Browse

You are looking at 51 - 60 of 196 items for

  • Refine by access: Open Access content only x
Clear All
William Beimers Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

Search for other papers by William Beimers in
Google Scholar
PubMed
Close
,
Megan Braun Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

Search for other papers by Megan Braun in
Google Scholar
PubMed
Close
,
Kaleb Schwinefus Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

Search for other papers by Kaleb Schwinefus in
Google Scholar
PubMed
Close
,
Keenan Pearson Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

Search for other papers by Keenan Pearson in
Google Scholar
PubMed
Close
,
Brandon Wilbanks Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

Search for other papers by Brandon Wilbanks in
Google Scholar
PubMed
Close
, and
Louis James Maher Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA

Search for other papers by Louis James Maher in
Google Scholar
PubMed
Close

A fascinating class of familial paraganglioma (PGL) neuroendocrine tumors is driven by the loss of the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) resulting in succinate accumulation as an oncometabolite and other metabolic derangements. Here, we exploit a Saccharomyces cerevisiae yeast model of SDH loss where accumulating succinate, and possibly reactive oxygen species, poison a dioxygenase enzyme required for sulfur scavenging. Using this model, we performed a chemical suppression screen for compounds that relieve dioxygenase inhibition. After testing 1280 pharmaceutically active compounds, we identified meclofenoxate HCl and its hydrolysis product, dimethylaminoethanol (DMAE), as suppressors of dioxygenase intoxication in SDH-loss yeast cells. We show that DMAE acts to alter metabolism so as to normalize the succinate:2-ketoglutarate ratio, improving dioxygenase function. This study raises the possibility that oncometabolite effects might be therapeutically suppressed by drugs that rewire metabolism to reduce the flux of carbon into pathological metabolic pathways.

Open access
Susan Richter Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Search for other papers by Susan Richter in
Google Scholar
PubMed
Close
,
Bei Qiu Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Search for other papers by Bei Qiu in
Google Scholar
PubMed
Close
,
Mirthe Ghering Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands

Search for other papers by Mirthe Ghering in
Google Scholar
PubMed
Close
,
Carola Kunath Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Search for other papers by Carola Kunath in
Google Scholar
PubMed
Close
,
Georgiana Constantinescu Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Search for other papers by Georgiana Constantinescu in
Google Scholar
PubMed
Close
,
Charlotte Luths Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Search for other papers by Charlotte Luths in
Google Scholar
PubMed
Close
,
Christina Pamporaki Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Search for other papers by Christina Pamporaki in
Google Scholar
PubMed
Close
,
Nicole Bechmann Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Search for other papers by Nicole Bechmann in
Google Scholar
PubMed
Close
,
Leah Meuter Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Leah Meuter in
Google Scholar
PubMed
Close
,
Aleksandra Kwapiszewska Department of Hypertension, Institute of Cardiology, Warsaw, Poland

Search for other papers by Aleksandra Kwapiszewska in
Google Scholar
PubMed
Close
,
Timo Deutschbein Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
Medicover Oldenburg MVZ, Oldenburg, Germany

Search for other papers by Timo Deutschbein in
Google Scholar
PubMed
Close
,
Svenja Nölting Medizinische Klinik and Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
Department for Endocrinology, Diabetology and Clinical Nutrition, UniversitätsSpital Zürich, Zurich, Switzerland

Search for other papers by Svenja Nölting in
Google Scholar
PubMed
Close
,
Mirko Peitzsch Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Search for other papers by Mirko Peitzsch in
Google Scholar
PubMed
Close
,
Mercedes Robledo Hereditary Endocrine Cancer Group, CNIO, Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

Search for other papers by Mercedes Robledo in
Google Scholar
PubMed
Close
,
Aleksander Prejbisz Department of Hypertension, Institute of Cardiology, Warsaw, Poland

Search for other papers by Aleksander Prejbisz in
Google Scholar
PubMed
Close
,
Karel Pacak Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Karel Pacak in
Google Scholar
PubMed
Close
,
Volker Gudziol Department of Otorhinolaryngology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und Hals-Chirurgie, Plastische Operationen, Städtisches Klinikum Dresden, Akademisches Lehrkrankenhaus der Technischen Universität Dresden, Dresden, Germany

