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Castration-resistant prostate cancer

Rachael McCool, Kelly Fleetwood, Julie Glanville, Mick Arber, Howard Goodall, Shevani Naidoo
OBJECTIVES: To estimate the relative effectiveness of enzalutamide in chemotherapy-naive metastatic castration-resistant prostate cancer by conducting a systematic literature review and a network meta-analysis (NMA). METHODS: A systematic literature review identified randomized controlled trials comparing enzalutamide, abiraterone/prednisone, radium-223, sipuleucel-T, or docetaxel with each other or placebo in chemotherapy-naive or mixed populations (with and without prior chemotherapy) with asymptomatic/mildly symptomatic metastatic castration-resistant prostate cancer...
October 2018: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
Nitya V Sharma, Kathryn L Pellegrini, Veronique Ouellet, Felipe O Giuste, Selvi Ramalingam, Kenneth Watanabe, Eloise Adam-Granger, Lucresse Fossouo, Sungyong You, Michael R Freeman, Paula Vertino, Karen Conneely, Adeboye O Osunkoya, Dominique Trudel, Anne-Marie Mes-Masson, John A Petros, Fred Saad, Carlos S Moreno
BACKGROUND: Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived and the responses variable. ADT failure results in castration-resistant prostate cancer (CRPC), which inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis. RESULTS: We performed whole transcriptome analysis of 20 patient-matched Pre-ADT biopsies and 20 Post-ADT prostatectomy specimens, and identified two subgroups of patients (high impact and low impact groups) that exhibited distinct transcriptional changes in response to ADT...
October 11, 2018: Cancers
Wei-Yu Chen, Tao Zeng, Yu-Chng Wen, Hsiu-Lien Yeh, Kuo-Ching Jiang, Wei-Hao Chen, Qingfu Zhang, Jiaoti Huang, Yen-Nien Liu
Androgen receptor (AR) targeting is an important therapeutic strategy for treating prostate cancer. Most tumors progress to castration-resistant prostate cancer (CRPC) and develop the neuroendocrine (NE) phenotype under androgen deprivation therapy (ADT). The molecular basis for NE transdifferentiation after ADT remains incompletely understood. Herein, we show that an immunocyte expression protein, ZBTB46, induces inflammatory response gene expression and contributes to NE differentiation of prostate cancer cells...
October 9, 2018: Cancer Letters
Young A Yoo, Rajita Vatapalli, Barbara Lysy, Hanlin Mok, Mohamed M Desouki, Sarki A Abdulkadir
Background: Recurrence following androgen-deprivation therapy is associated with adverse clinical outcomes in prostate cancer, but the cellular origins and molecular mechanisms underlying this process are poorly defined. We previously identified a population of castration-resistant luminal progenitor cells expressing Bmi1 in the normal mouse prostate that can serve as a cancer cell-of-origin. Here, we investigate the potential of Bmi1-expressing tumor cells that survive castration to initiate recurrence in vivo...
October 11, 2018: Journal of the National Cancer Institute
Giulia Baciarello, Marco Gizzi, Karim Fizazi
Prostate cancer is the second most common cause of cancer worldwide and is the most frequently detected cancer in the European Union in men over 50 years of age. Androgen deprivation therapy remains the cornerstone of treatment for recurrent or metastatic disease. Unfortunately, nearly all patients will develop resistance to androgen blockade leading to castration-resistant prostate cancer (CRPC). Over the last 10 years, new treatments have dramatically improved overall survival of men with mCRPC. Current therapies are based on AR-axis inhibitors and taxane-based chemotherapies, as well as radiopharmaceuticals and Sipuleucel T...
October 12, 2018: Expert Opinion on Pharmacotherapy
Jong-Lyul Park, Seon-Kyu Kim, Jeong-Hwan Kim, Seok Joong Yun, Wun-Jae Kim, Won Tae Kim, Pildu Jeong, Ho Won Kang, Seon-Young Kim
Because castration-resistant prostate cancer (CRPC) does not respond to androgen deprivation therapy and has a very poor prognosis, it is critical to identify a prognostic indicator for predicting high-risk patients who will develop CRPC. Here, we report a dataset of whole genomes from four pairs of primary prostate cancer (PC) and CRPC samples. The analysis of the paired PC and CRPC samples in the whole-genome data showed that the average number of somatic mutations per patients was 7,927 in CRPC tissues compared with primary PC tissues (range, 1,691 to 21,705)...
September 2018: Genomics & Informatics
Pingyuan Wang, Jia Zhou
Great success has been achieved in small molecule drug discovery programs, making extraordinary contributions for human health, especially in targeted therapy. Taking anticancer drug discovery as an example, small molecules traditionally inhibit the target protein enzyme activities and induce cancer cell apoptosis through the target binding. However, the target protein within tumor cells often recovers its activities, leading to acquired drug-resistance through the overexpression of the target protein or the generation of new mutations in the target protein [1]...
