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https://www.readbyqxmd.com/read/28229393/mechanisms-of-therapeutic-resistance-in-prostate-cancer
#1
REVIEW
Mary Nakazawa, Channing Paller, Natasha Kyprianou
Prostate cancer is the second leading cause of cancer deaths in the USA. The challenge in managing castration-resistant prostate cancer (CRPC) stems not from the lack of therapeutic options but from the limited duration of clinical and survival benefit offered by treatments in this setting due to primary and acquired resistance. The remarkable molecular heterogeneity and tumor adaptability in advanced prostate cancer necessitate optimization of such treatment strategies. While the future of CRPC management will involve newer targeted therapies in deliberately biomarker-selected patients, interventions using current approaches may exhibit improved clinical benefit if employed in the context of optimal sequencing and combinations...
February 2017: Current Oncology Reports
https://www.readbyqxmd.com/read/28220804/impact-of-symptomatic-skeletal-events-on-health-care-resource-utilization-and-quality-of-life-among-patients-with-castration-resistant-prostate-cancer-and-bone-metastases
#2
R McKay, B Haider, M S Duh, A Valderrama, M Nakabayashi, M Fiorillo, L Ristovska, L Wen, P Kantoff
BACKGROUND: Data regarding the impact of symptomatic skeletal events (SSEs) on health economics and patient-reported outcomes in men with castration-resistant prostate cancer (CRPC) and bone metastases from a clinical setting are lacking. Hence, this study aimed to quantify the effects of SSEs on health-care resource utilization (HRU), health-related quality of life (HRQoL) and pain in men with CRPC metastasized to bone. METHODS: This cohort study included men with CRPC and bone metastasis treated at a tertiary center during December 1996-July 2015...
February 21, 2017: Prostate Cancer and Prostatic Diseases
https://www.readbyqxmd.com/read/28215159/the-potential-roles-of-radionanomedicine-and-radioexosomic-in-prostate-cancer-research-and-treatment
#3
Martin K Bakht, So Won Oh, Do Won Hwang, Yun-Sang Lee, Hyewon Youn, Lisa A Porter, Gi Jeong Cheon, Cheol Kwak, Dong Soo Lee, Keon Wook Kang
The artificial nanostructures such as nanoparticles and natural nanostructures such as secreted nano-sized extracellular vesicles known as exosomes are promising tools for the realization of personalized medicine. Radionanomedicine is a recently coined term for the simultaneous application of either radiation technology or nuclear medicine with nanomedicine. In addition, radioexosomics is our suggested term for the study of exosomes functions, cytotoxicity, cancerogenicity, and biodistribution using radiation technology and nuclear medicine tracing technology...
February 16, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28209757/cdk4-6-therapeutic-intervention-and-viable-alternative-to-taxanes-in-crpc
#4
James P Stice, Suzanne E Wardell, John D Norris, Alexander P Yllanes, Holly M Alley, Victoria O Haney, Hannah S White, Rachid Safi, Peter S Winter, Kimberly J Cocce, Rigel J Kishton, Scott A Lawrence, Jay C Strum, Donald P McDonnell
: Resistance to second generation AR antagonists and CYP17 inhibitors in patients with castrationresistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to androgen receptor (AR) overexpression, production of constitutively active AR splice variants, or the selection for AR mutants with altered ligand binding specificity. It has been established that androgens induce cell cycle progression, in part, through upregulation of cyclin D1 (CCND1) expression and subsequent activation of cyclin-dependent kinases 4 and 6 (CDK4/6)...
