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Siddharth Sukumaran, Crystal Zhang, Douglas D Leipold, Ola M Saad, Keyang Xu, Kapil Gadkar, Divya Samineni, Bei Wang, Marija Milojic-Blair, Montserrat Carrasco-Triguero, Bonnee Rubinfeld, Paul Fielder, Kedan Lin, Saroja Ramanujan
Antibody drug conjugates (ADC), in which small molecule cytotoxic agents are non-specifically linked to antibodies, can enable targeted delivery of chemotherapeutics to tumor cells. ADCs are often produced and administered as a mixture of conjugated antibodies with different drug to antibody ratios (DAR) resulting in complex and heterogeneous disposition kinetics. We developed a mechanism-based platform model that can describe and predict the complex pharmacokinetic (PK) behavior of ADCs with protease-cleavable valine-citrulline (VC) linker linked to Monomethylmonomethyl auristatin F/E by incorporating known mechanisms of ADC disposition...
September 27, 2016: AAPS Journal
David Schirmer, Thomas G P Grünewald, Richard Klar, Oxana Schmidt, Dirk Wohlleber, Rebeca Alba Rubío, Wolfgang Uckert, Uwe Thiel, Felix Bohne, Dirk H Busch, Angela M Krackhardt, Stefan Burdach, Günther H S Richter
Pediatric cancers, including Ewing sarcoma (ES), are only weakly immunogenic and the tumor-patients' immune system often is devoid of effector T cells for tumor elimination. Based on expression profiling technology, targetable tumor-associated antigens (TAA) are identified and exploited for engineered T-cell therapy. Here, the specific recognition and lytic potential of transgenic allo-restricted CD8(+) T cells, directed against the ES-associated antigen 6-transmembrane epithelial antigen of the prostate 1 (STEAP1), was examined...
June 2016: Oncoimmunology
Wenyu Wang, Yang Liu, Jingcan Hao, Shuyu Zheng, Yan Wen, Xiao Xiao, Awen He, Qianrui Fan, Feng Zhang, Ruiyu Liu
Hip cartilage destruction is consistently observed in the non-traumatic osteonecrosis of femoral head (NOFH) and accelerates its bone necrosis. The molecular mechanism underlying the cartilage damage of NOFH remains elusive. In this study, we conducted a systematically comparative study of gene expression profiles between NOFH and osteoarthritis (OA). Hip articular cartilage specimens were collected from 12 NOFH patients and 12 controls with traumatic femoral neck fracture for microarray (n=4) and quantitative real-time PCR validation experiments (n=8)...
October 10, 2016: Gene
Ching-Hsiao Lee, Sung-Lang Chen, Wen-Wei Sung, Hung-Wen Lai, Ming-Ju Hsieh, Hsu-Heng Yen, Tzu-Cheng Su, Yu-Hu Chiou, Chia-Yu Chen, Cheng-Yu Lin, Mei-Ling Chen, Chih-Jung Chen
STEAP1 (six transmembrane epithelial antigen of the prostate 1) is a transmembrane protein that functions as a potential channel or transporter protein. It is overexpressed in certain cancers and is viewed as a promising therapeutic target. However, the prognostic role of STEAP1 is still controversial, and no role for STEAP1 has yet been indicated in colorectal cancer. The aim of this study was to investigate the possible association of STEAP1 expression with colorectal cancer prognosis. STEAP1 expression was analyzed by immunohistochemical staining of a tissue array of 165 cancer specimens from primary colorectal cancer patients...
2016: International Journal of Molecular Sciences
Federica Cappuccini, Stephen Stribbling, Emily Pollock, Adrian V S Hill, Irina Redchenko
Prostate cancer possesses several characteristics that make it a suitable candidate for immunotherapy; however, prostate cancer vaccines to date demonstrate modest efficacy and low immunogenicity. The goal of the present pre-clinical study was to explore the immunogenic properties and protective efficacy of a novel prostate cancer immunotherapy based on the heterologous prime-boost viral-vectored vaccination platform. The simian adenovirus, ChAdOx1, and modified vaccinia Ankara virus, MVA, encoding a prostate cancer-associated antigen, the six transmembrane epithelial antigen of the prostate 1 (STEAP1), induced strong sustained antigen-specific CD8+ T-cell responses in C57BL/6 and BALB/c male mice...
