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Anton G T Terwisscha van Scheltinga, Annie Ogasawara, Glenn Pacheco, Alexander Vanderbilt, Jeff Tinianow, Nidhi Gupta, Dongwei Li, Ron Firestein, Jan Marik, Suzie J Scales, Simon-Peter Williams
Antibody-drug conjugates (ADCs) use monoclonal antibodies (mAb) as vehicles to deliver potent cytotoxic drugs selectively to tumor cells expressing the target. Molecular imaging with zirconium-89 (89Zr) labeled mAbs recapitulates similar targeting biology and might help predict the efficacy of these ADCs. An anti-mesothelin antibody (AMA, MMOT0530A) was used to make comparisons between its efficacy as an ADC and its tumor uptake as measured by 89Zr immunoPET imaging. Mesothelin-targeted tumor growth inhibition by monomethyl auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), was measured in mice bearing xenografts of ovarian cancer OVCAR-3 X2...
October 19, 2016: Molecular Cancer Therapeutics
Marc A Schneider, Thomas Muley, Nicolas C Kahn, Arne Warth, Michael Thomas, Felix J F Herth, Hendrik Dienemann, Michael Meister
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a short survival time arising from the mesothelial cells of the pleura. Soluble mesothelin-related peptide (SMRP), osteopontin or EFEMP1 (Fibulin-3) are well described biomarkers for malignant mesothelioma with moderate sensitivity and specificity. In this study, we characterized the expression of glycodelin, a marker for risk pregnancy, in MPM by RNA and protein analyses and investigated its potential as a MPM biomarker. We were able to detect glycodelin in the serum of MPM patients...
October 4, 2016: Oncotarget
Alessandra Bonotti, Silvia Simonini, Elena Pantani, Laura Giusti, Elena Donadio, Maria Rosa Mazzoni, Antonio Chella, Letizia Marconi, Nicolino Ambrosino, Marco Lucchi, Alfredo Mussi, Alfonso Cristaudo, Rudy Foddis
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a relatively rare tumor, with the epithelioid type occurring more frequently. Several biomarkers have been suggested for screening and early diagnosis of MPM. Currently, high levels of soluble mesothelin-related peptides (SMRP), plasma osteopontin (pOPN) and vimentin have been reported in patients with MPM as promising markers for diagnosis, but their clinical use in monitoring is still discussed. The aim of our study was to evaluate the usefulness of these substances as markers of the clinical response to treatment in patients suffering from epithelioid mesothelioma...
September 14, 2016: International Journal of Biological Markers
Jingli Zhang, Swati Khanna, Qun Jiang, Christine Alewine, Markku Miettinen, Ira Pastan, Raffit Hassan
PURPOSE: Evaluate anti-tumor efficacy of the reduced immunogenicity anti-mesothelin immunotoxin RG7787 plus nab-Paclitaxel against primary mesothelioma cell lines and tumor xenografts and utility of mesothelin as a biomarker of tumor response. EXPERIMENTAL DESIGN: Early passage human malignant mesothelioma cell lines NCI-Meso16, NCI-Meso19, NCI-Meso21 and NCI-Meso29 were evaluated for sensitivity to RG7787 or nab-Paclitaxel alone or in combination. In addition, the anti-tumor activity of RG7787 plus nab-Paclitaxel was evaluated using NCI-Meso16, NCI-Meso21 and NCI-Meso29 tumor xenografts in immunodeficient mice...
September 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Salma Mahmoud, Mohammed Ibrahim, Ahmed Hago, Yuhong Huang, Yuanyi Wei, Jun Zhang, Qingqing Zhang, Yu Xiao, Jingwen Wang, Munkaila Adam, Yu Guo, Li Wang, Shuting Zhou, Boyi Xin, Wei Xuan
Lymphatic vessels function as transport channels for tumor cells to metastasize from the primary site into the lymph nodes. In this experiment we evaluated the effect of Sulfatase-1 (Sulf-1) on metastasis by upregulating it in murine hepatocarcinoma cell line Hca-F with high lymph node metastatic rate of >75%. The study in vitro showed that up regulation of Sulf-1 in Hca-F cells significantly reduced cell proliferation, migration and invasion (p<0.05). Also, the forced expression of Sulf-1 down regulated Mesothelin (Msln) at both the protein and mRNA levels...
September 10, 2016: Oncotarget
Seunggu J Han, Gerald Reis, Gary Kohanbash, Shruti Shrivastav, Stephen T Magill, Annette M Molinaro, Michael W McDermott, Philip V Theodosopoulos, Manish K Aghi, Mitchel S Berger, Nicholas A Butowski, Igor Barani, Joanna J Phillips, Arie Perry, Hideho Okada
While immunotherapy may offer promising new approaches for high grade meningiomas, little is currently known of the immune landscape in meningiomas. We sought to characterize the immune microenvironment and a potentially targetable antigen mesothelin across WHO grade I-III cases of meningiomas, and how infiltrating immune populations relate to patient outcomes. Immunohistochemistry was performed on tissue microarrays constructed from 96 meningioma cases. The cohort included 16 WHO grade I, 62 WHO grade II, and 18 WHO grade III tumors...
