165 mRNA transcripts were differentially expressed between PCa and PAd. Enrichment analysis demonstrated that dysregulated transcripts were involved mainly in the extracellular matrix (ECM)–receptor interaction and energy metabolism pathways. Bioinformatics analysis suggested that ATF3, ID1, FOXM1, EZH2 and MITF may be crucial to parathyroid carcinogenesis. Series test of cluster analysis segregated differentially expressed lncRNAs and mRNAs into several expression profile models, among which the ‘plateau’ profile representing components specific to parathyroid carcinogenesis was selected to build a co-expression network. Seven lncRNAs and three mRNAs were selected for quantitative RT-PCR validation in 16 PCa, 41 PAd and 4 PaN samples. Receiver-operator characteristic curves analysis showed that lncRNA PVT1 and GLIS2-AS1 yielded the area under the curve values of 0.871 and 0.860, respectively. Higher hybridization signals were observed in PCa for PVT1 and PAd for GLIS2-AS1. In conclusion, the current evidence indicates that PAd and PCa partially share common signalling molecules and pathways, but have independent transcriptional events. Differentially expressed lncRNAs and mRNAs have intricate interactions and are involved in parathyroid tumourigenesis. The lncRNA PVT1 and GLIS2-AS1 may be new potential markers for the diagnosis of PCa.

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Mimi I Hu, Rossella Elisei, Marek Dedecjus, Aron Popovtzer, Maralyn Druce, Ellen Kapiteijn, Furio Pacini, Laura Locati, Jolanta Krajewska, Richard Weiss and Robert F Gagel

Vandetanib is an oral tyrosine kinase inhibitor approved for treatment of advanced symptomatic or progressive medullary thyroid cancer (MTC). The current study (Nbib1496313) evaluated the benefit–risk of two starting doses of vandetanib in patients with symptomatic or progressive MTC. Patients were randomized 1:1 to receive vandetanib 150 or 300 mg daily and followed for a maximum of 14 months (Part A), with the option to then enter an open-label phase (Part B) investigating vandetanib 100, 150, 200 and 300 mg daily doses. Efficacy was assessed in Part A, and safety and tolerability during Parts A and B up to 2 years post randomization. Eighty-one patients were randomized in Part A and 61 patients entered Part B, of whom 37 (60.7%) received 2 years of treatment. Overall, 25% of patients experienced an objective response (OR) at 14 months (OR rate, 0.29 (95% CI, 0.176–0.445) for 300 mg, and 0.20 (95% CI, 0.105–0.348) for 150 mg; one-sided P value approximately 0.43). The most common adverse events (AEs) included diarrhea, hypocalcemia, asthenia, QTc prolongation, hypokalemia and keratopathy, all at generally higher incidence with 300 vs 150 mg (Part A). Part B safety and tolerability was consistent with Part A. OR was observed with both vandetanib doses; the 300 mg dose showed a more favorable trend vs 150 mg as initial dose. Thus, for most patients, 300 mg vandetanib is the most appropriate starting dose; dose reductions to manage AEs and lower initial doses for patients with particular comorbidities can be considered.

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Isobel C Mouat, Kei Omata, Andrew S McDaniel, Namita G Hattangady, Debnita Talapatra, Andi K Cani, Daniel H Hovelson, Scott A Tomlins, William E Rainey, Gary D Hammer, Thomas J Giordano and Tobias Else

Several somatic mutations specific to aldosterone-producing adenomas (APAs) have been described. A small proportion of adrenocortical carcinomas (ACCs) are associated with hyperaldosteronism, either primary aldosteronism or hyperreninemic hyperaldosteronism. However, it is unknown whether they harbor mutations of the same spectrum as APAs. The objective of this study is to describe the clinical phenotype and molecular genotype of ACCs with hyperaldosteronism, particularly the analysis for common APA-associated genetic changes. Patients were identified by retrospective chart review at a specialized referral center and by positive staining for CYP11B2 of tissue microarrays. Twenty-five patients with ACC and hyperaldosteronism were initially identified by retrospective chart review, and tissue for further analysis was available on 13 tumors. Seven patients were identified by positive staining for CYP11B2 in a tissue microarray, of which two were already identified in the initial chart review. Therefore, a total number of 18 patients with a diagnosis of ACC and features of either primary aldosteronism or hyperreninemic hyperaldosteronism were therefore included in the final study. Mutational status for a select list of oncogenes, tumor suppressor genes and genes known to carry mutations in APAs were analyzed by next-generation sequencing. Review of clinical data suggested autonomous aldosterone production in the majority of cases, while for some cases, hyperreninemic hyperaldosteronism was the more likely mechanism. The mutational landscape of ACCs associated with hyperaldosteronism was not different from ACCs with a different hormonal phenotype. None of the ACCs harbored mutations of known APA-associated genes, suggesting an alternative mechanism conferring aldosterone production.