June 2016: Cancer Immunology, Immunotherapy: CII
Simon-Peter Williams, Annie Ogasawara, Jeff N Tinianow, Judith E Flores, David Kan, Jeffrey Lau, MaryAnn Go, Alexander N Vanderbilt, Herman S Gill, Li Miao, Joshua Goldsmith, Bonnee Rubinfeld, Weiguang Mao, Ron Firestein, Shang-Fan Yu, Jan Marik, Anton G T Terwisscha van Scheltinga
The efficacy of antibody-drug conjugates (ADCs) targeted to solid tumors depends on biological processes that are hard to monitor in vivo. 89Zr-immunoPET of the ADC antibodies could help understand the performance of ADCs in the clinic by confirming the necessary penetration, binding, and internalization. This work studied monomethyl auristatin E (MMAE) ADCs against two targets in metastatic castration-resistant prostate cancer, TENB2 and STEAP1, in four patient-derived tumor models (LuCaP35V, LuCaP70, LuCaP77, LuCaP96...
May 3, 2016: Oncotarget
Mark D Kleven, Mensur Dlakić, C Martin Lawrence
Six-transmembrane epithelial antigen of the prostate 3 (Steap3) is the major ferric reductase in developing erythrocytes. Steap family proteins are defined by a shared transmembrane domain that in Steap3 has been shown to function as a transmembrane electron shuttle, moving cytoplasmic electrons derived from NADPH across the lipid bilayer to the extracellular face where they are used to reduce Fe(3+) to Fe(2+) and potentially Cu(2+) to Cu(1+). Although the cytoplasmic N-terminal oxidoreductase domain of Steap3 and Steap4 are relatively well characterized, little work has been done to characterize the transmembrane domain of any member of the Steap family...
September 11, 2015: Journal of Biological Chemistry
Hubert Kübler, Birgit Scheel, Ulrike Gnad-Vogt, Kurt Miller, Wolfgang Schultze-Seemann, Frank Vom Dorp, Giorgio Parmiani, Christian Hampel, Steffen Wedel, Lutz Trojan, Dieter Jocham, Tobias Maurer, Gerd Rippin, Mariola Fotin-Mleczek, Florian von der Mülbe, Jochen Probst, Ingmar Hoerr, Karl-Josef Kallen, Thomas Lander, Arnulf Stenzl
BACKGROUND: CV9103 is a prostate-cancer vaccine containing self-adjuvanted mRNA (RNActive®) encoding the antigens PSA, PSCA, PSMA, and STEAP1. This phase I/IIa study evaluated safety and immunogenicity of CV9103 in patients with advanced castration-resistant prostate-cancer. METHODS: 44 Patients received up to 5 intra-dermal vaccinations. Three dose levels of total mRNA were tested in Phase I in cohorts of 3-6 patients to determine a recommended dose. In phase II, 32 additional patients were treated at the recommended dose...
2015: Journal for Immunotherapy of Cancer
X Zhuang, J M J Herbert, P Lodhia, J Bradford, A M Turner, P M Newby, D Thickett, U Naidu, D Blakey, S Barry, D A E Cross, R Bicknell
BACKGROUND: Lung cancer remains the leading cause of cancer-related death, largely owing to the lack of effective treatments. A tumour vascular targeting strategy presents an attractive alternative; however, the molecular signature of the vasculature in lung cancer is poorly explored. This work aimed to identify novel tumour vascular targets in lung cancer. METHODS: Enzymatic digestion of fresh tissue followed by endothelial capture with Ulex lectin-coated magnetic beads was used to isolate the endothelium from fresh tumour specimens of lung cancer patients...