September 13, 2016: Journal of Neuro-oncology
Xiu Fen Liu, Laiman Xiang, Qi Zhou, Jean-Philippe Carralot, Marco Prunotto, Gerhard Niederfellner, Ira Pastan
RG7787 is a mesothelin-targeted immunotoxin designed to have low-immunogenicity, high-cytotoxic activity and fewer side effects. RG7787 kills many types of mesothelin-expressing cancer cells lines and causes tumor regressions in mice. Safety and immunogenicity of RG7787 is now being assessed in a phase I trial. To enhance the antitumor activity of RG7787, we screened for clinically used drugs that can synergize with RG7787. Actinomycin D is a potent transcription inhibitor that is used for treating several cancers...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Olca Basturk, Sun M Chung, Ralph H Hruban, N Volkan Adsay, Gokce Askan, Christine Iacobuzio-Donahue, Serdar Balci, Sui Y Zee, Bahar Memis, Jinru Shia, David S Klimstra
Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is classified as a variant of intraductal papillary mucinous neoplasm (IPMN) in the WHO guidelines. However, the neoplastic cells of IOPNs are unique, with distinctive architecture/oncocytic cytoplasm. Although molecular/immunohistochemical features of other IPMN variants have been extensively studied, those of IOPNs have not been well characterized. Expression profile of antibodies associated with genetic alterations previously described for ductal adenocarcinomas (DAs) and IPMNs (SMAD4/β-catenin/p53/mesothelin/claudin-4) as well as antibodies to mucins and differentiation markers [MUC1/MUC2/MUC5AC/MUC6/CDX2/hepatocyte paraffin-1 (HepPar-1)] was investigated in 24 IOPNs and 22 IPMNs to assess the similarities/differences between these tumors...
September 3, 2016: Virchows Archiv: An International Journal of Pathology
Mei Wang, Aihua Li, Guangwen Sun, Lawrence Mbuagbaw, Susan Reid, Peter J Lovrics, Lehana Thabane
BACKGROUND: Mesothelin is a membrane-bound glycoprotein. Although the biologic function of mesothelin is not very clear, researchers have found that it plays a role in the survival, proliferation, and migration of tumor cells. Identified as a tumor-associated biomarker, mesothelin is more often overexpressed in triple-negative breast cancer (TNBC) than in common luminal breast tumor subtype or normal tissues. The objective of this review is to determine the association between the expression of mesothelin and overall survival in patients with TNBC...
2016: Systematic Reviews
Frieder Bauss, Martin Lechmann, Ben-Fillippo Krippendorff, Roland Staack, Frank Herting, Matthias Festag, Sabine Imhof-Jung, Friederike Hesse, Marc Pompiati, Gwendlyn Kollmorgen, Rita da Silva Mateus Seidl, Birgit Bossenmaier, Wilma Lau, Christian Schantz, Jan O Stracke, Ulrich Brinkmann, Masanori Onda, Ira Pastan, Klaus Bosslet, Gerhard Niederfellner
Mesothelin overexpression in lung adenocarcinomas correlates with the presence of activating KRAS mutations and poor prognosis. Hence SS1P, a mesothelin-targeted immunotoxin, could offer valuable treatment options for these patients, but its use in solid tumor therapy is hampered by high immunogenicity and non-specific toxicity. To overcome both obstacles we developed RG7787, a de-immunized cytotoxic fusion protein comprising a humanized SS1 Fab fragment and a truncated, B-cell epitope silenced, 24 kD fragment of Pseudomonas exotoxin A (PE24)...
October 2016: Molecular Oncology
Wilson Petrushnko, Justin S Gundara, Philip R De Reuver, Greg O'Grady, Jaswinder S Samra, Anubhav Mittal
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) continues to be associated with a poor prognosis. This systematic review aimed to summarize the literature regarding potential prognostic biomarkers to facilitate validation studies and clinical application. METHODS: A systematic review was performed (2004-2014) according to PRISMA guidelines. Studies were ranked using REMARK criteria and the following outcomes were examined: overall/disease free survival, nodal involvement, tumour characteristics, metastasis, recurrence and resectability...
August 2016: HPB: the Official Journal of the International Hepato Pancreato Biliary Association
Leonid Cherkassky, Aurore Morello, Jonathan Villena-Vargas, Yang Feng, Dimiter S Dimitrov, David R Jones, Michel Sadelain, Prasad S Adusumilli
Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication...
August 1, 2016: Journal of Clinical Investigation
Xiaoqing He, Emily Despeaux, Todd A Stueckle, Alexander Chi, Vincent Castranova, Cerasela Zoica Dinu, Liying Wang, Yon Rojanasakul
Carbon nanotubes (CNTs) have been likened to asbestos in terms of morphology and toxicity. CNT exposure can lead to pulmonary fibrosis and promotion of tumorigenesis. However, the mechanisms underlying CNT-induced carcinogenesis are not well defined. Mesothelin (MSLN) is overexpressed in many human tumors, including mesotheliomas and pancreatic and ovarian carcinomas. In this study, the role of MSLN in the carcinogenic transformation of human bronchial epithelial cells chronically exposed to single-walled CNT (BSW) was investigated...