Open access

Jonathan W Nyce

We recently reported our detection of an anthropoid primate-specific, ‘kill switch’ tumor suppression system that reached its greatest expression in humans, but that is fully functional only during the first twenty-five years of life, corresponding to the primitive human lifespan that has characterized the majority of our species' existence. This tumor suppression system is based upon the kill switch being triggered in cells in which p53 has been inactivated; such kill switch consisting of a rapid, catastrophic increase in ROS caused by the induction of irreversible uncompetitive inhibition of glucose-6- phosphate dehydrogenase (G6PD), which requires high concentrations of both inhibitor (DHEA) and G6P substrate. While high concentrations of intracellular DHEA are readily available in primates from the importation and subsequent de-sulfation of circulating DHEAS into p53-affected cells, both an anthropoid primate-specific sequence motif (GAAT) in the glucose-6-phosphatase (G6PC) promoter, and primate-specific inactivation of de novo synthesis of vitamin C by deletion of gulonolactone oxidase (GLO) were required to enable accumulation of G6P to levels sufficient to enable irreversible uncompetitive inhibition of G6PD. Malignant transformation acts as a counterforce opposing vertebrate speciation, particularly increases in body size and lifespan that enable optimized exploitation of particular niches. Unique mechanisms of tumor suppression that evolved to enable niche exploitation distinguish vertebrate species, and prevent one vertebrate species from serving as a valid model system for another. This here-to-fore unrecognized element of speciation undermines decades of cancer research data, using murine species, which presumed universal mechanisms of tumor suppression, independent of species. Despite this setback, the potential for pharmacological reconstitution of the kill switch tumor suppression system that distinguishes our species suggests that ‘normalization’ of human cancer risk, from its current 40% to the 4% of virtually all other large, long-lived species, represents a realistic near-term goal.

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M Cives, J Strosberg, S Al Diffalha and D Coppola

Immune checkpoint inhibitors have shown promising results in different cancers, and correlation between immune infiltration, expression of programmed death-ligand 1 (PD-L1) by tumor cells and response to immunotherapy has been reported. There is limited knowledge regarding the immune microenvironment of small bowel (SB) neuroendocrine tumors (NETs). This work was aimed at characterizing the immune landscape of SB NETs. Expression of PD-L1 and programmed death-1 (PD-1) was evaluated by immunohistochemistry in 102 surgically resected, primary NETs of the duodenum, jejunum and ileum. Extent and characteristics of the tumor-associated immune infiltrate were also assessed and investigated in their prognostic potential. We detected the expression of PD-L1 in ≥1 and ≥50% of tumor cells in 40/102 (39%; 95% CI, 30–49%) and 14/102 (14%; 95% CI, 8–22%) cases respectively. Intratumor host immune response was apparently absent in 35/102 cases (34%; 95% CI, 25–44%), mild to moderate in 46/102 samples (45%, 95% CI, 35–55%), intense in 21/102 tumors (21%, 95% CI, 13–30%). Expression of PD-L1 and extent of immune infiltration were significantly higher in duodenal NETs as compared with jejunal/ileal NETs. A marked peritumoral host response was organized as ectopic lymph node-like structures in 18/102 cases (18%; 95% CI, 11–26%). Neither PD-L1 expression nor the degree of immune infiltration showed any prognostic significance. Overall, the immune landscape of SB NETs is heterogeneous, with adaptive immune resistance mechanisms prevailing in duodenal NETs. Clinical trials of immune checkpoint inhibitors should take into account the immune heterogeneity of SB NETs.