Search for other papers by Volker Gudziol in
Google Scholar
PubMed
Close
,
Henri J L M Timmers Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands

Search for other papers by Henri J L M Timmers in
Google Scholar
PubMed
Close
, and
Graeme Eisenhofer Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Search for other papers by Graeme Eisenhofer in
Google Scholar
PubMed
Close

Head and neck paragangliomas (HNPGLs) are tumors of parasympathetic origin that occur at variable locations and are often secondary to germline mutations in succinate dehydrogenase (SDH) subunit genes. Occasionally, these tumors produce catecholamines. Here, we assessed whether different locations of HNPGLs relate to the presence of SDHx mutations, catecholamine production and other presentations. In this multicenter study, we collected clinical and biochemical data from 244 patients with HNPGLs and 71 patients without HNPGLs. We clarified that jugulotympanic HNPGLs have distinct features. In particular, 88% of jugulotympanic HNPGLs arose in women, among whom only 24% occurred due to SDHx mutations compared to 55% in men. Jugulotympanic HNPGLs were also rarely bilateral, were of a smaller size and were less often metastatic compared to carotid body and vagal HNPGLs. Furthermore, we showed that plasma concentrations of methoxytyramine (MTY) were higher (P  < 0.0001) in patients with HNPGL than without HNPGL, whereas plasma normetanephrine did not differ. Only 3.7% of patients showed strong increases in plasma normetanephrine. Plasma MTY was positively related to tumor size but did not relate to the presence of SDHx mutations or tumor location. Our findings confirm that increases in plasma MTY represent the main catecholamine-related biochemical feature of patients with HNPGLs. We expect that more sensitive analytical methods will make biochemical testing of HNPGLs more practical in the future and enable more than the current 30% of patients to be identified with dopamine-producing HNPGLs. The sex-dependent differences in the development of HNPGLs may have relevance to the diagnosis, management and outcomes of these tumors.

Open access
Salma Kaochar Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Salma Kaochar in
Google Scholar
PubMed
Close
,
Aleksandra Rusin Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Aleksandra Rusin in
Google Scholar
PubMed
Close
,
Christopher Foley Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Christopher Foley in
Google Scholar
PubMed
Close
,
Kimal Rajapakshe Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Kimal Rajapakshe in
Google Scholar
PubMed
Close
,
Matthew Robertson Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Matthew Robertson in
Google Scholar
PubMed
Close
,
Darlene Skapura Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Darlene Skapura in
Google Scholar
PubMed
Close
,
Cammy Mason Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Cammy Mason in
Google Scholar
PubMed
Close
,
Karen Berman De Ruiz Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Karen Berman De Ruiz in
Google Scholar
PubMed
Close
,
Alexey Mikhailovich Tyryshkin Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Alexey Mikhailovich Tyryshkin in
Google Scholar
PubMed
Close
,
Jenny Deng Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Jenny Deng in
Google Scholar
PubMed
Close
,
Jin Na Shin Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Jin Na Shin in
Google Scholar
PubMed
Close
,
Warren Fiskus Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Warren Fiskus in
Google Scholar
PubMed
Close
,
Jianrong Dong Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Jianrong Dong in
Google Scholar
PubMed
Close
,
Shixia Huang Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
Department of Education, Innovation, and Technology, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Shixia Huang in
Google Scholar
PubMed
Close
,
Nora M Navone Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Nora M Navone in
Google Scholar
PubMed
Close
,
Christel M Davis Avera Institute for Human Genetics, Sioux Falls, South Dakota, USA

Search for other papers by Christel M Davis in
Google Scholar
PubMed
Close
,
Erik A Ehli Avera Institute for Human Genetics, Sioux Falls, South Dakota, USA

Search for other papers by Erik A Ehli in
Google Scholar
PubMed
Close
,
Cristian Coarfa Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Cristian Coarfa in
Google Scholar
PubMed
Close
, and
Nicholas Mitsiades Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by Nicholas Mitsiades in
Google Scholar
PubMed
Close

Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.