September 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
F Lamers, M Bot, R Jansen, M K Chan, J D Cooper, S Bahn, B W J H Penninx
Depression is a highly heterogeneous disorder. Accumulating evidence suggests biological and genetic differences between subtypes of depression that are homogeneous in symptom presentation. We aimed to evaluate differences in serum protein profiles between persons with atypical and melancholic depressive subtypes, and compare these profiles with serum protein levels of healthy controls. We used the baseline data from the Netherlands Study of Depression and Anxiety on 414 controls, 231 persons with a melancholic depressive subtype and 128 persons with an atypical depressive subtype for whom the proteomic data were available...
2016: Translational Psychiatry
Sakthivel Muniyan, Dhanya Haridas, Seema Chugh, Satyanarayana Rachagani, Imayavaramban Lakshmanan, Suprit Gupta, Parthasarathy Seshacharyulu, Lynette M Smith, Moorthy P Ponnusamy, Surinder K Batra
MUC16, a heavily glycosylated type-I transmembrane mucin is overexpressed in several cancers including pancreatic ductal adenocarcinoma (PDAC). Previously, we have shown that MUC16 is significantly overexpressed in human PDAC tissues. However, the functional consequences and its role in PDAC is poorly understood. Here, we show that MUC16 knockdown decreases PDAC cell proliferation, colony formation and migration in vitro. Also, MUC16 knockdown decreases the tumor formation and metastasis in orthotopic xenograft mouse model...
March 2016: Genes & Cancer
Fang Liu, Wenjun Le, Tianxiao Mei, Tiegong Wang, Luguang Chen, Yi Lei, Shaobin Cui, Bingdi Chen, Zheng Cui, Chengwei Shao
Pancreatic cancer is a highly malignant disease with a 5-year survival rate <5% mainly due to lack of early diagnosis and effective therapy. In an effort to improve the early diagnostic rate of pancreatic cancer, a nanoprobe Fe3O4@SiO2 modified with anti-mesothelin antibody (A-MFS) was prepared to target cells and tumor tissues highly expressing mesothelin in vitro (human pancreatic cancer cell line SW1990) and in vivo (subcutaneously transplanted tumors) studies. The A-MFS probe was successfully prepared and was spherical and uniform with a hydrodynamic diameter between 110 and 130 nm...
2016: International Journal of Nanomedicine
Luigina Micolucci, Most Mauluda Akhtar, Fabiola Olivieri, Maria Rita Rippo, Antonio Domenico Procopio
BACKGROUND: Asbestos is a harmful and exceptionally persistent natural material. Malignant mesothelioma (MM), an asbestos-related disease, is an insidious, lethal cancer that is poorly responsive to current treatments. Minimally invasive, specific, and sensitive biomarkers providing early and effective diagnosis in high-risk patients are urgently needed. MicroRNAs (miRNAs, miRs) are endogenous, non-coding, small RNAs with established diagnostic value in cancer and pollution exposure. A systematic review and a qualitative meta-analysis were conducted to identify high-confidence miRNAs that can serve as biomarkers of asbestos exposure and MM...
June 1, 2016: Oncotarget
Kristian Madeira, Eduardo R Dondossola, Bruna F DE Farias, Carla S Simon, Maria C M Alexandre, Bruno R Silva, Maria Inês Rosa
The objective of this work was to estimate the accuracy of mesothelin as a biomarker for ovarian cancer. A quantitative systematic review was performed. A comprehensive search of the Medline, LILACS, SCOPUS, Embase, Cochrane Central Register of Controlled Trials, Biomed Central, and ISI Web of Science databases was conducted from January 1990 to June 2015. For inclusion in this systematic review, the papers must have measured mesothelin levels in at least two histological diagnoses; ovarian cancer (borderline or ovarian tumor) vs...
May 31, 2016: Anais da Academia Brasileira de Ciências
Anish Thomas
No abstract text is available yet for this article.
July 2016: Expert Review of Anticancer Therapy
Prince Awuah, Tapan K Bera, Messan Folivi, Oleg Chertov, Ira Pastan
Mesothelin (MSLN) is a differentiation antigen that is highly expressed in many epithelial cancers. MSLN is an important therapeutic target due to its high expression in cancers and limited expression in normal human tissues. Although it has been assumed that shed antigen is a barrier to immunotoxin action, a modeling study predicted that shed MSLN may enhance the action of MSLN-targeting recombinant immunotoxins such as SS1P and similar therapeutics by facilitating their redistribution within tumors. We aimed to determine whether shed MSLN enhances or reduces the antitumor effect of MSLN-targeting immunotoxins SS1P and RG7787...
July 2016: Molecular Cancer Therapeutics
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