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https://www.readbyqxmd.com/read/29228299/development-of-cell-penetrating-bispecific-antibodies-targeting-the-n-terminal-domain-of-androgen-receptor-for-prostate-cancer-therapy
#1
Nancy L Goicochea, Maria Garnovskaya, Mary G Blanton, Grace Chan, Richard Weisbart, Michael B Lilly
Castration-resistant prostate cancer cells exhibit continued androgen receptor signaling in spite of low levels of ligand. Current therapies to block androgen receptor signaling act by inhibiting ligand production or binding. We developed bispecific antibodies capable of penetrating cells and binding androgen receptor outside of the ligand-binding domain. Half of the bispecific antibody molecule consists of a single-chain variable fragment of 3E10, an anti-DNA antibody that enters cells. The other half is a single-chain variable fragment version of AR441, an anti-AR antibody...
December 6, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/29227196/immunotherapeutics-for-the-treatment-of-prostate-cancer-a-patent-landscape-based-on-key-therapeutic-mechanisms-of-actions
#2
Elaine Harris
The area of immunotherapeutics for the treatment of metastatic castrate-resistant prostate cancer has made significant progress since the autologous cell-based vaccine sipuleucel T became the first and to date only immunotherapy for its treatment. This review focuses on a broad patent landscaping exercise of this therapeutic area and considers if basing this landscaping on key mechanisms of action is appropriate to elicit the main patenting trends.
December 11, 2017: Pharmaceutical Patent Analyst
https://www.readbyqxmd.com/read/29225693/cytoreductive-prostate-radiotherapy-in-oligometastatic-prostate-cancer-a-single-centre-analysis-of-toxicity-and-clinical-outcome
#3
Giulia Riva, Giulia Marvaso, Matteo Augugliaro, Dario Zerini, Cristiana Fodor, Gennaro Musi, Ottavio De Cobelli, Roberto Orecchia, Barbara Alicja Jereczek-Fossa
Objectives: The current standard of care for patients with metastatic prostate cancer (mPCa) at diagnosis is androgen deprivation therapy (ADT) with or without anti-androgen and chemotherapy. The aim of this study was to define the role of a local radiotherapy (RT) treatment in the mPCa setting. Methods: We retrospectively reviewed data of patients with PCa and bone oligometastases at diagnosis treated in our institution with ADT followed by cytoreductive prostate-RT with or without RT on metastases...
2017: Ecancermedicalscience
https://www.readbyqxmd.com/read/29225078/regulation-of-androgen-receptor-activity-by-transient-interactions-of-its-transactivation-domain-with-general-transcription-regulators
#4
Eva De Mol, Elzbieta Szulc, Claudio Di Sanza, Paula Martínez-Cristóbal, Carlos W Bertoncini, R Bryn Fenwick, Marta Frigolé-Vivas, Marianela Masín, Irene Hunter, Víctor Buzón, Isabelle Brun-Heath, Jesús García, Gianni De Fabritiis, Eva Estébanez-Perpiñá, Iain J McEwan, Ángel R Nebreda, Xavier Salvatella
The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF...
December 6, 2017: Structure
https://www.readbyqxmd.com/read/29222530/seizure-rates-in-enzalutamide-treated-men-with-metastatic-castration-resistant-prostate-cancer-and-risk-of-seizure-the-upward-study
#5
Susan Slovin, William Clark, Joan Carles, Andrew Krivoshik, Jung Wook Park, Fong Wang, Daniel George
Importance: The androgen receptor inhibitor enzalutamide prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). In controlled clinical studies, 0.5% (10 of 2051) of patients experienced seizure, but patients with a history of or risk factors for seizure were excluded. Men with mCRPC and seizure risk factors have an estimated seizure rate of 2.8 per 100 patient-years without enzalutamide exposure. Objective: To assess seizure incidence in patients with seizure risk factors who were receiving enzalutamide for mCRPC...
December 7, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/29221985/hotair-mediated-reciprocal-regulation-of-ezh2-and-dnmt1-contribute-to-polyphyllin-i-inhibited-growth-of-castration-resistant-prostate-cancer-cells-in-vitro-and-in-vivo
#6
SongTao Xiang, PeiLiang Zou, Qing Tang, Fang Zheng, JingJing Wu, ZhiQiang Chen, Swei Sunny Hann
BACKGROUND: Polyphyllin I (PPI), one of the steroidal saponins in paris polyphylla, has been reported to exhibit antitumor effects. However, the detailed molecular mechanism underlying this has not been elucidated. METHODS: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and Flow cytometry assays, respectively. Cell invasion and migration were examined by Transwell invasion and wound healing assays...