Open access
Andreas Venizelos K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Oncology, Haukeland University Hospital, Bergen, Norway

Search for other papers by Andreas Venizelos in
Google Scholar
PubMed
Close
,
Hege Elvebakken Department of Oncology, Ålesund Hospital, Møre og Romsdal Hospital Trust, Ålesund, Norway
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway

Search for other papers by Hege Elvebakken in
Google Scholar
PubMed
Close
,
Aurel Perren Institute of Pathology, University of Bern, Bern, Switzerland

Search for other papers by Aurel Perren in
Google Scholar
PubMed
Close
,
Oleksii Nikolaienko K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Oncology, Haukeland University Hospital, Bergen, Norway

Search for other papers by Oleksii Nikolaienko in
Google Scholar
PubMed
Close
,
Wei Deng K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Oncology, Haukeland University Hospital, Bergen, Norway

Search for other papers by Wei Deng in
Google Scholar
PubMed
Close
,
Inger Marie B Lothe Department of Pathology, Oslo University Hospital, Oslo, Norway

Search for other papers by Inger Marie B Lothe in
Google Scholar
PubMed
Close
,
Anne Couvelard Department of Pathology, Université de Paris, Bichat Hospital, AP-HP, Paris, France

Search for other papers by Anne Couvelard in
Google Scholar
PubMed
Close
,
Geir Olav Hjortland Department of Oncology, Oslo University Hospital, Oslo, Norway

Search for other papers by Geir Olav Hjortland in
Google Scholar
PubMed
Close
,
Anna Sundlöv Departmentt of Oncology, Skåne University Hospital, Lund, Sweden
Department of Medical Radiation Physics, Lund University, Lund, Sweden

Search for other papers by Anna Sundlöv in
Google Scholar
PubMed
Close
,
Johanna Svensson Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden

Search for other papers by Johanna Svensson in
Google Scholar
PubMed
Close
,
Harrish Garresori Department of Oncology, Stavanger University Hospital, Stavanger, Norway

Search for other papers by Harrish Garresori in
Google Scholar
PubMed
Close
,
Christian Kersten Department of Research, Hospital of Southern Norway, Kristiansand, Norway

Search for other papers by Christian Kersten in
Google Scholar
PubMed
Close
,
Eva Hofsli Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
Department of Oncology, St.Olavs Hospital, Trondheim, Norway

Search for other papers by Eva Hofsli in
Google Scholar
PubMed
Close
,
Sönke Detlefsen Department of Pathology, Odense University Hospital, Odense, Denmark
Department of Clinical Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

Search for other papers by Sönke Detlefsen in
Google Scholar
PubMed
Close
,
Merete Krogh Department of Oncology, Odense University Hospital, Odense, Denmark

Search for other papers by Merete Krogh in
Google Scholar
PubMed
Close
,
Halfdan Sorbye Department of Oncology, Haukeland University Hospital, Bergen, Norway
Department of Clinical Science, University of Bergen, Bergen, Norway

Search for other papers by Halfdan Sorbye in
Google Scholar
PubMed
Close
, and
Stian Knappskog K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Oncology, Haukeland University Hospital, Bergen, Norway

Search for other papers by Stian Knappskog in
Google Scholar
PubMed
Close

High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments.

Open access
Luise Eckardt Target Discovery Institute, University of Oxford, Oxford, UK
Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany

Search for other papers by Luise Eckardt in
Google Scholar
PubMed
Close
,
Maria Prange-Barczynska Target Discovery Institute, University of Oxford, Oxford, UK
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK

Search for other papers by Maria Prange-Barczynska in
Google Scholar
PubMed
Close
,
Emma J Hodson The Francis Crick Institute, London, UK
The Department of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK

Search for other papers by Emma J Hodson in
Google Scholar
PubMed
Close
,
James W Fielding Target Discovery Institute, University of Oxford, Oxford, UK
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK

Search for other papers by James W Fielding in
Google Scholar
PubMed
Close
,
Xiaotong Cheng Target Discovery Institute, University of Oxford, Oxford, UK
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK

Search for other papers by Xiaotong Cheng in
Google Scholar
PubMed
Close
,
Joanna D C C Lima Target Discovery Institute, University of Oxford, Oxford, UK

Search for other papers by Joanna D C C Lima in
Google Scholar
PubMed
Close
,
Samvid Kurlekar Target Discovery Institute, University of Oxford, Oxford, UK

Search for other papers by Samvid Kurlekar in
Google Scholar
PubMed
Close
,
Gillian Douglas BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK

Search for other papers by Gillian Douglas in
Google Scholar
PubMed
Close
,
Peter J Ratcliffe Target Discovery Institute, University of Oxford, Oxford, UK
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
The Francis Crick Institute, London, UK

Search for other papers by Peter J Ratcliffe in
Google Scholar
PubMed
Close
, and
Tammie Bishop Target Discovery Institute, University of Oxford, Oxford, UK

Search for other papers by Tammie Bishop in
Google Scholar
PubMed
Close

Despite a general role for the HIF hydroxylase system in cellular oxygen sensing and tumour hypoxia, cancer-associated mutations of genes in this pathway, including PHD2, PHD1, EPAS1 (encoding HIF-2α) are highly tissue-restricted, being observed in pseudohypoxic pheochromocytoma and paraganglioma (PPGL) but rarely, if ever, in other tumours. In an effort to understand that paradox and gain insights into the pathogenesis of pseudohypoxic PPGL, we constructed mice in which the principal HIF prolyl hydroxylase, Phd2, is inactivated in the adrenal medulla using TH-restricted Cre recombinase. Investigation of these animals revealed a gene expression pattern closely mimicking that of pseudohypoxic PPGL. Spatially resolved analyses demonstrated a binary distribution of two contrasting patterns of gene expression among adrenal medullary cells. Phd2 inactivation resulted in a marked shift in this distribution towards a Pnmt /Hif-2α +/Rgs5 + population. This was associated with morphological abnormalities of adrenal development, including ectopic TH+ cells within the adrenal cortex and external to the adrenal gland. These changes were ablated by combined inactivation of Phd2 with Hif-2α, but not Hif-1α. However, they could not be reproduced by inactivation of Phd2 in adult life, suggesting that they arise from dysregulation of this pathway during adrenal development. Together with the clinical observation that pseudohypoxic PPGL manifests remarkably high heritability, our findings suggest that this type of tumour likely arises from dysregulation of a tissue-restricted action of the PHD2/HIF-2α pathway affecting adrenal development in early life and provides a model for the study of the relevant processes.

Open access
Adel Mandl Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Adel Mandl in
Google Scholar
PubMed
Close
,
James M Welch Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by James M Welch in
Google Scholar
PubMed
Close
,
Gayathri Kapoor Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Gayathri Kapoor in
Google Scholar
PubMed
Close
,
Vaishali I Parekh Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Vaishali I Parekh in
Google Scholar
PubMed
Close
,
David S Schrump Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Search for other papers by David S Schrump in
Google Scholar
PubMed
Close
,
R Taylor Ripley Division of General Thoracic Surgery, Baylor College of Medicine, Houston, Texas, USA

Search for other papers by R Taylor Ripley in
Google Scholar
PubMed
Close
,
Mary F Walter NIDDK Clinical Core, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Mary F Walter in
Google Scholar
PubMed
Close
,
Jaydira Del Rivero Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

Search for other papers by Jaydira Del Rivero in
Google Scholar
PubMed
Close
,
Smita Jha Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Smita Jha in
Google Scholar
PubMed
Close
,
William F Simonds Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by William F Simonds in
Google Scholar
PubMed
Close
,
Robert T Jensen Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Robert T Jensen in
Google Scholar
PubMed
Close
,
Lee S Weinstein Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Lee S Weinstein in
Google Scholar
PubMed
Close
,
Jenny E Blau Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Jenny E Blau in
Google Scholar
PubMed
Close
, and
Sunita K Agarwal Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Sunita K Agarwal in
Google Scholar
PubMed
Close

Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome carry germline heterozygous loss-of-function mutations in the MEN1 gene which predisposes them to develop various endocrine and non-endocrine tumors. Over 90% of the tumors show loss of heterozygosity (LOH) at chromosome 11q13, the MEN1 locus, due to somatic loss of the wild-type MEN1 allele. Thymic neuroendocrine tumors (NETs) or thymic carcinoids are uncommon in MEN1 patients but are a major cause of mortality. LOH at the MEN1 locus has not been demonstrated in thymic tumors. The goal of this study was to investigate the molecular aspects of MEN1-associated thymic tumors including LOH at the MEN1 locus and RNA-sequencing (RNA-Seq) to identify genes associated with tumor development and potential targeted therapy. A retrospective chart review of 294 patients with MEN1 germline mutations identified 14 patients (4.8%) with thymic tumors (12 thymic NETs and 2 thymomas). LOH at the MEN1 locus was identified in 10 tumors including the 2 thymomas, demonstrating that somatic LOH at the MEN1 locus is also the mechanism for thymic tumor development. Unsupervised principal component analysis and hierarchical clustering of RNA-Seq data showed that thymic NETs formed a homogenous transcriptomic group separate from thymoma and normal thymus. KSR2 (kinase suppressor of Ras 2), that promotes Ras-mediated signaling, was abundantly expressed in thymic NETs, a potential therapeutic target. The molecular insights gained from our study about thymic tumors combined with similar data from other MEN1-associated tumors may lead to better surveillance and treatment of these rare tumors.

Open access
Ville Paakinaho Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland

Search for other papers by Ville Paakinaho in
Google Scholar
PubMed
Close
and
Jorma J Palvimo Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland

Search for other papers by Jorma J Palvimo in
Google Scholar
PubMed
Close

Steroid receptors (SRs) constitute an important class of signal-dependent transcription factors (TFs). They regulate a variety of key biological processes and are crucial drug targets in many disease states. In particular, estrogen (ER) and androgen receptors (AR) drive the development and progression of breast and prostate cancer, respectively. Thus, they represent the main specific drug targets in these diseases. Recent evidence has suggested that the crosstalk between signal-dependent TFs is an important step in the reprogramming of chromatin sites; a signal-activated TF can expand or restrict the chromatin binding of another TF. This crosstalk can rewire gene programs and thus alter biological processes and influence the progression of disease. Lately, it has been postulated that there may be an important crosstalk between the AR and the ER with other SRs. Especially, progesterone (PR) and glucocorticoid receptor (GR) can reprogram chromatin binding of ER and gene programs in breast cancer cells. Furthermore, GR can take the place of AR in antiandrogen-resistant prostate cancer cells. Here, we review the current knowledge of the crosstalk between SRs in breast and prostate cancers. We emphasize how the activity of ER and AR on chromatin can be modulated by other SRs on a genome-wide scale. We also highlight the knowledge gaps in the interplay of SRs and their complex interactions with other signaling pathways and suggest how to experimentally fill in these gaps.

Open access
Alexa Childs UCL Cancer Institute, University College London, London, UK

Search for other papers by Alexa Childs in
Google Scholar
PubMed
Close
,
Christopher D Steele UCL Cancer Institute, University College London, London, UK

Search for other papers by Christopher D Steele in
Google Scholar
PubMed
Close
,
Clare Vesely UCL Cancer Institute, University College London, London, UK

Search for other papers by Clare Vesely in
Google Scholar
PubMed
Close
,
Francesca M Rizzo UCL Cancer Institute, University College London, London, UK

Search for other papers by Francesca M Rizzo in
Google Scholar
PubMed
Close
,
Leah Ensell UCL Cancer Institute, University College London, London, UK

Search for other papers by Leah Ensell in
Google Scholar
PubMed
Close
,
Helen Lowe UCL Cancer Institute, University College London, London, UK