February 16, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28205582/aurora-a-regulates-expression-of-ar-v7-in-models-of-castrate-resistant-prostate-cancer
#5
Dominic Jones, Martin Noble, Steve R Wedge, Craig N Robson, Luke Gaughan
Androgen receptor variants (AR-Vs) provide a mechanism of therapy evasion in castrate-resistant prostate cancer (CRPC), yet mechanisms of regulation remain largely unknown. Here we investigate the role of Aurora A kinase on AR-Vs in models of CRPC and show depletion of Aurora A reduces AR-V target gene expression. Importantly, knockdown of Aurora A reconfigures splicing of AR pre-mRNA to discriminately down-regulate synthesis of AR-V transcripts, including AR-V7, without effecting full-length AR mRNA; and as a consequence, AR-V-driven proliferation and survival of CRPC cells is markedly reduced...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28186973/upregulation-of-fam84b-during-prostate-cancer-progression
#6
Nicholas Wong, Yan Gu, Anil Kapoor, Xiaozeng Lin, Diane Ojo, Fengxiang Wei, Judy Yan, Jason de Melo, Pierre Major, Geoffrey Wood, Tariq Aziz, Jean-Claude Cutz, Michael Bonert, Arthur J Patterson, Damu Tang
Although the FAM84B gene lies within chromosome 8q24, a locus frequently altered in prostate cancer (PC), its alteration during prostate tumorigenesis has not been well studied. We report here FAM84B upregulation in DU145 cell-derived prostate cancer stem-like cells (PCSLCs) and DU145 cell-produced lung metastases compared to subcutaneous xenograft tumors. FAM84B protein was detected in bone metastases and primary PCs. Nanostring examination of 7 pairs of tumor adjacent normal and PC tissues revealed elevations in FAM84B mRNA levels in all carcinomas...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28181296/molecular-dynamics-studies-on-the-enzalutamide-resistance-mechanisms-induced-by-androgen-receptor-mutations
#7
Hongli Liu, Lingyan Wang, Jiaqi Tian, Jiazhong Li, Huanxiang Liu
The second-generation antiandrogen enzalutamide, targeting androgen receptor (AR), was approved to treat castration resistant prostate cancer (CRPC) in 2012. Its resistance was observed when it was in the clinical research stage. AR mutation is the main factor of enzalutamide resistance. AR F876L and F876L_T877A mutations were reported to switch enzalutamide from AR antagonist to agonist, but W741C cannot. There are various mutations in the ligand binding domain of androgen receptor (AR LBD), such as L701H, W741L, H874Y, T877A and M895T, if these mutations can lead to drug resistance problem or not is not known...
February 9, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28174422/antarlides-f-h-new-members-of-the-antarlide-family-produced-by-streptomyces-sp-bb47
#8
Shun Saito, Takahiro Fujimaki, Watanalai Panbangred, Ryuichi Sawa, Yasuhiro Igarashi, Masaya Imoto
Castration-resistant prostate cancer (CRPC) is the most aggressive form of this disease. CRPC remains dependent on androgen receptor (AR) signaling. Therefore, a novel AR antagonist, enzalutamide, is used clinically for the treatment of men with metastatic CRPC. However, enzalutamide-resistant AR has appeared, and a new type of AR antagonist is desired. Previously, in the course of screening for a new type of AR antagonist, we isolated a series of compounds, designated antarlides A-E, that share a novel 22-membered-ring macrocyclic structure and are produced by Streptomyces sp...
February 8, 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28144973/minnelide-inhibits-androgen-dependent-castration-resistant-prostate-cancer-growth-by-decreasing-expression-of-androgen-receptor-full-length-and-splice-variants
#9
Sumit Isharwal, Shrey Modi, Nivedita Arora, Charles Uhlrich, Bhuwan Giri, Usman Barlass, Ayman Soubra, Rohit Chugh, Scott M Dehm, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee, Badrinath Konety
BACKGROUND: With almost 30,000 deaths per year, prostate cancer is the second-leading cause of cancer-related death in men. Androgen Deprivation Therapy (ADT) has been the corner stone of prostate cancer treatment for decades. However, despite an initial response of prostate cancer to ADT, this eventually fails and the tumors recur, resulting in Castration Resistant Prostate Cancer (CRPC). Triptolide, a diterpene triepoxide, has been tested for its anti-tumor properties in a number of cancers for over a decade...
February 1, 2017: Prostate
https://www.readbyqxmd.com/read/28144969/high-levels-of-the-ar-v7-splice-variant-and-co-amplification-of-the-golgi-protein-coding-yipf6-in-ar-amplified-prostate-cancer-bone-metastases
#10
Erik Djusberg, Emma Jernberg, Elin Thysell, Irina Golovleva, Pia Lundberg, Sead Crnalic, Anders Widmark, Anders Bergh, Maria Brattsand, Pernilla Wikström
BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis...