December 5, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29216925/silencing-of-mir-193a-5p-increases-the-chemosensitivity-of-prostate-cancer-cells-to-docetaxel
#7
Zhan Yang, Jin-Suo Chen, Jin-Kun Wen, Hai-Tao Gao, Bin Zheng, Chang-Bao Qu, Kai-Long Liu, Man-Li Zhang, Jun-Fei Gu, Jing-Dong Li, Yan-Ping Zhang, Wei Li, Xiao-Lu Wang, Yong Zhang
BACKGROUND: Docetaxel-based chemotherapy failure in advanced prostate carcinoma has partly been attributed to the resistance of prostate cancer (PC) cells to docetaxel-induced apoptosis. Hence, there is an urgent need to identify mechanisms of docetaxel chemoresistance and to develop new combination therapies. METHODS: miR-193a-5p level was evaluated by qPCR in prostate tissues and cell lines, and its expression in the tissues was also examined by in situ hybridization...
December 8, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29216878/adaptive-phenotype-drives-resistance-to-androgen-deprivation-therapy-in-prostate-cancer
#8
Nicoletta Ferrari, Ilaria Granata, Matteo Capaia, Marina Piccirillo, Mario Rosario Guarracino, Roberta Venè, Antonella Brizzolara, Andrea Petretto, Elvira Inglese, Martina Morini, Simonetta Astigiano, Adriana Agnese Amaro, Francesco Boccardo, Cecilia Balbi, Paola Barboro
BACKGROUND: Prostate cancer (PCa), the second most common cancer affecting men worldwide, shows a broad spectrum of biological and clinical behaviour representing the epiphenomenon of an extreme heterogeneity. Androgen deprivation therapy is the mainstay of treatment for advanced forms but after few years the majority of patients progress to castration-resistant prostate cancer (CRPC), a lethal form that poses considerable therapeutic challenges. METHODS: Western blotting, immunocytochemistry, invasion and reporter assays, and in vivo studies were performed to characterize androgen resistant sublines phenotype in comparison to the parental cell line LNCaP...
December 8, 2017: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/29213237/effectiveness-of-deferred-combined-androgen-blockade-therapy-predicts-efficacy-in-abiraterone-acetate-treated-metastatic-castration-resistant-prostate-cancer-patients-after-docetaxel
#9
Jian-Ri Li, Kun-Yuan Chiu, Shian-Shiang Wang, Cheng-Kuang Yang, Chuan-Shu Chen, Hao-Chung Ho, Chi-Feng Hung, Chen-Li Cheng, Chi-Rei Yang, Cheng-Che Chen, Shu-Chi Wang, Chia-Yen Lin, Chao-Hsiang Chang, Chiann-Yi Hsu, Yen-Chuan Ou
Introduction: Conventional anti-androgen regimens were widely used as an initiation or combined androgen blockade (CAB) therapy in advanced prostate cancer patients. Currently, new androgen pathway inhibitors such as abiraterone acetate (AA) and enzalutamide had been proven effective in metastatic castration resistant prostate cancer. In this study, we attempt to analyze the role of conventional anti-androgen drugs as deferred CAB therapy in castration-resistant prostate cancer patients. Materials and Methods: From 2012 to 2017, 48 metastatic castration-resistant prostate cancer (CRPC) patients who received sequential treatments with primary androgen blockade, oral anti-androgen regimens, and docetaxel followed by AA treatment were included...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29212226/transcribed-ultraconserved-region-uc-63-promotes-resistance-to-docetaxel-through-regulation-of-androgen-receptor-signaling-in-prostate-cancer
#10
Yohei Sekino, Naoya Sakamoto, Keisuke Goto, Ririno Honma, Yoshinori Shigematsu, Kazuhiro Sentani, Naohide Oue, Jun Teishima, Akio Matsubara, Wataru Yasui
Docetaxel is the standard chemotherapy for metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients ultimately become refractory due to the development of docetaxel resistance. The transcribed ultraconserved regions (T-UCRs) are a novel class of non-coding RNAs that are absolutely conserved across species and are involved in carcinogenesis including prostate cancer (PC). In this study, we investigated the transcriptional levels of 26 representative T-UCRs and determined the regions that were differentially expressed in PC...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29210989/supraphysiologic-testosterone-therapy-in-the-treatment-of-prostate-cancer-models-mechanisms-and-questions
#11
REVIEW
Osama S Mohammad, Michael D Nyquist, Michael T Schweizer, Stephen P Balk, Eva Corey, Stephen Plymate, Peter S Nelson, Elahe A Mostaghel
Since Huggins defined the androgen-sensitive nature of prostate cancer (PCa), suppression of systemic testosterone (T) has remained the most effective initial therapy for advanced disease although progression inevitably occurs. From the inception of clinical efforts to suppress androgen receptor (AR) signaling by reducing AR ligands, it was also recognized that administration of T in men with castration-resistant prostate cancer (CRPC) could result in substantial clinical responses. Data from preclinical models have reproducibly shown biphasic responses to T administration, with proliferation at low androgen concentrations and growth inhibition at supraphysiological T concentrations...