February 3, 2015: British Journal of Cancer
Michael G Doran, Philip A Watson, Sarah M Cheal, Daniel E Spratt, John Wongvipat, Jeffrey M Steckler, Jorge A Carrasquillo, Michael J Evans, Jason S Lewis
UNLABELLED: Antibodies and antibody-drug conjugates targeting the cell surface protein 6 transmembrane epithelial antigen of prostate 1 (STEAP1) are in early clinical development for the treatment of castration-resistant prostate cancer (PCa). In general, antigen expression directly affects the bioactivity of therapeutic antibodies, and the biologic regulation of STEAP1 is unusually complicated in PCa. Paradoxically, STEAP1 can be induced or repressed by the androgen receptor (AR) in different human PCa models, while also expressed in AR-null PCa...
December 2014: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Siddharth Sukumaran, Kapil Gadkar, Crystal Zhang, Sunil Bhakta, Luna Liu, Keyang Xu, Helga Raab, Shang-Fan Yu, Elaine Mai, Aimee Fourie-O'Donohue, Katherine R Kozak, Saroja Ramanujan, Jagath R Junutula, Kedan Lin
PURPOSE: THIOMAB™ drug conjugates (TDCs) with engineered cysteine residues allow site-specific drug conjugation and defined Drug-to-Antibody Ratios (DAR). In order to help elucidate the impact of drug-loading, conjugation site, and subsequent deconjugation on pharmacokinetics and efficacy, we have developed an integrated mathematical model to mechanistically characterize pharmacokinetic behavior and preclinical efficacy of MMAE conjugated TDCs with different DARs. General applicability of the model structure was evaluated with two different TDCs...
June 2015: Pharmaceutical Research
Helen Whiteland, Samantha Spencer-Harty, Claire Morgan, Howard Kynaston, David Hywel Thomas, Pradeep Bose, Neil Fenn, Paul Lewis, Spencer Jenkins, Shareen H Doak
Prostate adenocarcinoma is the second most frequent cancer worldwide and is one of the leading causes of male cancer-related deaths. However, it varies greatly in its behaviour, from indolent non-progressive disease to metastatic cancers with high associated mortality. The aim of this study was to identify predictive biomarkers for patients with localised prostate tumours most likely to progress to aggressive disease, to facilitate future tailored clinical treatment and identify novel therapeutic targets. The expression of 602 genes was profiled using oligoarrays, across three prostate cancer cell lines: CA-HPV-10, LNCaP and PC3, qualitatively identifying several potential prognostic biomarkers...
December 2014: Clinical & Experimental Metastasis
Inês M Gomes, Cecília R Santos, Cláudio J Maia
STEAP1 gene is overexpressed in several kinds of tumors, particularly in prostate cancer. Besides STEAP1, there is another related gene, STEAP1B, which may encode two different transcripts. Although several studies have been pointing STEAP1 as a putative immunotherapeutic target and biomarker, the mechanisms underlying its regulation are not fully understood. In silico analysis allowed us to show that STEAP1 and STEAP1B share high homology, but with slight differences at structural level. Experiments with prostate cells showed that STEAP1B2 is overexpressed in cancer cells...
March 2014: Genes & Cancer
Bianca Altvater, Sareetha Kailayangiri, Nadine Theimann, Martina Ahlmann, Nicole Farwick, Christiane Chen, Sibylle Pscherer, Ilka Neumann, Gabriele Mrachatz, Anna Hansmeier, Jendrik Hardes, Georg Gosheger, Heribert Juergens, Claudia Rossig
Disseminated or relapsed Ewing sarcoma (EwS) has remained fatal in the majority of patients. A promising approach to preventing relapse after conventional therapy is to establish tumor antigen-specific immune control. Efficient and specific T cell memory against the tumor depends on the expansion of rare T cells with native specificity against target antigens overexpressed by the tumor. Candidate antigens in EwS include six-transmembrane epithelial antigen of the prostate-1 (STEAP1), and the human cancer/testis antigens X-antigen family member 1 (XAGE1) and preferentially expressed antigen in melanoma (PRAME)...
