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Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
Samir S Taneja
No abstract text is available yet for this article.
November 2016: Journal of Urology
Oliver Sartor
Radiopharmaceuticals used in the treatment of castrate-resistant prostate cancer are reviewed herein with an emphasis on sequential and combination therapies. Four bone-seeking radiopharmaceuticals had been approved in the United States. Three of these are β-emitters (phosphorus-32, strontium-89, samarium-153-ethylenediaminetetramethylene-phosphonic acid) that are approved for palliative purposes. One α-emitter (radium-223 [Ra]) is approved for prolongation of survival in bone metastatic castrate-resistant prostate cancer...
September 2016: Cancer Journal
Sankar N Maity, Mark A Titus, Revekka Gyftaki, Guanglin Wu, Jing-Fang Lu, S Ramachandran, Elsa M Li-Ning-Tapia, Christopher J Logothetis, John C Araujo, Eleni Efstathiou
Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation...
October 17, 2016: Scientific Reports
Che-Kai Tsao, John Sfakianos, Bobby Liaw, Kiev Gimpel-Tetra, Margaret Kemeny, Linda Bulone, Mohammad Shahin, William Kyu Oh, Matthew David Galsky
LESSONS LEARNED: The safety and activity findings of abiraterone acetate plus prednisone treatment in black men with mCRPC were similar to results from previously conducted studies with largely white populations.Poor trial accrual continues to be a challenge in black men with mCRPC and further efforts are needed to address such underrepresentation. BACKGROUND: Self-identified black men have higher incidence and mortality from prostate cancer in the United States compared with white men but are dramatically underrepresented in clinical trials exploring novel therapies for metastatic castration-resistant prostate cancer (mCRPC)...
October 14, 2016: Oncologist
Marzia Del Re, Elisa Biasco, Stefania Crucitta, Lisa Derosa, Eleonora Rofi, Cinzia Orlandini, Mario Miccoli, Luca Galli, Alfredo Falcone, Guido W Jenster, Ron H van Schaik, Romano Danesi
BACKGROUND: The androgen receptor splice variant 7 (AR-V7) is associated with resistance to hormonal therapy in castration-resistant prostate cancer (CRPC). Due to limitations of the methods available for AR-V7 analysis, the identification of a reliable detection method may facilitate the use of this biomarker in clinical practice. OBJECTIVE: To confirm AR-V7 as a predictor of resistance to hormonal therapy and develop a new approach to assess AR-V7 by highly sensitive digital droplet polymerase chain reaction (ddPCR) in plasma-derived exosomal RNA...
August 26, 2016: European Urology
Edel McCrea, Tristan M Sissung, Douglas K Price, Cindy H Chau, William D Figg
Significant therapeutic progress has been made in treating prostate cancer in recent years. Drugs such as enzalutamide, abiraterone, and cabazitaxel have expanded the treatment armamentarium, although it is not completely clear which of these drugs are the most-effective option for individual patients. Moreover, such advances have been tempered by the development of therapeutic resistance. The purpose of this review is to summarize the current literature pertaining to the biochemical effects of AR variants and their consequences on prostate cancer therapies at both the molecular level and in clinical treatment...
October 7, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Jesse Aidan Dinh, Danial Baker, Manpreet Chahal
OBJECTIVE: To provide an overview of the efficacy, tolerability, drug interactions, dosing, and administration issues associated with enzalutamide, abiraterone, and radium-223 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). DATA SOURCES: MEDLINE and Web of Science were used to search for relevant articles using a key-word search (enzalutamide, abiraterone, radium-223, and phase 3). No restriction was placed on the date of publication...
2016: Consultant Pharmacist: the Journal of the American Society of Consultant Pharmacists
Mark C Markowski, Michael A Carducci
Since 2010, five new antineoplastic therapies have been FDA approved for the treatment of metastatic prostate cancer. With additional treatment options, questions arose about the optimal sequence of these agents. Until recently, chemotherapy has been deferred until later in the disease course in favor of next-generation androgen deprivation therapy. Prior to the development of abiraterone acetate and enzalutamide, clinical trials were opened investigating the combination of chemotherapy with androgen deprivation therapy in patients with metastatic hormone-sensitive disease...
October 3, 2016: Cancer Treatment Reviews
Pradeep S Jadhavar, Sreekanth A Ramachandran, Eduardo Riquelme, Ashu Gupta, Kevin P Quinn, Devleena Shivakumar, Soumya Ray, Dnyaneshwar Zende, Anjan K Nayak, Sandeep K Miglani, Balaji D Sathe, Mohd Raja, Olivia Farias, Ivan Alfaro, Sebastián Belmar, Javier Guerrero, Sebastián Bernales, Sarvajit Chakravarty, David T Hung, Jeffrey N Lindquist, Roopa Rai
While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios...
October 4, 2016: Bioorganic & Medicinal Chemistry Letters
Sebastien J Hotte
Despite the significant survival benefit of taxane therapy in metastatic castration-resistant prostate cancer (mCRPC), all patients inevitably develop treatment resistance. An understanding of resistance mechanisms has led to new therapies for prostate cancer (cabazitaxel, abiraterone and enzalutamide), all of which have improved survival following first-line docetaxel. Another treatment, currently in development, targets the prosurvival molecule clusterin. Custirsen, an antisense molecule that inhibits clusterin production, has shown promise in combination with docetaxel in mCRPC patients at risk for poor outcomes...