October 9, 2018: Current Topics in Medicinal Chemistry
Yutaka Yamamoto, Yasunori Akashi, Takahumi Minami, Masahiro Nozawa, Keisuke Kiba, Motokiyo Yoshikawa, Akihide Hirayama, Hirotsugu Uemura
Introduction: The treatment strategy for castration-resistant prostate cancer (CRPC) has changed with the approval of several new agents. In 2011, abiraterone acetate was approved for the treatment of metastatic CRPC; however abiraterone is known to cause mineralocorticoid excess syndrome characterized by hypokalemia, fluid retention, and hypertension. We experienced two cases of grade 4 hypokalemia associated with abiraterone treatment. Case Presentation: Case 1: a 71-year-old male with metastatic CRPC presented with convulsive seizures two weeks after receiving abiraterone plus prednisone...
2018: Case Reports in Urology
Frédéric E Lecouvet, Daniela E Oprea-Lager, Yan Liu, Piet Ost, Luc Bidaut, Laurence Collette, Christophe M Deroose, Karolien Goffin, Ken Herrmann, Otto S Hoekstra, Gem Kramer, Yolande Lievens, Egesta Lopci, David Pasquier, Lars J Petersen, Jean-Noël Talbot, Helle Zacho, Bertrand Tombal, Nandita M deSouza
Oligometastatic disease represents a clinical and anatomical manifestation between localised and polymetastatic disease. In prostate cancer, as with other cancers, recognition of oligometastatic disease enables focal, metastasis-directed therapies. These therapies potentially shorten or postpone the use of systemic treatment and can delay further metastatic progression, thus increasing overall survival. Metastasis-directed therapies require imaging methods that definitively recognise oligometastatic disease to validate their efficacy and reliably monitor response, particularly so that morbidity associated with inappropriately treating disease subsequently recognised as polymetastatic can be avoided...
October 2018: Lancet Oncology
Scott T Tagawa, Emmanuel S Antonarakis, Ada Gjyrezi, Giuseppe Galletti, Seaho Kim, Daniel Worroll, John Stewart, Atef Zaher, Ted P Szatrowski, Karla V Ballman, Katsuhiro Kita, Shinsuke Tasaki, Yang Bai, Luigi Portella, Brian J Kirby, Fred Saad, Mario A Eisenberger, David M Nanus, Paraskevi Giannakakou
PURPOSE: Biomarkers aiding treatment optimization in metastatic castration-resistant prostate cancer (mCRPC) are scarce. Presence or absence of androgen receptor (AR) splice variants, AR-V7 and ARv567es, in mCRPC patient circulating tumor cells (CTCs) may be associated with taxane treatment outcomes. METHODS: A novel digital droplet PCR (ddPCR) assay assessed AR splice variant expression in patient CTCs receiving docetaxel or cabazitaxel in TAXYNERGY (NCT01718353)...
October 9, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ludwike van Kalmthout, Anine Stam, Renze Gans, Marnix Lam
This report describes a case of a 54-year-old man who underwent lutetium-177-PSMA therapy in the setting of metastatic castration-resistant prostate cancer (mCRPC) in the University Medical Center Utrecht. Following administration of the second cycle, patient presented with a slowly impairing, bilateral visual loss. This clinical presentation was most likely the result of the high intracranial pressure due to impediment of cerebrospinal fluid circulation, possibly related to obstructive dural thickness, being either caused by dural and/or leptomeningeal metastases of advanced mCRPC or by local radiation effects following lutetium-177-PSMA therapy...
October 8, 2018: BMJ Case Reports
Shih-Yin Huang, Guan-Jhong Huang, Hsi-Chin Wu, Ming-Ching Kao, Wen-Chin Huang
Recent research suggests that the activation of lipid biosynthesis (lipogenesis) is linked with prostate cancer (PCa) malignancy. Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcriptional regulator controlling lipogenesis. Moreover, androgen receptor (AR) has been well defined to play an important role in lethal PCa aggressiveness from androgen-responsive to castration-resistant status. In this study, we showed that the quality-assured Ganoderma tsugae ethanol extract (GTEE), a Chinese natural and herbal product, significantly inhibited expression of SREBP-1 and its downstream genes associated with lipogenesis in PCa cells...
October 5, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Yohann Loriot, Stéphane Supiot, Jean-Baptiste Beauval, Friederike Schlürmann, Gilles Pasticier, Paul Sargos, Philippe Barthélémy, Géraldine Pignot, Denis Maillet, Sébastien Vincendeau, Emmanuel Gross, Guillaume Ploussard, Marc-Olivier Timsit, Delphine Borchiellini
Management of non metastatic castrate resistant prostate cancer is challenging for clinicians due to the heterogeneity of the disease and to the scarce clinical data available in this setting. Recent results obtained with the new generation hormone therapies (NGHT) apalutamide and enzalutamide bring a new perspective for the treatment strategy. The authors present here a systematic review of the treatment options.
