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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

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Aleksandra Rusin Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

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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

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Kimal Rajapakshe Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

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Matthew Robertson Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

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Darlene Skapura Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

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Cammy Mason Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

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Karen Berman De Ruiz Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

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Alexey Mikhailovich Tyryshkin Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

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Jenny Deng Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

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Jin Na Shin Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

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Warren Fiskus Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

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Jianrong Dong Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

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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

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Nora M Navone Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas Anderson Cancer Center, Houston, Texas, USA

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Christel M Davis Avera Institute for Human Genetics, Sioux Falls, South Dakota, USA

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Erik A Ehli Avera Institute for Human Genetics, Sioux Falls, South Dakota, USA

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Cristian Coarfa Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, USA
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

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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

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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.

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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

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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

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Aurel Perren Institute of Pathology, University of Bern, Bern, Switzerland

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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

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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

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Inger Marie B Lothe Department of Pathology, Oslo University Hospital, Oslo, Norway

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Anne Couvelard Department of Pathology, Université de Paris, Bichat Hospital, AP-HP, Paris, France

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Geir Olav Hjortland Department of Oncology, Oslo University Hospital, Oslo, Norway

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Anna Sundlöv Departmentt of Oncology, Skåne University Hospital, Lund, Sweden
Department of Medical Radiation Physics, Lund University, Lund, Sweden

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Johanna Svensson Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden

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Harrish Garresori Department of Oncology, Stavanger University Hospital, Stavanger, Norway

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Christian Kersten Department of Research, Hospital of Southern Norway, Kristiansand, Norway

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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

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Sönke Detlefsen Department of Pathology, Odense University Hospital, Odense, Denmark
Department of Clinical Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

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Merete Krogh Department of Oncology, Odense University Hospital, Odense, Denmark

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Halfdan Sorbye Department of Oncology, Haukeland University Hospital, Bergen, Norway
Department of Clinical Science, University of Bergen, Bergen, Norway

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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

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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.

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Tania Moujaber Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Crown Princess Mary Cancer Centre, Westmead Hospital, Western Sydney Local Health District, New South Wales, Australia
Blacktown Cancer and Haematology Centre, Blacktown Hospital, Western Sydney Local Health District, New South Wales, Australia

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Rosemary L Balleine Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Children’s Medical Research Institute, Sydney, New South Wales, Australia

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Bo Gao Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Crown Princess Mary Cancer Centre, Westmead Hospital, Western Sydney Local Health District, New South Wales, Australia
Blacktown Cancer and Haematology Centre, Blacktown Hospital, Western Sydney Local Health District, New South Wales, Australia

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Ida Madsen Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Department of Gynaecological Oncology, Westmead Hospital, Western Sydney Local Health District, New South Wales, Australia

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Paul R Harnett Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Crown Princess Mary Cancer Centre, Westmead Hospital, Western Sydney Local Health District, New South Wales, Australia

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Anna DeFazio Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
Department of Gynaecological Oncology, Westmead Hospital, Western Sydney Local Health District, New South Wales, Australia
The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council New South Wales, Sydney, New South Wales, Australia

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Low-grade serous ovarian cancer (LGSC) is a morphologically and molecularly distinct subtype of ovarian cancer, accounting for ~10% of serous carcinomas. Women typically present at a younger age and have a protracted clinical course compared with the more common, high-grade serous ovarian cancer. Currently, the primary treatment of LGSC is the same as other epithelial ovarian cancer subtypes, with treatment for most patients comprised of debulking surgery and platinum/taxane chemotherapy. Primary surgical cytoreduction to no visible residual disease remains a key prognostic factor; however, the use of platinum-based chemotherapy in both upfront and relapsed setting is being questioned due to low response rates in LGSC. Most LGSC expresses steroid hormone receptors, and selected patients may benefit from endocrine maintenance therapy following chemotherapy, in particular, those with evidence of residual disease at completion of surgery. In the recurrent setting, while hormonal therapies may offer disease stabilisation with relatively low toxicity, objective response rates remain low. Strategies to increase response rates, including combining with CDK4/6 inhibitors, are being investigated. LGSC has a high prevalence of activating somatic mutations in mitogen-activated protein kinase pathway genes, most commonly in KRAS, BRAF and NRAS. Trametinib, a MEK inhibitor, has shown efficacy over chemotherapy and endocrine therapy. The use of combination targeted therapies, immunotherapy and anti-angiogenic agents, remain active areas of investigation for the treatment of LGSC.