October 7, 2016: Future Oncology
Julia Corfield, Jack Crozier, Anthony Joshua, Damien Bolton, Nathan Lawrentschuck
OBJECTIVES: To examine the current literature and identify key consensus findings from the available studies to better educate urologists and medical oncologists on agents used in the treatment of metastatic prostate cancer (mPC). METHODS: Following PRISMA guidelines, we conducted a systematic review of the available literature on reported trials of systemic therapies for mPC. Two search terms were used: 'metastatic prostate cancer' and 'treatment'. RESULTS: A variety of agents have demonstrated improved overall survival in patients with mPC...
October 6, 2016: BJU International
Mary-Ellen Taplin, Rana R McKay, Lillian Werner, Elahe A Mostaghel, Rosina T Lis, Olga Voznesensky, Zhenwei Zhang, Brett Marck, Alvin M Matsumoto, Liran Domachevsky, Katherine A Zukotynski, Manoj K Bhasin, Glenn J Bubley, Bruce Montgomery, Philip W Kantoff, Steven P Balk
PURPOSE: Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride. EXPERIMENTAL DESIGN: Eligible metastatic CRPC patients underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles...
September 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
K Miller, J Gschwend, J-M Wolff
At present, abiraterone acetate and enzalutamide are the most commonly used substances in the first-line treatment of asymptomatic or mildly symptomatic metastatic castration-resistant prostate carcinoma (mCRPC). Since the relevant pivotal trials have demonstrated comparable clinical efficacy for both substances, further factors should be considered for the choice of treatment. As mCRPC patients usually receive several lines of treatment, different adaptation and resistance mechanisms leading to treatment failure could be important...
September 2016: Aktuelle Urologie
G Sonpavde, G R Pond, A J Templeton, E D Kwon, J S De Bono
BACKGROUND: Despite palliative benefits and PSA responses, the objective clinical impact of daily oral prednisone (P) for metastatic castration-resistant prostate cancer (mCRPC) is unknown. We performed a pooled analysis of control arms of randomized trials that either did or did not administer single-agent P to evaluate its impact on overall survival (OS) and toxicities. METHODS: Individual patient data from control arms of randomized trials of men with mCRPC who received placebo or P+placebo post docetaxel were eligible for analysis...
September 27, 2016: Prostate Cancer and Prostatic Diseases
Fable Zustovich, Davide Pastorelli
Bone metastases affect the majority of patients with castration-resistant prostate cancer (CRPC), resulting in significant morbidity and mortality. This review describes the current therapies available for the management of CRPC patients with bone metastases. Areas covered: Studies on the use of currently available therapeutic approaches for palliating pain, delaying skeletal-related events (SREs) and prolonging survival in CRPC patients with bone metastases have been examined. PubMed database was searched in May 2016 starting with the following keywords: ('castration-resistant prostate cancer' OR 'CRPC') AND 'bone metastases', and approximately 270 results were retrieved...
October 6, 2016: Expert Review of Anticancer Therapy
Carlo Buonerba, Giuseppe Di Lorenzo, Guru Sonpavde
Currently, clinical factors related to the malignancy and patient-related factors such as performance status and comorbidities are employed to select agents to treat metastatic castration resistant prostate cancer (mCRPC). Areas covered: This paper covers emerging molecular panels that may be used in the clinic as prognostic or predictive biomarkers to treat mCRPC. Expert commentary: The expression of androgen receptor variant (AR-V)-7 in circulating tumor cells appears especially promising to select patients for taxane chemotherapy versus androgen inhibitors, abiraterone and enzalutamide...
October 2016: Expert Review of Molecular Diagnostics
Rana R McKay, Susanna Jacobus, Matthew Fiorillo, Elisa M Ledet, Patrick M Cotogna, Allie E Steinberger, Heather A Jacene, Oliver Sartor, Mary-Ellen Taplin
BACKGROUND: Radium-223 has shown clinical efficacy in metastatic castration-resistant prostate cancer. Despite improvement in quality of life and survival, practice patterns and utility of this agent outside the context of clinical trials have not been fully characterized. The primary objective in this study was to evaluate variables associated with completion of 5 to 6 radium-223 doses. PATIENTS AND METHODS: We conducted retrospective analyses of patients who received radium-223 (n = 135)...
August 20, 2016: Clinical Genitourinary Cancer
S M Green, A Kaipainen, K Bullock, A Zhang, J M Lucas, C Matson, W A Banks, E A Mostaghel
BACKGROUND: Epidemiologic and in vitro studies suggest that SLCO-encoded organic anion transporting polypeptide (OATP) transporters influence the response of prostate cancer (PCa) to androgen deprivation by altering intratumor androgens. We have previously shown that castration-resistant metastases express multiple SLCO transporters at significantly higher levels than primary PCa, suggesting that OATP-mediated steroid transport is biologically relevant in advanced disease. However, whether OATP-mediated steroid transport can actually modify prostate tumor androgen levels in vivo has never been demonstrated...
September 20, 2016: Prostate Cancer and Prostatic Diseases
Xiaomin Yi, Jingfang Zhang, Fei Yan, Zifan Lu, Jiaoti Huang, Chongxian Pan, Jiarui Yuan, Wanxiang Zheng, Keke Zhang, Di Wei, Wei He, Jianlin Yuan
Near-infrared fluorescence (NIRF) imaging is a novel imaging modality that allows for detection and real‑time monitoring of various pathophysiological states. IR-780 iodide has been used as an ideal platform to construct theranostic agents for cancer imaging and therapy. Abiraterone is a 17α‑hydroxylase/C17, 20‑lyase (CYP17) inhibitor that has been approved for use in patients with prostate cancer after androgen deprivation therapy. We report the synthesis and characterization of IR-780 conjugated abiraterone for the dual purpose of prostate cancer imaging and therapy...
September 16, 2016: International Journal of Oncology
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