September 21, 2018: Cancer Treatment Reviews
Chao Wang, Jiahuan Chen, Qianfei Zhang, Wang Li, Shengbo Zhang, Yanjie Xu, Fang Wang, Bing Zhang, Yan Zhang, Wei-Qiang Gao
Androgen deprivation therapy (ADT) is a main treatment for prostate cancer (PCa) but the disease often recurs and becomes castration-resistant in nearly all patients. Recent data implicate the involvement of immune cells in the development of this castration-resistant prostate cancer (CRPC). In particular, T cells have been found to be expanded in both PCa patients and mouse models shortly after androgen deprivation. However, whether or which of the T cell subtypes play an important role during the development of CRPC is unknown...
October 8, 2018: Cell Research
Jun Dong, Zeyu Wu, Dan Wang, Laura E Pascal, Joel B Nelson, Peter Wipf, Zhou Wang
The androgen receptor (AR) is a key driver and therapeutic target in androgen-sensitive prostate cancer, castration resistant prostate cancer (CRPC), and CRPC resistant to abiraterone and enzalutamide, two second generation inhibitors of AR signaling. Since current AR inhibitors target a functioning C-terminal ligand binding domain (LBD), the identification and characterization of co-factors interacting with the N-terminal domain (NTD) of AR may lead to new approaches to target AR signaling in CRPC. Using a pulldown approach coupled with proteomics, we have identified Hsp70 as a co-factor for the NTD of AR in prostate cancer cells...
October 8, 2018: Molecular Cancer Therapeutics
Zsófia Küronya, Krisztina Bíró, Lajos Géczi, Anikó Maráz
The treatment of metastatic prostate cancer can be divided into two pathophysiological phases: hormone-sensitive and castration-resistant phases. Huggins' observation in the year 1941, which was awarded with the Nobel Prize in 1966, has a key role in treatment during the hormone-sensitive phase, stating that if the testicles are removed, the size of the prostate cancer decreases. Inducing androgen deprivation, i.e., testosterone depletion is the basic treatment of metastatic prostate cancer that patients have to receive life-long...
October 2018: Orvosi Hetilap
Pedro Isaacsson Velho, Fahad Qazi, Sayeedul Hassan, Michael A Carducci, Samuel R Denmeade, Mark C Markowski, Daniel L Thorek, Theodore L DeWeese, Daniel Y Song, Phuoc T Tran, Mario A Eisenberger, Emmanuel S Antonarakis
BACKGROUND: Pathogenic mutations in genes mediating homologous recombination (HR) DNA repair are present in 20-30% of men with metastatic castrate-resistant prostate cancer (mCRPC). Radium-223 is a bone-seeking α-emitter that induces double-strand DNA breaks, thereby killing cancer cells in the bone microenvironment. OBJECTIVE: To evaluate the potential impact of germline or somatic HR-deficiency (HRD) mutations on radium-223 efficacy in mCRPC with bone metastasis...
October 4, 2018: European Urology
A Gómez-Caamaño, C González-San Segundo, I Henríquez, X Maldonado, A Zapatero
BACKGROUND: The knowledge in the field of castration-resistant prostate cancer (CRPC) is developing rapidly, with emerging new therapies and advances in imaging. Nonetheless, in multiple areas there is still a lack of or very limited evidence, and clear guidance from clinicians regarding optimal strategy is required. METHODS: A modified Delphi method, with 116 relevant questions divided into 7 different CRPC management topics, was used to develop a consensus statement by the URONCOR group...
October 6, 2018: Clinical & Translational Oncology
Woong Sub Byun, Minkyung Jin, Jinha Yu, Won Kyung Kim, Jayoung Song, Hwa-Jin Chung, Lak Shin Jeong, Sang Kook Lee
Prostate cancer (PC) is the most common disease in men over age 50, and its prevalence rate has been gradually increasing since 1980. Taxane-derived anticancer agents are the primary agents used to treat metastatic prostate cancer patients; however, the side effects and acquired drug resistance limit the success of these therapies. Because there is no specific treatment for paclitaxel-resistant prostate cancer, it is necessary to develop new targets and therapeutic strategies to overcome the acquired resistance...
October 5, 2018: Biochemical Pharmacology
John A Violet, Price Jackson, Justin Ferdinandus, Shahneen Sandhu, Tim Akhurst, Amir Iravani, Grace Kong, Aravind Ravi Kumar, Sue Ping Thang, Peter Eu, Mark Scalzo, Declan Murphy, Scott G Williams, Rodney J Hicks, Michael S Hofman
177 Lu-PSMA-617 enables targeted delivery of beta-particle radiation to prostate cancer. We determined its radiation dosimetry and relationships to pre-therapeutic imaging and outcomes. METHODS: 30 patients with prostate cancer receiving 177 Lu-PSMA-617 within a prospective clinical trial (ACTRN12615000912583) were studied. Screening 68 Ga-PSMA-11 PET-CT demonstrated high PSMA-expression in all patients. Following therapy patients underwent quantitative SPECT-CT at 4, 24 and 96 hours. Pharmacokinetic uptake and clearance at a voxel level was calculated and translated into absorbed dose using voxel S values...
October 5, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
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