Search for other papers by Helen Lowe in
Google Scholar
PubMed
Close
,
Pawan Dhami UCL Cancer Institute, University College London, London, UK

Search for other papers by Pawan Dhami in
Google Scholar
PubMed
Close
,
Heli Vaikkinen UCL Cancer Institute, University College London, London, UK

Search for other papers by Heli Vaikkinen in
Google Scholar
PubMed
Close
,
Tu Vinh Luong Department of Histopathology, Royal Free London NHS Foundation Trust, London, UK

Search for other papers by Tu Vinh Luong in
Google Scholar
PubMed
Close
,
Lucia Conde UCL Cancer Institute, University College London, London, UK

Search for other papers by Lucia Conde in
Google Scholar
PubMed
Close
,
Javier Herrero UCL Cancer Institute, University College London, London, UK

Search for other papers by Javier Herrero in
Google Scholar
PubMed
Close
,
Martyn Caplin Department of Gastroenterology, Royal Free London NHS Foundation Trust, London, UK

Search for other papers by Martyn Caplin in
Google Scholar
PubMed
Close
,
Christos Toumpanakis Department of Gastroenterology, Royal Free London NHS Foundation Trust, London, UK

Search for other papers by Christos Toumpanakis in
Google Scholar
PubMed
Close
,
Christina Thirlwell UCL Cancer Institute, University College London, London, UK
Department of Oncology, Royal Free London NHS Foundation Trust, London, UK

Search for other papers by Christina Thirlwell in
Google Scholar
PubMed
Close
,
John A Hartley UCL Cancer Institute, University College London, London, UK

Search for other papers by John A Hartley in
Google Scholar
PubMed
Close
,
Nischalan Pillay Research Department of Pathology, Cancer Institute, University College London, London, UK
Department of Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, UK

Search for other papers by Nischalan Pillay in
Google Scholar
PubMed
Close
, and
Tim Meyer UCL Cancer Institute, University College London, London, UK
Department of Oncology, Royal Free London NHS Foundation Trust, London, UK

Search for other papers by Tim Meyer in
Google Scholar
PubMed
Close

Single-cell profiling of circulating tumor cells (CTCs) as part of a minimally invasive liquid biopsy presents an opportunity to characterize and monitor tumor heterogeneity and evolution in individual patients. In this study, we aimed to compare single-cell copy number variation (CNV) data with tissue and define the degree of intra- and inter-patient genomic heterogeneity. We performed next-generation sequencing (NGS) whole-genome CNV analysis of 125 single CTCs derived from seven patients with neuroendocrine neoplasms (NEN) alongside matched white blood cells (WBC), formalin-fixed paraffin-embedded (FFPE), and fresh frozen (FF) samples. CTC CNV profiling demonstrated recurrent chromosomal alterations in previously reported NEN copy number hotspots, including the prognostically relevant loss of chromosome 18. Unsupervised hierarchical clustering revealed CTCs with distinct clonal lineages as well as significant intra- and inter-patient genomic heterogeneity, including subclonal alterations not detectable by bulk analysis and previously unreported in NEN. Notably, we also demonstrated the presence of genomically distinct CTCs according to the enrichment strategy utilized (EpCAM-dependent vs size-based). This work has significant implications for the identification of therapeutic targets, tracking of evolutionary change, and the implementation of CTC-biomarkers in cancer.

Open access
J T W Kwon Department of Oncology, University of Oxford, Oxford, UK

Search for other papers by J T W Kwon in
Google Scholar
PubMed
Close
,
R J Bryant Department of Oncology, University of Oxford, Oxford, UK
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK

Search for other papers by R J Bryant in
Google Scholar
PubMed
Close
, and
E E Parkes Department of Oncology, University of Oxford, Oxford, UK