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Courtney A Dreyer Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, California, USA

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Kacey VanderVorst Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, California, USA

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Savannah Free Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, California, USA

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Ashley Rowson-Hodel Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, California, USA

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Kermit L Carraway III Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, California, USA

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A major barrier to the emergence of distant metastases is the survival of circulating tumor cells (CTCs) within the vasculature. Lethal stressors, including shear forces from blood flow, anoikis arising from cellular detachment, and exposure to natural killer cells, combine to subvert the ability of primary tumor cells to survive and ultimately seed distant lesions. Further attenuation of this rate-limiting process via therapeutic intervention offers a very attractive opportunity for improving cancer patient outcomes, in turn prompting the need for a deeper understanding of the molecular and cellular mechanisms underlying CTC viability. MUC4 is a very large and heavily glycosylated protein expressed at the apical surfaces of the epithelia of a variety of tissues, is involved in cellular growth signaling and adhesiveness, and contributes to the protection and lubrication of cellular linings. Analysis of patient-matched breast tumor specimens has demonstrated that MUC4 protein levels are upregulated in metastatic lesions relative to primary tumor among all breast tumor subtypes, pointing to a possible selective advantage for MUC4 overexpression in metastasis. Analysis of a genetically engineered mouse model of HER2-positive breast cancer has demonstrated that metastatic efficiency is markedly suppressed with Muc4 deletion and Muc4-knockout tumor cells are poorly associated with platelets and white blood cells known to support CTC viability. In this review, we discuss the diverse roles of MUC4 in tumor progression and metastasis and propose that intervening in MUC4 intercellular interactions with binding partners on blood-borne aggregating cells could potentially thwart breast cancer metastatic efficiency.

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

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Maria Prange-Barczynska Target Discovery Institute, University of Oxford, Oxford, UK
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK

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Emma J Hodson The Francis Crick Institute, London, UK
The Department of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK

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James W Fielding Target Discovery Institute, University of Oxford, Oxford, UK
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK

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Xiaotong Cheng Target Discovery Institute, University of Oxford, Oxford, UK
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK

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Joanna D C C Lima Target Discovery Institute, University of Oxford, Oxford, UK

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Samvid Kurlekar Target Discovery Institute, University of Oxford, Oxford, UK

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Gillian Douglas BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK

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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

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Tammie Bishop Target Discovery Institute, University of Oxford, Oxford, UK

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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.

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James F H Pittaway Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Constantinos Lipsos Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Katia Mariniello Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Leonardo Guasti Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Delta-like non-canonical Notch ligand 1 (DLK1) is a cleavable single-pass transmembrane protein and a member of the Notch/Delta/Serrate family. It is paternally expressed and belongs to a group of imprinted genes located on chromosome band 14q32 in humans and 12qF1 in mice. DLK1 is expressed in many human tissues during embryonic development but in adults expression is low and is mostly restricted to (neuro)endocrine tissues and other immature stem/progenitor cells (notably hepatoblasts). However, DLK1 is expressed at a high frequency in many common malignancies (liver, breast, brain, pancreas, colon and lung). More recently, high levels of expression have been identified in endocrine-related cancers such as ovarian and adrenocortical carcinoma. There is growing evidence that DLK1 expression in cancer is associated with worse prognosis and that DLK1 may be a marker of cancer stem cells. Although the exact mechanism through which DLK1 functions is not fully understood, it is known to maintain cells in an undifferentiated phenotype and has oncogenic properties. These effects are partly exacted through interaction with the Notch signalling pathway. In this review, we have detailed the functional role of DLK1 within physiology and malignancy and posited a mechanism for how it exacts its oncogenic effects. In describing the expression of DLK1 in cancer and in healthy tissue, we have highlighted the potential for its use both as a biomarker and as a potential therapeutic target.

