Prostate cancer (CaP) is the second leading cause of cancer-related deaths in Western men. Because androgens drive CaP by activating the androgen receptor (AR), blocking AR’s ligand activation, known as androgen deprivation therapy (ADT), is the default treatment for metastatic CaP. Despite an initial remission, CaP eventually develops resistance to ADT and progresses to castration-recurrent CaP (CRPC). CRPC continues to rely on aberrantly activated AR that is no longer inhibited effectively by available therapeutics. Interference with signaling pathways downstream of activated AR that mediate aggressive CRPC behavior may lead to alternative CaP treatments. Developing such therapeutic strategies requires a thorough mechanistic understanding of the most clinically relevant and druggable AR-dependent signaling events. Recent proteomics analyses of CRPC clinical specimens indicate a shift in the phosphoproteome during CaP progression. Kinases and phosphatases represent druggable entities, for which clinically tested inhibitors are available, some of which are incorporated already in treatment plans for other human malignancies. Here, we reviewed the AR-associated transcriptome and translational regulon, and AR interactome involved in CaP phosphorylation events. Novel and for the most part mutually exclusive AR-dependent transcriptional and post-transcriptional control over kinase and phosphatase expression was found, with yet other phospho-regulators interacting with AR. The multiple mechanisms by which AR can shape and fine-tune the CaP phosphoproteome were reflected in diverse aspects of CaP biology such as cell cycle progression and cell migration. Furthermore, we examined the potential, limitations and challenges of interfering with AR-mediated phosphorylation events as alternative strategy to block AR function during CaP progression.
Varadha Balaji Venkadakrishnan, Salma Ben-Salem, and Hannelore V Heemers
Germano Gaudenzi, Silvia Carra, Alessandra Dicitore, Maria Celeste Cantone, Luca Persani, and Giovanni Vitale
Neuroendocrine tumors (NETs) are a class of rare and heterogeneous neoplasms that originate from the neuroendocrine system. In several cases, these neoplasms can release bioactive hormones leading to characteristic clinical syndromes and hormonal dysregulations with detrimental impact on the quality of life and survival of these patients. Only few animal models are currently available to investigate pathogenesis, progression and functional syndromes in NETs and to identify new therapeutic strategies. The tropical teleost zebrafish (Danio rerio) is a popular vertebrate model system that offers unique advantages for the study of several biological processes, ranging from embryonic development to human diseases such as cancer. In this review, we summarize recent advances on zebrafish models for NET preclinical research that take advantage of modern genetic and transplantable technologies. In the future, these tools may have a role in the treatment decision-making and tertiary prevention of NETs.
Amit Tirosh, Ahmed Hamimi, Fabio Faucz, Genya Aharon-Hananel, Phaedon D Zavras, Belen Bonella, Adi Auerbach, David Gillis, Charalampos Lyssikatos, Elena Belyavskaya, Constantine A Stratakis, and Ahmed M Gharib
This study aimed to evaluate liver involvement in patients with Carney complex (CNC) based on a large cohort and to analyze any germline PRKAR1A genotype–phenotype association of liver disease. The study included 83 patients with CNC, followed between 1995 and 2018 at a tertiary research center. We reviewed liver images, recorded types and number of lesions and analyzed per genotype: all patients were sequenced for the PRKAR1A gene. A total of 29/83 patients (24.0%) had liver radiological findings. Patients with liver lesion had a significantly higher rate of pathogenic variants detected in the PRKAR1A gene (72.4 vs 38.9%, P = 0.005, respectively). Patients with a pathogenic variant detected on germline PRKAR1A analysis had a higher risk for having a liver lesion compared with patients with wild-type (WT) PRKAR1A alleles (21/42 (50.0%) vs 8/41 (19.5%), respectively, P = 0.004). Among patients with liver lesions, those with a nonsense PRKAR1A pathogenic-variant had more liver lesions (7/7) than among those with other pathogenic-variant types (8/22, P = 0.001). In multivariable analysis, detection of liver lesion(s) was associated with an odds ratio of 5.2 for cardiac myxomas (95% CI 1.55–17.49, P = 0.008). In conclusion, patients with CNC, particularly with a PRKAR1A pathogenic variant, have a higher rate of liver lesions. Additionally, liver lesions are associated with a high risk for cardiac myxomas in this population.