December 6, 2017: Cancers
https://www.readbyqxmd.com/read/29207190/anticancer-potential-of-novel-curcumin-analogs-towards-castrate-resistant-prostate-cancer
#12
Shuli Chen, Mhairi Nimick, Andrew G Cridge, Bill C Hawkins, Rhonda J Rosengren
Prostate cancer is initially sensitive to hormone therapy; however, over time the majority of patients progress to a hormone-insensitive form classified as castration-resistant prostate cancer (CRPC). CRPC is highly metastatic and patients have a poor prognosis. Thus, new drugs for the treatment of this disease are required. In this study, we therefore examined the cytotoxic effects and anticancer mechanism(s) of action of second generation curcumin analogs towards CRPC cells. For this purpose, PC3 and DU145 cells were treated with a series of curcumin analogs at 0-10 µM for 72 h and cytotoxicity was determined by the sulforhodamine B (SRB) assay...
November 20, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29206995/concordance-of-circulating-tumor-dna-and-matched-metastatic-tissue-biopsy-in-prostate-cancer
#13
Alexander W Wyatt, Matti Annala, Rahul Aggarwal, Kevin Beja, Felix Feng, Jack Youngren, Adam Foye, Paul Lloyd, Matti Nykter, Tomasz M Beer, Joshi J Alumkal, George V Thomas, Robert E Reiter, Matthew B Rettig, Christopher P Evans, Allen C Gao, Kim N Chi, Eric J Small, Martin E Gleave
Background: Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling...
December 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29203894/combining-intratumoral-treg-depletion-with-androgen-deprivation-therapy-adt-preclinical-activity-in-the-myc-cap-model
#14
Ying-Chun Shen, Ali Ghasemzadeh, Christina M Kochel, Thomas R Nirschl, Brian J Francica, Zoila A Lopez-Bujanda, Maria A Carrera Haro, Ada Tam, Robert A Anders, Mark J Selby, Alan J Korman, Charles G Drake
BACKGROUND: Immune checkpoint blockade has shown promising antitumor activity against a variety of tumor types. However, responses in castration-resistant prostate cancer remain relatively rare-potentially due to low baseline levels of infiltration. Using an immunocompetent cMyc-driven model (Myc-CaP), we sought to understand the immune infiltrate induced by androgen deprivation therapy (ADT) and to leverage that infiltration toward therapeutic benefit. METHODS: Using flow cytometry, qPCR and IHC, we quantified ADT-induced immune infiltration in terms of cell type and function...
December 4, 2017: Prostate Cancer and Prostatic Diseases
https://www.readbyqxmd.com/read/29203251/androgen-receptor-ar-degradation-enhancer-asc-j9%C3%A2-in-an-fda-approved-formulated-solution-suppresses-castration-resistant-prostate-cancer-cell-growth
#15
Max A Cheng, Fu-Ju Chou, Keliang Wang, Rachel Yang, Jie Ding, Qiaoxia Zhang, Gonghui Li, Shuyuan Yeh, Defeng Xu, Chawnshang Chang
ASC-J9® is a recently-developed androgen receptor (AR)-degradation enhancer that effectively suppresses castration resistant prostate cancer (PCa) cell proliferation and invasion. The optimal half maximum inhibitory concentrations (IC50) of ASC-J9® at various PCa cell confluences (20%, 50%, and 100%) were assessed via both short-term MTT growth assays and long-term clonogenic proliferation assays. Our results indicate that the IC50 values for ASC-J9® increased with increasing cell confluency. The IC50 values were significantly decreased in PCa AR-positive cells compared to PCa AR-negative cells or in normal prostate cells...
