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castration refractory

Nada Lallous, Eric Leblanc, Ravi Sn Munuganti, Mohamed D H Hassona, Nader Al Nakouzi, Shannon Awrey, Helene Morin, Mani Roshan-Moniri, Kriti Singh, Sam Lawn, Takeshi Yamazaki, Hans H Adomat, Christophe Andre, Mads Daugaard, Robert N Young, Emma S Tomlinson Guns, Paul S Rennie, Artem Cherkasov
The development of new anti-androgens such as enzalutamide or androgen synthesis inhibitors like abiraterone have improved patient outcomes in the treatment of advanced prostate cancer (PCa). However, due to the development of drug resistance and tumor cell survival, the majority of these patients progress to the refractory state of castration-resistant prostate cancer (CRPC). Thus, newer therapeutic agents and a better understanding of their mode of action are needed for treating these CRPC patients. We demonstrated previously that targeting the Binding Function 3 (BF3) pocket of the androgen receptor (AR) has great potential for treating patients with CRPC...
October 7, 2016: Molecular Cancer Therapeutics
Yohei Sekino, Naohide Oue, Yoshinori Shigematsu, Akira Ishikawa, Naoya Sakamoto, Kazuhiro Sentani, Jun Teishima, Akio Matsubara, Wataru Yasui
OBJECTIVES: Prostate cancer (PCa) is a common malignancy worldwide. Docetaxel has been an important treatment option for patients with metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients with CRPC treated with docetaxel eventually become refractory. In the present study, we analyzed the expression and distribution of kinesin family member C1 (KIFC1) in human PCa by immunohistochemistry and examined the effect of inhibiting KIFC1 expression on docetaxel resistance...
September 21, 2016: Urologic Oncology
Xiao Wei, Carl Schlenkhoff, Claudia Sopora, Markus Essler, Hojjat Ahmadzadehfar
An 81-year-old castrate-resistant prostate cancer man with multiple lymph node, bone, and hepatic metastases received four cycles of Lu-PSMA-617 treatments at our department from May to December 2015. All of his liver metastases showed PSMA expression in Ga-PSMA PET performed before the first cycle. Under this therapy, all of the metastases showed significant regression in size and PSMA expression over time.
November 2016: Clinical Nuclear Medicine
Justin Ferdinandus, Elisabeth Eppard, Florian Gärtner, Stefan Kürpig, Rolf Fimmers, Anna Yordanova, Stefan Hauser, Georg Feldmann, Markus Essler, Hojjat Ahmadzadehfar
PURPOSE: Radioligand therapy (RLT) with (177)Lu-PSMA-617 (Lu-PSMA-617) (prostate-specific membrane antigen) is a novel targeted therapy for metastatic prostate cancer. In this study, we evaluated the effect of different pre-therapeutic parameters on the therapeutic response measured by prostate-specific antigen(PSA) two months after RLT. METHODS: RLT was performed in 40 hormone and/or chemo refractory patients with distant metastases and progressive disease (mean age: 71...
September 1, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Diogo A Bastos, Emmanuel S Antonarakis
Major advances have been achieved recently in the treatment of metastatic castration-resistant prostate cancer, resulting in significant improvements in quality of life and survival with the use of several new agents, including the next-generation androgen receptor (AR)-targeted drugs abiraterone and enzalutamide. However, virtually all patients will eventually progress on these therapies and most will ultimately die of treatment-refractory metastatic disease. Recently, several mechanisms of resistance to AR-directed therapies have been uncovered, including the AR splice variant 7 (AR-V7), which is a ligand-independent constitutionally-active form of the AR that has been associated with poor outcomes to abiraterone and enzalutamide...
2016: Drug Design, Development and Therapy
Daisuke Nakata, Kazuhide Nakayama, Tsuneo Masaki, Akira Tanaka, Masami Kusaka, Tatsuya Watanabe
BACKGROUND: Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory). METHODS: JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration...
December 2016: Prostate
Meihua Liang, Fei Zhan, Juan Zhao, Qi Li, Jiazi Wuyang, Guannan Mu, Dianjun Li, Yanqiao Zhang, Xiaoyi Huang
BACKGROUND: Platinum-based chemotherapy is emerging as the first line of treatment for castration resistant prostate cancer. Among the family of platinum (IV)-based compounds, a member known as CPA-7 inhibits the growth of multiple cancer cell lines. However, how and to what extent CPA-7 elicits its anti-prostate cancer effects in vivo is largely unknown. METHODS: In this study, we firstly assessed the potential toxicity of the synthesized CPA-7 in a prostate cancer model as well as in normal mice...