February 1, 2017: Prostate
https://www.readbyqxmd.com/read/28144231/non-genomic-actions-of-the-androgen-receptor-in-prostate-cancer
#11
REVIEW
Jacky K Leung, Marianne D Sadar
Androgen receptor (AR) is a validated drug target for prostate cancer based on its role in proliferation, survival, and metastases of prostate cancer cells. Unfortunately, despite recent improvements to androgen deprivation therapy and the advent of better antiandrogens with a superior affinity for the AR ligand-binding domain (LBD), most patients with recurrent disease will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Expression of constitutively active AR splice variants that lack the LBD contribute toward therapeutic resistance by bypassing androgen blockade and antiandrogens...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28134791/a-tale-of-two-signals-ar-and-wnt-in-development-and-tumorigenesis-of-prostate-and-mammary-gland
#12
REVIEW
Hubert Pakula, Dongxi Xiang, Zhe Li
Prostate cancer (PCa) is one of the most common cancers and among the leading causes of cancer deaths for men in industrialized countries. It has long been recognized that the prostate is an androgen-dependent organ and PCa is an androgen-dependent disease. Androgen action is mediated by the androgen receptor (AR). Androgen deprivation therapy (ADT) is the standard treatment for metastatic PCa. However, almost all advanced PCa cases progress to castration-resistant prostate cancer (CRPC) after a period of ADT...
January 27, 2017: Cancers
https://www.readbyqxmd.com/read/28129617/computational-study-involving-identification-of-endocrine-disrupting-potential-of-herbicides-its-implication-in-tds-and-cancer-progression-in-crpc-patients
#13
Md Irshad Ahmad, Afia Usman, Masood Ahmad
Several environmental pollutants, including herbicides, act as endocrine disrupting chemicals (EDCs). They can cause cancer, diabetes, obesity, metabolic diseases and developmental problems. Present study was conducted to screen 608 herbicides for evaluating their endocrine disrupting potential. The screening was carried out with the help of endocrine disruptome docking program, http://endocrinedisruptome.ki.si (Kolsek et al., 2013). This program screens the binding affinity of test ligands to 12 major nuclear receptors...
January 16, 2017: Chemosphere
https://www.readbyqxmd.com/read/28110835/prognostic-value-of-automated-bone-scan-index-in-men-with-metastatic-castration-resistant-prostate-cancer-treated-with-enzalutamide-or-abiraterone-acetate
#14
Yasuhide Miyoshi, Koichi Uemura, Takashi Kawahara, Shuko Yoneyama, Yusuke Hattori, Jun-Ichi Teranishi, Jun-Ichi Ohta, Shigeo Takebayashi, Yumiko Yokomizo, Narihiko Hayashi, Masahiro Yao, Hiroji Uemura
PURPOSE: Bone scan index (BSI) is an objective tool for quantifying bone metastasis load. We assessed its prognostic usefulness in patients with metastatic castration-resistant prostate cancer (CRPC) treated with enzalutamide (ENZ) or abiraterone acetate (AA). MATERIALS AND METHODS: We analyzed 40 patients who received ENZ or AA treatment (ENZ/AA) for metastatic CRPC. The Cox proportional hazards model and a C-index were used to investigate associations between overall survival (OS) and BSI, and patient age, prostate-specific antigen, time to CRPC, previous docetaxel use, and pain...
December 29, 2016: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28109910/induction-of-neuroendocrine-differentiation-in-castration-resistant-prostate-cancer-cells-by-adipocyte-differentiation-related-protein-adrp-delivered-by-exosomes
#15
Li-Chiung Lin, Allen C Gao, Chih-Ho Lai, Jer-Tsong Hsieh, Ho Lin
Although overall mortality rate of prostate cancer (PCa) declines in recent years, castration-resistant prostate cancer (CRPC) remains incurable. Clinical evidence indicates that CRPC recurred from hormonal therapy exhibits neuroendocrine differentiated (NED) phenotypes, which could contribute to therapeutic resistance and poor survival. Understanding the onset of NED could lead us to develop new therapeutic strategies for CRPC. Although PCa is known as a lipid-enriched tumor, its role in CRPC development is not fully understood...