Search for other papers by E E Parkes in
Google Scholar
PubMed
Close

The landscape of cancer treatment has been transformed over the past decade by the success of immune-targeting therapies. However, despite sipuleucel-T being the first-ever approved vaccine for cancer and the first immunotherapy licensed for prostate cancer in 2010, immunotherapy has since seen limited success in the treatment of prostate cancer. The tumour microenvironment of prostate cancer presents particular barriers for immunotherapy. Moreover, prostate cancer is distinguished by being one of only two solid tumours where increased T cell-infiltration correlates with a poorer, rather than improved, outlook. Here, we discuss the specific aspects of the prostate cancer microenvironment that converge to create a challenging microenvironment, including myeloid-derived immune cells and cancer-associated fibroblasts. By exploring the immune microenvironment of defined molecular subgroups of prostate cancer, we propose an immunogenomic subtyping approach to single-agent and combination immune-targeting strategies that could lead to improved outcomes in prostate cancer treatment.

Open access
Ha Nguyen Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Ha Nguyen in
Google Scholar
PubMed
Close
,
Komal Shah Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Komal Shah in
Google Scholar
PubMed
Close
,
Steven G Waguespack Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Steven G Waguespack in
Google Scholar
PubMed
Close
,
Mimi I Hu Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Mimi I Hu in
Google Scholar
PubMed
Close
,
Mouhammed Amir Habra Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Mouhammed Amir Habra in
Google Scholar
PubMed
Close
,
Maria E Cabanillas Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Maria E Cabanillas in
Google Scholar
PubMed
Close
,
Naifa L Busaidy Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Naifa L Busaidy in
Google Scholar
PubMed
Close
,
Roland Bassett Division of Science, Department of Biostatistics, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Roland Bassett in
Google Scholar
PubMed
Close
,
Shouhao Zhou Division of Science, Department of Biostatistics, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Shouhao Zhou in
Google Scholar
PubMed
Close
,
Priyanka C Iyer Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Priyanka C Iyer in
Google Scholar
PubMed
Close
,
Garrett Simmons Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Garrett Simmons in
Google Scholar
PubMed
Close
,
Diana Kaya Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Diana Kaya in
Google Scholar
PubMed
Close
,
Marie Pitteloud Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Marie Pitteloud in
Google Scholar
PubMed
Close
,
Sumit K Subudhi Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Sumit K Subudhi in
Google Scholar
PubMed
Close
,
Adi Diab Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Adi Diab in
Google Scholar
PubMed
Close
, and
Ramona Dadu Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas Anderson Cancer Center, Houston, Texas, USA

Search for other papers by Ramona Dadu in
Google Scholar
PubMed
Close

Data on the diagnosis, natural course and management of immune checkpoint inhibitor (ICI)-related hypophysitis (irH) are limited. We propose this study to validate the diagnostic criteria, describe characteristics and hormonal recovery and investigate factors associated with the occurrence and recovery of irH. A retrospective study including patients with suspected irH at the University of Texas MD Anderson Cancer Center from 5/2003 to 8/2017 was conducted. IrH was defined as: (1) ACTH or TSH deficiency plus MRI changes or (2) ACTH and TSH deficiencies plus headache/fatigue in the absence of MRI findings. We found that of 83 patients followed for a median of 1.75 years (range 0.6–3), the proposed criteria used at initial evaluation accurately identified 61/62 (98%) irH cases. In the irH group (n = 62), the most common presentation was headache (60%), fatigue (66%), central hypothyroidism (94%), central adrenal insufficiency (69%) and MRI changes (77%). Compared with non-ipilimumab (ipi) regimens, ipi has a stronger association with irH occurrence (P = 0.004) and a shorter time to irH development (P < 0.01). Thyroid, gonadal and adrenal axis recovery occurred in 24, 58 and 0% patients, respectively. High-dose steroids (HDS) or ICI discontinuation was not associated with hormonal recovery. In the non-irH group (n = 19), one patient had isolated central hypothyroidism and six had isolated central adrenal insufficiency. All remained on hormone therapy at the last follow-up. We propose a strict definition of irH that identifies the vast majority of patients. HDS and ICI discontinuation is not always beneficial. Long-term follow-up to assess recovery is needed.

Open access