Kate M Warde, Erik Schoenmakers, Eduardo Ribes Martinez, Yi Jan Lim, Maeve Leonard, Sarah J Lawless, Paula O’Shea, Krishna V Chatterjee, Mark Gurnell, Constanze Hantel, and Michael Conall Dennedy
Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with a poor outcome largely due to limited treatment options. Here, we propose a novel therapeutic approach through modulating intracellular free cholesterol via the liver X receptor alpha (LXRα) in combination with current first-line pharmacotherapy, mitotane. H295R and MUC-1 ACC cell lines were pretreated with LXRα inhibitors in combination with mitotane. In H295R, mitotane (20, 40 and 50 µM) induced dose-dependent cell death; however, in MUC-1, this only occurred at a supratherapeutic concentration (200 µM). LXRα inhibition potentiated mitotane-induced cytotoxicity in both cell lines. This was confirmed through use of the CompuSyn model which showed moderate pharmacological synergism and was indicative of apoptotic cell death via an increase in annexinV and cleaved-caspase 3 expression. Inhibition of LXRα was confirmed through downregulation of cholesterol efflux pumps ABCA1 and ABCG1; however, combination treatment with mitotane attenuated this effect. Intracellular free-cholesterol levels were associated with increased cytotoxicity in H295R (r 2 = 0.5210) and MUC-1 (r 2 = 0.9299) cells. While both cell lines exhibited similar levels of free cholesterol at baseline, H295R were cholesterol ester rich, whereas MUC-1 were cholesterol ester poor. We highlight the importance of LXRα mediated cholesterol metabolism in the management of ACC, drawing attention to its role in the therapeutics of mitotane sensitive tumours. We also demonstrate significant differences in cholesterol storage between mitotane sensitive and resistant disease.
Manel Puig-Domingo, Joan Gil, Miguel Sampedro-Nuñez, Mireia Jordà, Susan M Webb, Guillermo Serra, Laura Pons, Isabel Salinas, Alberto Blanco, Montserrat Marques-Pamies, Elena Valassi, Antonio Picó, Araceli García-Martínez, Cristina Carrato, Raquel Buj, Carlos del Pozo, Gabriel Obiols, Carles Villabona, Rosa Cámara, Carmen Fajardo-Montañana, Clara V Alvarez, Ignacio Bernabéu, and Mónica Marazuela
Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P < 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.
Guido Rindi and Frediano Inzani
Neuroendocrine neoplasia is described in almost every tissue, either in the pure endocrine organs, the nerve structures or in the so-called diffuse neuroendocrine system. The current nomenclature contains time-honored, widely accepted definitions; however, it is different according to anatomical sites. Diverse definitions may generate confusion and non-standard patient management. The International Agency for Research on Cancer – World Health Organization (IARC-WHO) proposed a framework for universal classification of neuroendocrine neoplasia. Evidence indicates that neuroendocrine cancer is composed by cells with a distinctive phenotype characterized by the expression of general and specific neuroendocrine markers. The neuroendocrine phenotype is indicated as descriptor of a unique cancer category, now recommended for all organs as neuroendocrine neoplasm. Evidence indicates that neuroendocrine neoplasia may be well or poorly differentiated, with diverse incidence and prevalence in different organs. It is proposed that the well-differentiated neoplasm is universally defined as neuroendocrine tumor (NET) and the poorly differentiated as neoplasm neuroendocrine carcinoma (NEC). Evidence indicates that a cancer grading tool based on a proliferation measure by mitotic count, Ki67 % and/or necrosis assessment is useful to predict NET patient behavior. It is proposed to utilize this tool for grading NET universally, with site-specific cut-offs to be defined. It is also acknowledged that significant biological site-specific differences exist. It is recommended that current pathology reports contain this classification together with the current traditional classifiers. This IARC-WHO common classification framework for neuroendocrine neoplasm aims at uniformizing nomenclature toward different organs and at fostering the definition of a similar site-specific gene signature.
S M Sadowski, C R C Pieterman, N D Perrier, F Triponez, and G D Valk
Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. This systematic review aims to establish the current state of evidence regarding prognostic factors in MEN1-related NF-pNETs. We systematically searched four databases for studies assessing prognostic value of any factor on NF-pNET progression, development of distant metastases, and/or overall survival. In- and exclusion, critical appraisal and data-extraction were performed independently by two authors according to pre-defined criteria. Thirteen studies (370 unique patients) were included. Prognostic factors investigated were tumor size, timing of surgical resection, WHO grade, methylation, p27/p18 expression by immunohistochemistry (IHC), ARX/PDX1 IHC and alternative lengthening of telomeres. Results were complemented with evidence from studies in MEN1-related pNET for which data could not be separately extracted for NF-pNET and data from sporadic NF-pNET. We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs <2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs ≥2 cm. Grade 2 NF-pNETs should be considered high risk. The most promising and MEN1-relevant avenues of prognostic research are multi-analyte circulating biomarkers, tissue-based molecular factors and imaging-based prognostication. Multi-institutional collaboration between clinical, translation and basic scientists with uniform data and biospecimen collection in prospective cohorts should advance the field.