December 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29198908/overexpression-of-nuclear-ar-v7-protein-in-primary-prostate-cancer-is-an-independent-negative-prognostic-marker-in-men-with-high-risk-disease-receiving-adjuvant-therapy
#16
Xin Chen, Christof Bernemann, Yuri Tolkach, Martina Heller, Cathleen Nientiedt, Michael Falkenstein, Esther Herpel, Maximilian Jenzer, Carsten Grüllich, Dirk Jäger, Holger Sültmann, Anette Duensing, Sven Perner, Marcus V Cronauer, Carsten Stephan, Jürgen Debus, Andres Jan Schrader, Glen Kristiansen, Markus Hohenfellner, Stefan Duensing
BACKGROUND: Overexpression of the androgen receptor (AR) splice variant 7 (AR-V7) has recently been reported to be associated with resistance to antihormonal therapy. Herein, we address the question whether tumor cells with AR-V7 expression can be detected at the time of radical prostatectomy, that is, before long-term hormonal manipulation and castration resistance, and what the potential prognostic impact on the biochemical recurrence (BCR)-free survival may be. METHODS: An anti-AR-V7 antibody was first validated in a training set of prostate cancer specimens by a comparison of AR-V7 protein to AR-V7 mRNA expression...
November 29, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/29198640/serum-testosterone-levels-in-prostate-cancer-patients-undergoing-luteinizing-hormone-releasing-hormone-agonist-therapy
#17
Juan Morote, Inma Comas, Jacques Planas, Xavier Maldonado, Ana Celma, José Placer, Roser Ferrer, Joan Carles, Lucas Regis
BACKGROUND: Serum testosterone measurement is recommended to assess the efficacy of androgen deprivation therapy (ADT) and to diagnose castration resistance in patients with prostate cancer (PCa). Currently, the accepted castrate level of serum testosterone is 50 ng/dL. Liquid chromatography and tandem mass spectrometry (LC MSMS) is the appropriate method to measure testosterone, especially at low levels. However, worldwide, chemiluminescent assays (CLIAs) are used in clinical laboratories, despite their lack of accuracy and reproducibility, because they are automatable, fast, sensitive, and inexpensive...
November 30, 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/29198331/biomarkers-in-prostate-cancer-current-clinical-utility-and-future-perspectives
#18
REVIEW
Alexander Kretschmer, Derya Tilki
Current tendencies in the treatment course of prostate cancer patients increase the need for reliable biomarkers that help in decision-making in a challenging clinical setting. Within the last decade, several novel biomarkers have been introduced. In the following comprehensive review article, we focus on diagnostic (PHI®, 4K score, SelectMDx®, ConfirmMDx®, PCA3, MiPS, ExoDX®, mpMRI) and prognostic (OncotypeDX GPS®, Prolaris®, ProMark®, DNA-ploidy, Decipher®) biomarkers that are in widespread clinical use and are supported by evidence...
December 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29196733/regulation-of-hmgb3-by-antitumor-mir-205-5p-inhibits-cancer-cell-aggressiveness-and-is-involved-in-prostate-cancer-pathogenesis
#19
Yasutaka Yamada, Rika Nishikawa, Mayuko Kato, Atsushi Okato, Takayuki Arai, Satoko Kojima, Kazuto Yamazaki, Yukio Naya, Tomohiko Ichikawa, Naohiko Seki
Our recent determination of a microRNA (miRNA) expression signature in prostate cancer (PCa) revealed that miR-205-5p was significantly reduced in PCa tissues and that it acted as an antitumor miRNA. The aim of this study was to identify oncogenic genes and pathways in PCa cells that were regulated by antitumor miR-205-5p. Genome-wide gene expression analyses and in silico miRNA database searches showed that 37 genes were putative targets of miR-205-5p regulation. Among those genes, elevated expression levels of seven in particular (HMGB3, SPARC, MKI67, CENPF, CDK1, RHOU, and POLR2D) were associated with a shorter disease-free survival in a large number of patients in the The Cancer Genome Atlas (TCGA) database...
December 1, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/29196557/selexglm-differentiates-androgen-and-glucocorticoid-receptor-dna-binding-preference-over-an-extended-binding-site
#20
Liyang Zhang, Gabriella D Martini, H Tomas Rube, Judith F Kribelbauer, Chaitanya Rastogi, Vincent D FitzPatrick, Jon C Houtman, Harmen J Bussemaker, Miles A Pufall
The DNA-binding interfaces of the androgen (AR) and glucocorticoid (GR) receptors are virtually identical, yet these transcription factors share only about a third of their genomic binding sites and regulate similarly distinct sets of target genes. To address this paradox, we determined the intrinsic specificities of the AR and GR DNA binding domains using a refined version of SELEX-seq. We developed an algorithm, SelexGLM, that quantifies binding specificity over a large (31 bp) binding-site by iteratively fitting a feature-based generalized linear model to SELEX probe counts...
December 1, 2017: Genome Research
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