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Metastatic castrate resistant prostate cancer

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https://www.readbyqxmd.com/read/29439820/germline-dna-repair-gene-mutations-and-outcomes-in-men-with-metastatic-castration-resistant-prostate-cancer-receiving-first-line-abiraterone-and-enzalutamide
#1
Emmanuel S Antonarakis, Changxue Lu, Brandon Luber, Chao Liang, Hao Wang, Yan Chen, John L Silberstein, Danilo Piana, Zhao Lai, Yidong Chen, William B Isaacs, Jun Luo
BACKGROUND: Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. OBJECTIVE: To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations. DESIGN, SETTING, AND PARTICIPANTS: We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide...
February 10, 2018: European Urology
https://www.readbyqxmd.com/read/29438990/nuclear-receptor-lrh-1-functions-to-promote-castration-resistant-growth-of-prostate-cancer-via-its-promotion-of-intratumoral-androgen-biosynthesis
#2
Lijia Xiao, Yuliang Wang, Kexin Xu, Hao Hu, Zhenyu Xu, Dinglan Wu, Zhu Wang, Wenxing You, Chi-Fai Ng, Shan Yu, Franky Leung Chan
Targeting of steroidogenic enzymes (e.g. abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors...
February 8, 2018: Cancer Research
https://www.readbyqxmd.com/read/29436390/identification-of-galeterone-and-abiraterone-as-inhibitors-of-dehydroepiandrosterone-sulfonation-catalyzed-by-human-hepatic-cytosol-sult2a1-sult2b1b-and-sult1e1
#3
Caleb K Y Yip, Sumit Bansal, Siew Ying Wong, Aik Jiang Lau
Galeterone and abiraterone acetate are anti-androgens developed for the treatment of metastatic castration-resistant prostate cancer. In the present study, we investigated the effect of these drugs on dehydroepiandrosterone (DHEA) sulfonation catalyzed by human liver and intestinal cytosols and human recombinant sulfotransferase enzymes (SULT2A1, SULT2B1b, and SULT2E1), and compared their effects to those of other anti-androgens (cyproterone acetate, spironolactone, and danazol). Each of these chemicals (10 μM) inhibited DHEA sulfonation catalyzed by human liver and intestinal cytosols...
February 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29434990/abiraterone-acetate-withdrawal-syndrome-speculations-on-the-underlying-mechanisms
#4
Tomonori Kato, Akira Komiya, Joji Yuasa, Kanya Kaga, Mayuko Kaga, Satoko Kojima, Yukio Naya, Shigeo Isaka
A 72-year-old man initially presented with lumbar and right chest pain, but was later found out to also have an elevated prostate-specific antigen (PSA) level at 2,000.0 ng/ml. Further evaluation disclosed metastatic prostate cancer involving the bones and lymph nodes. The patient was initially treated with combined androgen blockade (CAB) with leuprolide acetate and bicalutamide. After 6 months of CAB, the patient's PSA level began to rise from the nadir (85.1 ng/ml) to 113.3 ng/ml. Bicalutamide was withdrawn in anticipation of anti-androgen withdrawal syndrome and the PSA level declined temporally...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29431639/cxcl12%C3%AE-%C3%A2-promotes-development-of-metastatic-castration-resistant-prostate-cancer-by-induction-of-cancer-stem-cell-and-neuroendocrine-phenotypes
#5
Younghun Jung, Frank C Cackowski, Kenji Yumoto, Ann Decker, Jingcheng Wang, Jinkoo Kim, Eunsohl Lee, Yugang Wang, Jae-Seung Chung, Amy M Gursky, Paul H Krebsbach, Kenneth J Pienta, Todd M Morgan, Russell S Taichman
There is evidence that cancer stem-like cells (CSC) and neuroendocrine (NE) behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limiting mechanistic understanding of how CSC and NE phenotypes impact the development of m-CRPC, which could improve opportunities to identify useful biomarkers and therapeutics. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and NE differentiation and its impact on m-CRPC...