Giancarlo Di Giuseppe, Aleksandra M Zuk, Jonathan D Wasserman, and Jason D Pole
Differentiated thyroid carcinoma (DTC) in children, adolescents, and young adults is associated with excellent prognosis. However, little is known about the long-term utilization of healthcare resources among survivors. The objective of this study was to compare the utilization of healthcare resources among DTC survivors to the general population, with a focus on pulmonary-related resource utilization. Population-based linked data were used to retrospectively ascertain DTC patients from the Ontario Cancer Registry, age <30 years at diagnosis between 1992 and 2011. DTC cases were individually matched 1:10 to the general population on age, sex, diagnosis year, and rural status. Billing records for all-cause hospitalizations, emergency department visits, pulmonary subspecialist visits, and chest imaging were compared using incidence rate ratios (IRR). A total of 2456 individuals with DTC were identified, with women representing the majority (82.8%) of cases. Compared to controls, hospitalization and emergency department visit IRRs were 2.56 (95% CI, 2.49–2.63) and 2.22 (95% CI, 2.18–2.26), respectively. An excess of pulmonary diagnostic imaging was observed for chest radiography (IRR, 2.7; 95% CI, 2.6–2.8) and pulmonary CT’s (IRR, 17.5; 95% CI, 15.8–19.3). Patients who underwent radioactive iodine therapy had a higher incidence of pulmonary-related healthcare utilization than those who did not. The highest healthcare utilization for all modalities was observed in the 30 to 90 days after DTC diagnosis with a steady decline further from diagnosis; however, elevated utilization was observed throughout the observation period. Health services utilization is high for primary DTC survivors, irrespective of the time since diagnosis. Radioactive iodine therapy is associated with higher rates of utilization. These findings have ramifications for treatment, surveillance and for policy formulation.
Alfred King-yin Lam
The aim is to review the features of 117 primary squamous cell carcinomas of thyroid which meet the histological criteria of the World Health Organization classification of endocrine tumours. The carcinomas occur in 83 women and 34 men (female to male ratio is 2.4 to 1) and with median age at presentation of 64. Half of these squamous cell carcinomas of thyroid were moderately differentiated. PAX-8 protein is a sensitive marker for confirming the thyroid origin of the carcinoma. The carcinoma is also positive for p63, p40, cytokeratins 5/6, 7,19 and negative for cytokeratins 20 and 10/13. P53 overexpression is common. The most important differential diagnosis is direct infiltration or metastatic involvement by squamous cell carcinoma from other organs. Limited mutation analysis revealed BRAF mutation in some squamous cell carcinomas of the thyroid. The genetic profile appears to be different from anaplastic thyroid carcinomas. Primary squamous cell carcinoma of thyroid had lymph node involvement in 59% and distant metastases in 26%. The median survival of the patients was 8 months. Curative surgery offers the best survival for the patients with the carcinoma. To conclude, primary squamous cell carcinoma of the thyroid gland has distinctive clinical, pathological and molecular profiles. It is important to recognize this unique variant of thyroid carcinoma for possible curative surgical resection and to do more genomic works on the entity to uncover the molecular pathogenesis.
Olimpia Alice Manzardo, Miriam Cellini, Rita Indirli, Alessia Dolci, Paolo Colombo, Flaminia Carrone, Elisabetta Lavezzi, Giovanna Mantovani, Gherardo Mazziotti, Maura Arosio, and Andrea Gerardo Antonio Lania
TNM 8th edition introduces changes in the staging of patients with differentiated thyroid carcinoma (DTC). This study aims at assessing the value of TNM 8th edition in predicting response to therapy and structural recurrence of DTC. Four hundred and eighty DTC patients were retrospectively evaluated by 7th and 8th editions of TNM staging system in relationship with risk stratification, response to therapy and recurrence of disease as defined by 2015 ATA guidelines. As compared to the 7th edition, TNM 8th led to downstage 136 patients (28.3%), with 97.5% of patients falling into lower stages (I–II) and only 2.5% remaining in higher stages (III–IV) (P < 0.001). Patients who were downstaged in stages I–II by TNM 8th were classified more frequently at intermediate-high risk (P < 0.001), had more frequently structural incomplete response to therapy (P = 0.009) and had higher risk of structural recurrence (P = 0.002) as compared to patients who were in the same TNM stages but were not downstaged. Specifically, the risk of structural recurrence was significantly higher in patients in whom the downstaging was induced by changes in tumour classification (hazard ratio (HR) 6.18, 95% CI 2.20–17.40; P = 0.001) but not in those who were downstaged for the increase in age cut-off (HR 2.80, 95% CI 0.86–9.19; P = 0.09). In conclusion, TNM 8th edition did not show reliability in predicting aggressiveness of DTC. In fact, the downstaging of DTC patients especially when performed due to changes in tumour classification may overlook patients predisposed to structural recurrence, potentially causing uncertainty in the therapeutic decision-making at the time of disease’s diagnosis.