October 2014: Cancer Immunology, Immunotherapy: CII
Pierlorenzo Pallante, Romina Sepe, Antonella Federico, Floriana Forzati, Mimma Bianco, Alfredo Fusco
BACKGROUND: We have previously shown that the expression of CBX7 is drastically decreased in several human carcinomas and that its expression progressively decreases with the appearance of a highly malignant phenotype. The aim of our study has been to investigate the mechanism by which the loss of CBX7 expression may contribute to the emergence of a more malignant phenotype. METHODS: We analyzed the gene expression profile of a thyroid carcinoma cell line after the restoration of CBX7 and, then, analyzed the transcriptional regulation of identified genes...
2014: PloS One
Inês M Gomes, Patrícia Arinto, Carlos Lopes, Cecília R Santos, Cláudio J Maia
BACKGROUND: Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a transmembrane protein of epithelial cells, mostly located at cell-cell junctions, and is overexpressed in several types of tumors, particularly prostate cancer. Several studies have pointed STEAP1 as a biomarker, but the clinical significance of its overexpression is not fully understood. Therefore, we aimed to establish the association of STEAP1 immunoreactivity with histologic diagnosis and clinical data of patients...
January 2014: Urologic Oncology
Shadia M Ihlaseh-Catalano, Sandra A Drigo, Carlos M N de Jesus, Maria Aparecida C Domingues, José Carlos S Trindade Filho, João Lauro V de Camargo, Silvia R Rogatto
AIMS: To investigate the prognostic value of expression levels of the genes STEAP1 and STEAP2, and of STEAP1 protein, in prostate carcinomas (PCa). METHODS AND RESULTS: STEAP1 and STEAP2 transcript levels were evaluated by RT-qPCR in samples from 35 PCa, 24 adjacent non-neoplastic prostate (AdjP) tissues, five cases of benign prostatic hyperplasia (BPH), and two histologically normal prostates (N). STEAP1 expression was assessed by immunohistochemistry in samples from 198 PCa, 76 AdjP, 22 BPH, and two N...
November 2013: Histopathology
Jerome Moreaux, Alboukadel Kassambara, Dirk Hose, Bernard Klein
The six-transmembrane epithelial antigen of prostate (STEAP) protein was identified in advanced prostate cancer and is up-regulated in multiple cancer cell lines, including prostate, bladder, colon, ovarian, and Ewing sarcoma. STEAP1 was described as a suitable antigen for T-cell-based or antibody-based immunotherapy. We have investigated the expression of STEAP1 in 40 human tumor types - brain, epithelial, lymphoid - and in their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database...
December 14, 2012: Biochemical and Biophysical Research Communications
Inês M Gomes, Cecília R Santos, Sílvia Socorro, Cláudio J Maia
BACKGROUND: STEAP1 is over-expressed in several types of tumors, especially prostate cancer, where it is localized in the plasma membrane of epithelial cells, at cell-cell junctions. Its role in prostate carcinogenesis and its regulation in prostate cells remain unknown. Therefore, we propose to study the effect of sex hormones in the regulation of STEAP1 expression in prostate cells in vitro and in vivo. METHODS: LNCaP prostate cells were incubated with fetal bovine serum (FBS), charcoal-stripped FBS (CS-FBS), 5α-dihydrotestosterone (DHT), and 17β-estradiol (E2 ) for different periods of stimulation...
May 2013: Prostate
Thomas G P Grunewald, Horacio Bach, Andrea Cossarizza, Isao Matsumoto
The human six-transmembrane epithelial antigen of the prostate (STEAP) protein family contains at least five homologous members. The necessity of multiple homologous STEAP proteins is still unclear, but their peculiar and tissue-specific expression suggests that they are assigned to distinct functional tasks. This concept is supported by the fact that especially STEAP1, and to a lesser extent STEAP2 and -4, are highly over-expressed in many different cancer entities, while being only minimally expressed in a few normal tissues...
November 2012: Biology of the Cell
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