February 5, 2018: Cancer Research
https://www.readbyqxmd.com/read/29431540/pharmacokinetic-pharmacodynamic-drug-evaluation-of-enzalutamide-for-treating-prostate-cancer
#6
Jeong Hee Hong
Enzalutamide is the first approved second-generation androgen receptor (AR) antagonist in the treatment of metastatic castration-resistant prostate cancer (mCRPC) with or without docetaxel-based chemotherapy. Over the past 5 years, a number of attempts were made to determine the efficacy of enzalutamide in the different clinical settings. Areas covered: A literature search was performed at the PubMed, Embase, and Web of Science database to collect the most relevant and impactful studies, including basic science investigations, clinical trials, and reviews...
February 12, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29431193/circulating-tumor-cells-and-survival-in-abiraterone-and-enzalutamide-treated-patients-with-castration-resistant-prostate-cancer
#7
Bram De Laere, Steffi Oeyen, Peter Van Oyen, Christophe Ghysel, Jozef Ampe, Piet Ost, Wim Demey, Lucien Hoekx, Dirk Schrijvers, Barbara Brouwers, Willem Lybaert, Els Everaert, Piet Van Kerckhove, Daan De Maeseneer, Michiel Strijbos, Alain Bols, Karen Fransis, Nick Beije, Inge de Kruijff, Valerie van Dam, Anja Brouwer, Pieter-Jan van Dam, Gert Van den Eynden, Annemie Rutten, Stefan Sleijfer, Jean Vandebroek, Steven Van Laere, Luc Dirix
BACKGROUND: The outcome to treatment administered to patients with metastatic castration-resistant prostate cancer (mCRPC) greatly differs between individuals, underlining the need for biomarkers guiding treatment decision making. OBJECTIVE: To investigate the prognostic value of circulating tumor cell (CTC) enumeration and dynamics, in the context of second-line endocrine therapies (ie, abiraterone acetate or enzalutamide), irrespective of prior systemic therapies...
February 12, 2018: Prostate
https://www.readbyqxmd.com/read/29429804/clinical-outcome-of-prostate-cancer-patients-with-germline-dna-repair-mutations-retrospective-analysis-from-an-international-study
#8
Joaquin Mateo, Heather H Cheng, Himisha Beltran, David Dolling, Wen Xu, Colin C Pritchard, Helen Mossop, Pasquale Rescigno, Raquel Perez-Lopez, Verena Sailer, Michael Kolinsky, Ada Balasopoulou, Claudia Bertan, David M Nanus, Scott T Tagawa, Heather Thorne, Bruce Montgomery, Suzanne Carreira, Shahneen Sandhu, Mark A Rubin, Peter S Nelson, Johann S de Bono
BACKGROUND: Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. OBJECTIVE: To determine whether gDDRm status impacts benefit from established therapies in mPC. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status...
January 29, 2018: European Urology
https://www.readbyqxmd.com/read/29423050/enhanced-anti-tumor-efficacy-and-mechanisms-associated-with-docetaxel-piperine-combination-in-vitro-and-in-vivo-investigation-using-a-taxane-resistant-prostate-cancer-model
#9
Chenrui Li, Zhijun Wang, Qian Wang, Rebecca Lucinda Ka Yan Ho, Ying Huang, Moses S S Chow, Christopher Wai Kei Lam, Zhong Zuo
Docetaxel (DTX) is widely used for metastatic castrated resistant prostate cancer, but its efficacy is often compromised by drug resistance associated with low intracellular concentrations. Piperine (PIP) could enhance the bioavailability of other drugs via the inhibition of CYPs and P-gp activities. Thus, we hypothesize a positive effect with the DTX-PIP combination on the anti-tumor efficacy and intra-tumor DTX concentrations in taxane-resistant prostate cancer. ICR-NOD/SCID mice implanted with taxane-resistant human prostate cancer cells were administrated with saline as well as PIP and DTX separately or in combination...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29421982/immune-based-therapies-for-metastatic-prostate-cancer-an-update
#10
Md Kamal Hossain, Kamrun Nahar, Osaana Donkor, Vasso Apostolopoulos
Prostate cancer (PC) is a common malignancy among elderly males and is noncurable once it becomes metastatic. In recent years, a number of antigen-delivery systems have emerged as viable and promising immunotherapeutic agents against PC. The approval of sipuleucel-T by the US FDA for the treatment of males with asymptomatic or minimally symptomatic castrate resistant PC was a landmark in cancer immunotherapy, making this the first approved immunotherapeutic. A number of vaccines are under clinical investigation, each having its own set of advantages and disadvantages...