2016: BMC Cancer
Nicholas James, Sarah Pirrie, Ann Pope, Darren Barton, Lazaros Andronis, Ilias Goranitis, Stuart Collins, Duncan McLaren, Joe O'Sullivan, Chris Parker, Emilio Porfiri, John Staffurth, Andrew Stanley, James Wylie, Sharon Beesley, Alison Birtle, Janet Brown, Prabir Chakraborti, Martin Russell, Lucinda Billingham
BACKGROUND: Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking...
July 2016: Health Technology Assessment: HTA
Georgios Kallifatidis, James Hoy, Bal L Lokeshwar
Prostate cancer (PCa), a hormonally-driven cancer, ranks first in incidence and second in cancer related mortality in men in most Western industrialized countries. Androgen and androgen receptor (AR) are the dominant modulators of PCa growth. Over the last two decades multiple advancements in screening, treatment, surveillance and palliative care of PCa have significantly increased quality of life and survival following diagnosis. However, over 20% of patients initially diagnosed with PCa still develop an aggressive and treatment-refractory disease...
June 28, 2016: Seminars in Cancer Biology
Eva De Mol, R Bryn Fenwick, Christopher T W Phang, Victor Buzón, Elzbieta Szulc, Alex de la Fuente, Albert Escobedo, Jesús García, Carlos W Bertoncini, Eva Estébanez-Perpiñá, Iain J McEwan, Antoni Riera, Xavier Salvatella
Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer...
September 16, 2016: ACS Chemical Biology
Sarah M Schwarzenböck, Matthias Eiber, Günther Kundt, Margitta Retz, Monique Sakretz, Jens Kurth, Uwe Treiber, Roman Nawroth, Ernst J Rummeny, Jürgen E Gschwend, Markus Schwaiger, Mark Thalgott, Bernd J Krause
PURPOSE: The aim of this study was to prospectively evaluate the value of [(11)C] Choline PET/CT in monitoring early and late response to a standardized first-line docetaxel chemotherapy in castration refractory prostate cancer (mCRPC) patients. METHODS: Thirty-two patients were referred for [(11)C] Choline PET/CT before the start of docetaxel chemotherapy, after one and ten chemotherapy cycles (or - in case of discontinuation - after the last administered cycle) for therapy response assessment...
June 17, 2016: European Journal of Nuclear Medicine and Molecular Imaging
Andrea K Miyahira, Jonathan W Simons, Howard R Soule
The 22nd Annual Prostate Cancer Foundation (PCF) Scientific Retreat was convened in Washington, D.C. from October 8 to 10, 2015. This event is the foremost scientific conference in the world focusing on basic, translational, and clinical prostate cancer research with the highest potential for accelerating the understanding of prostate cancer biology and improving the lives and outcomes of prostate cancer patients. Topics highlighted during the 2015 Retreat included: (i) new strategies and treatments for localized high-risk, hormone-naïve, oligometastatic, castrate-resistant, and treatment-refractory prostate cancer settings; (ii) the biology and genomics of tumor heterogeneity and tumor evolution; (iii) new understandings on the mechanisms and targeting of oncogenic drivers of prostate cancer; (iv) bioengineering of novel therapies and drug delivery methods; (v) innovative approaches to tumor immunotherapy; (vi) emerging molecular imaging technologies with improved sensitivity and specificity; and (vii) advancements in prognostic and predictive biomarkers and precision medicine strategies...
September 2016: Prostate
L Andronis, I Goranitis, S Pirrie, A Pope, D Barton, S Collins, A Daunton, D McLaren, J O'Sullivan, C Parker, E Porfiri, J Staffurth, A Stanley, J Wylie, S Beesley, A Birtle, J Brown, P Chakraborti, S Hussain, M Russell, L Billingham, N James
OBJECTIVES: To evaluate the cost-effectiveness of adding zoledronic acid (ZA) or strontium-89 (Sr89) to standard docetaxel chemotherapy for patients with castrate-refractory prostate cancer (CRPC). PATIENTS AND METHODS: Data on resource use and quality of life for 707 patients collected prospectively in the TRAPEZE 2x2 factorial randomised trial (ISRCTN 12808747) were used to assess the cost-effectiveness of i) zoledronic acid versus no zoledronic acid (ZA vs. no ZA), and ii) strontium-89 versus no strontium-89 (Sr89 vs...