January 18, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28108419/regulation-of-protein-kinase-c-related-kinase-prk-signalling-by-the-tp%C3%AE-and-tp%C3%AE-isoforms-of-the-human-thromboxane-a2-receptor-implications-for-thromboxane-and-androgen-dependent-neoplastic-and-epigenetic-responses-in-prostate-cancer
#16
Aine G O'Sullivan, Eamon P Mulvaney, B Therese Kinsella
The prostanoid thromboxane (TX) A2 and its T Prostanoid receptor (the TP) are increasingly implicated in prostate cancer (PCa). Mechanistically, we recently discovered that both TPα and TPβ form functional signalling complexes with members of the protein kinase C-related kinase (PRK) family, AGC- kinases essential for the epigenetic regulation of androgen receptor (AR)-dependent transcription and promising therapeutic targets for treatment of castrate-resistant prostate cancer (CRPC). Critically, similar to androgens, activation of the PRKs through the TXA2/TP signalling axis induces phosphorylation of histone H3 at Thr11 (H3Thr11), a marker of androgen-induced chromatin remodelling and transcriptional activation, raising the possibility that TXA2-TP signalling can mimic and/or enhance AR-induced cellular changes even in the absence of circulating androgens such as in CRPC...
January 18, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28107193/microrna-744-promotes-prostate-cancer-progression-through-aberrantly-activating-wnt-%C3%AE-catenin-signaling
#17
Han Guan, Chunhui Liu, Fang Fang, Yeqing Huang, Tao Tao, Zhixin Ling, Zonghao You, Xu Han, Shuqiu Chen, Bin Xu, Ming Chen
Accumulated evidence indicate that miR-744 functions as either tumor suppressor or oncogene in the progression of a variety of tumors, with a tumor type-specific way. However, little is known about how miR-744 impacts on the tumorigenesis of human prostate cancer. In this study, employing the analyses of microarray, qRT-PCR and re-analysis of MSKCC data, we found that CRPC tissues expressed much more miR-744 than ADPC tissues did, and the expression level of miR-744 was inversely associated with survival of CRPC patients...
January 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28105499/cx4945-suppresses-the-growth-of-castration-resistant-prostate-cancer-cells-by-reducing-ar-v7-expression
#18
Chuangzhong Deng, Jieping Chen, Shengjie Guo, Yanjun Wang, Qianghua Zhou, Zaishang Li, Xingping Yang, Xingsu Yu, Zhenfeng Zhang, Fangjian Zhou, Hui Han, Kai Yao
PURPOSE: The aberrant expression of casein kinase 2 (CK2) has been reported to be involved in the tumorigenesis and progression of prostate cancer. The inhibition of CK2 activity represses androgen-dependent prostate cancer cells by attenuating the androgen receptor (AR) signaling pathway. In this study, we examined the effect of CK2 inhibition in castration-resistant prostate cancer (CRPC) cells, in which AR variants (ARVs) play a predominant role. METHODS: A newly synthetic CK2 selective inhibitor CX4945 was utilized to study the effect of CK2 inhibition in CRPC cells by CCK8 assay and colony formation assay...
January 19, 2017: World Journal of Urology
https://www.readbyqxmd.com/read/28104311/comprehensive-profiling-of-the-androgen-receptor-in-liquid-biopsies-from-castration-resistant-prostate-cancer-reveals-novel-intra-ar-structural-variation-and-splice-variant-expression-patterns
#19
Bram De Laere, Pieter-Jan van Dam, Tom Whitington, Markus Mayrhofer, Emanuela Henao Diaz, Gert Van den Eynden, Jean Vandebroek, Jurgen Del-Favero, Steven Van Laere, Luc Dirix, Henrik Grönberg, Johan Lindberg
BACKGROUND: Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative. OBJECTIVE: To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy. DESIGN, SETTING, AND PARTICIPANTS: Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy...
January 16, 2017: European Urology
https://www.readbyqxmd.com/read/28099809/gemcitabine-based-peptide-conjugate-with-improved-metabolic-properties-and-dual-mode-of-efficacy
#20
Theodoros Karampelas, Eleni Skavatsou, Orestis Argyros, Demosthenes Fokas, Constantin Tamvakopoulos
Gemcitabine is a clinically established anticancer agent potent in various solid tumors but limited by its rapid metabolic inactivation and off-target toxicity. We have previously generated a metabolically superior to gemcitabine molecule (GSG) by conjugating gemcitabine to a gonadotropin releasing hormone receptor (GnRH-R) ligand peptide and showed that GSG was efficacious in a castration resistant prostate cancer (CRPC) animal model. The current article provides an in-depth metabolic and mechanistic study of GSG, coupled with toxicity assays that strengthen the potential role of GSG in the clinic...
February 1, 2017: Molecular Pharmaceutics
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