February 1, 2018: Immunotherapy
https://www.readbyqxmd.com/read/29419723/development-and-validation-of-a-bioanalytical-method-to-quantitate-enzalutamide-and-its-active-metabolite-n-desmethylenzalutamide-in-human-plasma-application-to-clinical-management-of-metastatic-castration-resistant-prostate-cancer-patients
#11
Guillemette E Benoist, Eric van der Meulen, Inge M van Oort, Jan Hendrik Beumer, Diederik M Somford, Jack A Schalken, David M Burger, Nielka P van Erp
BACKGROUND: Enzalutamide is a potent androgen-signaling receptor inhibitor and is licensed for the treatment of metastatic castration-resistant prostate cancer. N-desmethylenzalutamide is the active metabolite of enzalutamide. A method to quantitate enzalutamide and its active metabolite was developed and validated according to the European Medicine Agency (EMA) guidelines. METHODS: Enzalutamide and N-desmethylenzalutamide were extracted by protein precipitation, separated on a C18 column with gradient elution and analyzed with tandem quadruple mass spectrometry in positive ion mode...
February 5, 2018: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29419479/the-effect-of-total-tumor-volume-on-the-biologically-effective-dose-of-tumor-and-kidneys-for-177lu-labelled-psma-peptides
#12
Nusrat Begum, Anne Thieme, Nina Eberhardt, Robert Tauber, Ambros J Beer, Gerhard Glatting, Matthias Eiber, Peter Kletting
Aim: To simulate the effect of PSMA positive total tumor volume (TTV) on the tumor and organs at risk (OARs) biologically effective doses (BEDs) in patients with metastatic castration resistant prostate cancer (mCRPC) in 177Lu-PSMA radioligand therapy. Methods: A physiologically-based pharmacokinetic model was fitted to data of 13 patients treated with 177Lu-PSMA I&T. The tumor, kidneys and salivary glands BEDs were simulated for TTVs of 0.1-10 l. The activity and peptide amounts leading to an optimal tumor-to-kidneys BED ratio were also investigated...
February 1, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29404276/estrogens-and-their-receptors-in-prostate-cancer-therapeutic-implications
#13
REVIEW
Erika Di Zazzo, Giovanni Galasso, Pia Giovannelli, Marzia Di Donato, Gabriella Castoria
A major challenge in clinical management of prostate cancer (PC) is to limit tumor growth and prevent metastatic spreading. Considerable efforts have been made to discover new compounds for PC therapy and recent years have seen promising progress in this field. Pharmacological approaches have been designed to achieve benefits in PC treatment and avoid the negative side effects resulting from administration of antagonists or agonists or new drugs. Nonetheless, the currently available therapies frequently induce resistance and PC progresses toward castration-resistant forms that can be caused by the androgen receptor reactivation and/or mutations, or derangement of signaling pathways...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29402534/association-among-metabolic-syndrome-inflammation-and-survival-in-prostate-cancer
#14
Vincenza Conteduca, Orazio Caffo, Luca Galli, Antonio Maugeri, Emanuela Scarpi, Francesca Maines, Vincenzo Emanuele Chiuri, Cristian Lolli, Stefania Kinspergher, Giuseppe Schepisi, Matteo Santoni, Daniele Santini, Lucia Fratino, Salvatore Luca Burgio, Samanta Salvi, Cecilia Menna, Ugo De Giorgi
BACKGROUND: Metabolic syndrome (MS) and inflammation (INF) alterations are among the factors involved in cancer progression. The study aimed to assess the relationship between MS and INF and its effect on progression-free/overall survival (PFS/OS) in metastatic castration-resistant prostate cancer (mCRPC) treaed with abiraterone or enzalutamide. METHODS: We, retrospectively, evaluated patients with mCRPC in 7 Italian Institutes between March 2011 and October 2016...