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Hany Sadek Ayoub Ghaly School of Pharmacy (A15), The University of Sydney, Sydney, New South Wales, Australia

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Pegah Varamini School of Pharmacy (A15), The University of Sydney, Sydney, New South Wales, Australia
The University of Sydney Nano Institute, The University of Sydney, Sydney, New South Wales, Australia

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Cancer is the uncontrolled division of abnormal cells in a specific organ. Globally, about one in six deaths is due to cancer. Despite the plethora of research being undertaken worldwide to find a cure for cancer, it remains a significant challenge. Cancer targeting via agents designed to interfere with some specifically or highly expressed molecules in cancer cells has been a shift in the treatment of various forms of cancers. The development of drug delivery systems, specifically to cancer cells, is a common approach that succeeded in increasing the efficacy and reducing the side effects of different anticancer agents. Gonadotropin-releasing hormone (GnRH) is a naturally occurring hormone with receptors overexpressed in many types of cancers related or unrelated to the reproductive system. Several drug delivery systems were developed using GnRH derivatives as targeting agents. In this review, we first discuss the role of GnRH and its receptors in cancer. Then, we provide a detailed insight into different delivery systems developed using GnRH derivatives as targeting agents in various types of GnRH receptor overexpressing cancers. Some promising findings from these studies indicate that GnRH receptor targeting is a potential strategy to efficiently guide anticancer therapeutics, diagnostic agents, and nucleic acids directly to cancer cells. Lastly, some limitations of the current research and suggestions for more successful outcomes in clinical trials of these delivery systems are highlighted.

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

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James M Welch Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Gayathri Kapoor Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Vaishali I Parekh Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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David S Schrump Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

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R Taylor Ripley Division of General Thoracic Surgery, Baylor College of Medicine, Houston, Texas, USA

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Mary F Walter NIDDK Clinical Core, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Jaydira Del Rivero Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

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Smita Jha Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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William F Simonds Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Robert T Jensen Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Lee S Weinstein Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Jenny E Blau Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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Sunita K Agarwal Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

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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.

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Garcilaso Riesco-Eizaguirre Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
Department of Endocrinology and Nutrition, Hospital Universitario de Móstoles, Madrid, Spain
Molecular Endocrinology Group, Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain
Centro de Investigaciones Biomédicas en Red, CIBERONC, Instituto de Salud Carlos III, Madrid, Spain

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Pilar Santisteban Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
Centro de Investigaciones Biomédicas en Red, CIBERONC, Instituto de Salud Carlos III, Madrid, Spain

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Antonio De la Vieja Centro de Investigaciones Biomédicas en Red, CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
Endocrine Tumors Unit, Unidad Funcional de Investigación en Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, Madrid, Spain

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The sodium/iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland and into several extrathyroidal tissues. NIS-mediated iodide uptake plays a pivotal role in the biosynthesis of thyroid hormones, of which iodide is an essential constituent. For 80 years, radioiodide has been used for the diagnosis and treatment of thyroid cancer, a successful theranostic agent that is extending its use to extrathyroidal malignancies. The purpose of this review is to focus on the most recent findings regarding the mechanisms that regulate NIS both in thyroid and extra-thyroidal tissues. Among other issues, we discuss the different transcriptional regulatory elements that govern NIS transcription in different tissues, the epigenetic modifications that regulate its expression, and the role that miRNAs play in fine-tuning NIS after being transcribed. A review on how hormones, cytokines, and iodide itself regulate NIS is provided. We also review the present stage of understanding NIS dysregulation in cancer, occupied mainly by convergent signaling pathways and by new insights in the route that NIS follows through different subcellular compartments to the plasma membrane. Furthermore, we cover NIS distribution and function in the increasing number of extrathyroidal tissues that express the symporter, as well as the role that NIS plays in tumor progression independently of its transport activity.

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