June 3, 2016: BJU International
M Luz Flores, Carolina Castilla, Jessica Gasca, Rafael Medina, Begoña Pérez-Valderrama, Francisco Romero, Miguel A Japón, Carmen Sáez
Prostate cancer is the leading cause of cancer-related death among men in developed countries. Although castration therapy is initially effective, prostate cancers progress to hormone-refractory disease and in this case taxane-based chemotherapy is widely used. Castration-resistant prostate cancer cells often develop resistance to chemotherapy agents and the search for new therapeutic strategies is necessary. In this article, we demonstrate that PKCδ silencing favors mitotic arrest after paclitaxel treatment in PC3 and LNCaP cells; however, this is associated with resistance to paclitaxel-induced apoptosis...
July 2016: Molecular Cancer Therapeutics
N Geifman, A J Butte
Open clinical trial data offer many opportunities for the scientific community to independently verify published results, evaluate new hypotheses and conduct meta-analyses. These data provide valuable opportunities for scientific advances in medical research. Herein we present the comparative meta-analysis of different standard of care treatments from newly available comparator arm data from several prostate cancer clinical trials. Comparison of survival rates following treatment with mitoxantrone or docetaxel in combination with prednisone as well as prednisone alone, validated the previously demonstrated superiority of treatment with docetaxel...
2016: Scientific Data
Neeraj Agarwal, Anitha B Alex, James M Farnham, Shiven Patel, David Gill, Tyler H Buckley, Robert A Stephenson, Lisa Cannon-Albright
PURPOSE: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict the response to abiraterone acetate in men with metastatic, castration refractory prostate cancer. The variations may serve as prognostic and predictive biomarkers to allow for more individualized therapy. MATERIALS AND METHODS: We evaluated 832 single nucleotide polymorphisms from the OmniExpress genotyping platform (Illumina®) in the boundaries of 61 candidate genes reported to be involved in the androgen metabolic pathway...
October 2016: Journal of Urology
Jonathan L Muldermans, Lindsay B Romak, Eugene D Kwon, Sean S Park, Kenneth R Olivier
PURPOSE: To review outcomes of patients with oligometastatic prostate cancer (PCa) treated with stereotactic body radiation therapy (SBRT) and to identify variables associated with local failure. METHODS AND MATERIALS: We retrospectively reviewed records of patients treated with SBRT for oligometastatic PCa. Metastasis control (ie, control of the treated lesion, MC), biochemical progression-free survival, distant progression-free survival, and overall survival were estimated with the Kaplan-Meier method...
June 1, 2016: International Journal of Radiation Oncology, Biology, Physics
A Süner, D Aydın, M B Hacıoğlu, G G Doğu, G I İmamoğlu, S Menekşe, K N Pilancı, Ö K Yazıcı, D Koca, M Karaağaç, M Akyol, T Akman, S Ergen, N Avcı, T Kaçan, O Bozkurt, U Kefeli, Z Urakçı, M Araz, E Arpacı, H Harputlu, A Sevinç
OBJECTIVE: Prostate cancer is among the most common cancers in males. Prostate cancer is androgen dependent in the beginning, but as time progresses, it becomes refractory to androgen deprivation treatment. At this stage, docetaxel has been used as standard treatment for years. Cabazitaxel has become the first chemotherapeutic agent which has been shown to increase survival for patients with metastatic Castrate Resistant Prostate Cancer (mCRPC) that progresses after docetaxel. Phase 3 TROPIC study demonstrated that cabazitaxel prolongs survival...
April 2016: European Review for Medical and Pharmacological Sciences
Shian-Ying Sung, Junn-Liang Chang, Kuan-Chou Chen, Shauh-Der Yeh, Yun-Ru Liu, Yen-Hao Su, Chia-Yen Hsueh, Leland W K Chung, Chia-Ling Hsieh
Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E) containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene...
2016: PloS One
Paolo Tralongo, Sebastiano Bordonaro, Annamaria Di Mari, Francesco Cappuccio, Sebastiano Rametta Giuliano
BACKGROUND: In elderly patients affected by metastatic castration-resistant prostate cancer (mCRPC) chemotherapic treatment may be the choice if one considers not only the chronological age, but also the clinical status, the functional reserve, and the vulnerability of patients. Several studies have confirmed the survival benefit of docetaxel and vinorelbine among every class of age. Most CRP elderly patients are defined as frail, maybe due to comorbidities: these patients, who are unable to be candidates for a standard treatment, should be candidates for a more tolerable treatment...
March 2016: Prostate International
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