February 2, 2018: Urologic Oncology
https://www.readbyqxmd.com/read/29398263/expression-of-androgen-receptor-splice-variant-7-or-9-in-whole-blood-does-not-predict-response-to-androgen-axis-targeting-agents-in-metastatic-castration-resistant-prostate-cancer
#15
Sarah Q To, Edmond M Kwan, Heidi C Fettke, Andrew Mant, Maria M Docanto, Luciano Martelotto, Patricia Bukczynska, Nicole Ng, Lisa-Jane K Graham, Phillip Parente, Carmel Pezaro, Kate Mahon, Lisa Horvath, Tilman Todenhöfer, Arun A Azad
In 2014, a landmark study was published demonstrating that the expression of androgen receptor splice variant (AR-V) 7 was a negative predictive biomarker for response to abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients. However, these results were not supported by the recently reported ARMOR3-SV phase III clinical trial, which employed an identical circulating tumour cell assay to assess AR-V7 expression. Therefore, the predictive utility of AR-V7 expression in mCRPC remains uncertain, as does any potential association between other AR-Vs and treatment response...
February 2, 2018: European Urology
https://www.readbyqxmd.com/read/29395951/epigenetic-reprogramming-a-key-mechanism-driving-therapeutic-resistance
#16
REVIEW
Anjali V Sheahan, Leigh Ellis
Prostate cancer initiation, development and progression is driven by androgen receptor (AR) signaling. Androgen deprivation therapy is the primary treatment for patients that present with locally advanced or metastatic disease. However, androgen deprivation therapy is not curative, and patients will progress to castrate-resistant disease (CRPC). Although most patient's progress to CRPC via restoration of AR signaling (CRPC-Ad), approximately a quarter of patients will progress via mechanisms independent of AR signaling...
January 26, 2018: Urologic Oncology
https://www.readbyqxmd.com/read/29395685/when-and-how-to-use-carboplatin-in-metastatic-castration-resistant-prostate-cancer
#17
EDITORIAL
A Omlin, S Gillessen
No abstract text is available yet for this article.
January 27, 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29391917/injection-of-botulinum-toxin-for-preventing-salivary-gland-toxicity-after-psma-radioligand-therapy-an-empirical-proof-of-a-promising-concept
#18
Richard P Baum, Thomas Langbein, Aviral Singh, Mostafa Shahinfar, Christiane Schuchardt, Gerd Fabian Volk, Harshad Kulkarni
The dose-limiting salivary gland toxicity of 225Ac-labelled PSMA for treatment of metastatic, castration-resistant prostate cancer remains unresolved. Suppressing the metabolism of the gland by intraparenchymal injections of botulinum toxin appears to be a promising method to reduce off-target uptake. A 68Ga-PSMA PET/CT scan performed 45 days after injection of 80 units of botulinum toxin A into the right parotid gland in a 63-year-old patient showed a decrease in the SUVmean in the right parotid gland of up to 64% as compared with baseline...
February 2018: Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/29388415/innovations-in-imaging-modalities-for-recurrent-and-metastatic-prostate-cancer-a-systematic-review
#19
Simone Albisinni, Fouad Aoun, Quentin Marcelis, Claude Jungels, Walid Al Hajj Obeid, Marc Zanaty, Andrea Tubaro, Thierry Roumeguere, Cosimo DE Nunzio
INTRODUCTION: The last decade has witnessed tremendous changes in the management of advanced and metastatic castration resistant prostate cancer (mCRPC). In the current systematic review, we analyze novel imaging techniques in the setting of recurrent and metastatic PCa, exploring available data and highlighting future exams which could enter clinical practice in the upcoming years. EVIDENCE ACQUISITION: The National Library of Medicine Database was searched for relevant articles published between January 2012 and August 2017...
January 31, 2018: Minerva Urologica e Nefrologica, the Italian Journal of Urology and Nephrology
https://www.readbyqxmd.com/read/29388324/taxane-chemotherapy-versus-anti-androgen-agents-as-first-line-therapy-for-metastatic-castration-resistant-prostate-cancer
#20
Guru Sonpavde, Ahong Huang, Li Wang, Onur Baser, Raymond Miao
OBJECTIVES: To assess treatment patterns and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy or anti-androgen therapy. PATIENTS AND METHODS: Patients initiating first-line anti-androgen therapy (abiraterone, enzalutamide) or chemotherapy (taxane) from Oct/2012-Sept/2014 were retrospectively identified in the US Veterans Health Administration (VHA) database. The impact of anti-androgen therapy versus chemotherapy on overall survival (OS) and time to discontinuation was assessed using Cox proportional hazard models, adjusting for prior androgen deprivation therapy (ADT) duration and available prognostic factors...
February 1, 2018: BJU International
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