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Thomas A Hope, Charles C Truillet, Eric C Ehman, Ali Afshar-Oromieh, Rahul Aggarwal, Charles J Ryan, Peter R Carroll, Eric J Small, Michael John Evans
PURPOSE: To evaluate the effect of androgen receptor (AR) inhibition on Prostate Specific Membrane Antigen (PSMA) uptake imaged using (68)Ga-PSMA-11 Positron Emission Tomography (PET) in a mouse xenograft model and in a patient with castration sensitive prostate cancer. PROCEDURES: We imaged three groups of four mice bearing LNCaP-AR xenografts before and seven days after treatment with ARN-509, orchiectomy and control vehicle. Additionally, we imaged one patient with castration sensitive prostate cancer before and four weeks after treatment with androgen deprivation therapy (ADT)...
September 22, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Anca Azoitei, Axel S Merseburger, Beate Godau, M Raschid Hoda, Evi Schmid, Marcus V Cronauer
A mechanism allowing castration resistant prostate cancer cells to escape the effects of conventional anti-hormonal treatments is the synthesis of constitutively active, C-terminally truncated androgen receptor (AR)-variants. Lacking the entire or vast parts of the ligand binding domain, the intended target of traditional endocrine therapies, these AR-variants (termed ARΔLBD) are insensitive to all traditional treatments including second generation compounds like abiraterone, enzalutamide or ARN-509. Although ARΔLBD are predominantly products of alternative splicing, they can also be products of nonsense mutations or proteolytic cleavage...
June 21, 2016: Journal of Steroid Biochemistry and Molecular Biology
Matthew R Smith, Emmanuel S Antonarakis, Charles J Ryan, William R Berry, Neal D Shore, Glenn Liu, Joshi J Alumkal, Celestia S Higano, Edna Chow Maneval, Rajesh Bandekar, Carla J de Boer, Margaret K Yu, Dana E Rathkopf
BACKGROUND: Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. OBJECTIVE: To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). DESIGN, SETTING, AND PARTICIPANTS: We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo)...
May 6, 2016: European Urology
Athanasios Dellis, Athanasios G Papatsoris
INTRODUCTION: Prostate cancer is the most common cancer in elderly males. Regardless of the initial hormonal treatment in metastatic disease, a significant proportion of patients develop castration resistant prostate cancer (CRPC). A better understanding of the molecular mechanisms behind castration resistance has led to the approval of oral medications such as abiraterone acetate and enzalutamide. Relevant research is accelerated with numerous agents being tested for the management of CRPC...
June 2016: Expert Opinion on Investigational Drugs
Ji Ho Suh, Arundhati Chattopadhyay, Douglas H Sieglaff, Cheryl Storer Samaniego, Marc B Cox, Paul Webb
The androgen receptor (AR) surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC) cells. These effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared MJC13 and classic AR antagonists such as flutamide and bicalutamide. Microarray analysis and confirmatory qRT-PCR reveals that MJC13 and flutamide inhibit dihydrotestosterone (DHT)-dependent genes in LNCaP PC cells. Both compounds are equally effective on a genome wide basis and as effective as second generation AR antagonists (MDV3100, ARN-509) at selected genes...
2015: PloS One
Richard M Bambury, Dana E Rathkopf
The approval of abiraterone and enzalutamide for the treatment of advanced castration-resistant prostate cancer heralded a paradigm shift in the management of this disease. Nevertheless, new and improved treatments are needed since the disease remains incurable for the majority of these patients. In this article, we review the biology of castration-resistant disease as well as emerging therapeutic compounds directed at the androgen receptor, including galeterone, VT-464, ARN-509, and ODM-201. Mechanisms of action, early clinical data, and ongoing clinical studies for these compounds are all reviewed...
August 2016: Urologic Oncology
Anu-Maarit Moilanen, Reetta Riikonen, Riikka Oksala, Laura Ravanti, Eija Aho, Gerd Wohlfahrt, Pirjo S Nykänen, Olli P Törmäkangas, Jorma J Palvimo, Pekka J Kallio
Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC...
2015: Scientific Reports
Florian Jentzmik, Anca Azoitei, Friedemann Zengerling, Ilija Damjanoski, Marcus V Cronauer
Prostate cancer is the most prevalent non-skin cancer and the second leading cause of cancer death in men of the western world. As growth and differentiation of prostate cancer largely depend on androgens, inhibition of the androgen/androgen receptor signaling axis is the main treatment for locally advanced and/or metastatic tumors. Although first-line androgen deprivation therapies like chemical/surgical castration and/or administration of anti-androgens are able to control the disease for several years, prostate cancer almost invariably recurs as castration-resistant prostate cancer...
March 2016: World Journal of Urology
Constance Thibault, Christophe Massard
Therapeutic arsenal in prostate cancer widens for several years. New hormonal therapies such as acetate abiraterone or enzalutamide were the first molecules to revolutionize the treatment of metastatic castration resistant prostate cancer. Several other treatments are on trial targeting different pathways: androgene pathway (TAK-007, ARN-509, ODM-201, TOK-001), immune system (sipuleucel, ipilimumab, PROSTVAC-V/F, tasquinimod), but also tumor cell (PARP inhibitor, cabozantinib). The treatment sequencing will therefore soon be problematic, raising the necessity to identify predictive markers of response to the new therapies...
June 2015: Bulletin du Cancer
Daan Joost De Maeseneer, Charles Van Praet, Nicolaas Lumen, Sylvie Rottey
Prostate cancer (PCa) is a hormone-sensitive disease. Androgen deprivation therapy lowers serum testosterone levels (castration) or blocks the androgen receptor (AR) ligand-binding domain. Especially in metastatic disease, hormonal therapy has been able to delay disease progression, reduce symptoms, and improve overall survival. Despite subsequent disease progression and development of castration resistance, PCa remains AR driven. Secondary hormonal treatments such as abiraterone acetate or enzalutamide have demonstrated increased overall survival...
July 2015: Urologic Oncology
Martin Boegemann, Andres-Jan Schrader, Laura-Maria Krabbe, Edwin Herrmann
INTRODUCTION: Recently, an increasing number of systemic therapies with life extending capacity have become available in metastatic castration resistant prostate cancer (mCRPC) i.e. Abiraterone acetate, Enzalutamide, Sipuleucel-T, Docetaxel, Cabazitaxel and Radium-223. More compounds are currently being evaluated in promising pivotal trials (e.g. Tasquinimod, ARN-509, ODM-201, and more). Limitations of the currently available biomarkers make treatment decisions challenging. Considering the ever increasing complexity of treatment algorithms in mCRPC the current demand of research is to find and characterize biomarkers with prognostic, predictive and surrogate quality, allowing for information on clinically meaningful outcomes and on which therapy to offer patients in different and complex scenarios...
2015: Current Cancer Drug Targets
Hiroji Uemura
Androgen ablation therapy is performed for prostate cancer patients especially with advanced stage. Nevertheless, outgrowth of hormone independent cancer cells occurs within several years and leads to a lethal condition, so-called castration resistant prostate cancer (CRPC). Even in CRPC cells under low levels of serum androgens, androgen receptor (AR) signaling still functions and is engaged in the establishment of CRPC. Recently, novel AR antagonists have been developed such as enzalutamide or ARN-509. This review focuses on these AR antagonists that have some features including high affinity to AR compared with bicalutamide, preventing nuclear translocation and DNA binding...
December 2014: Nihon Rinsho. Japanese Journal of Clinical Medicine
Theodoros Karantanos, Christopher P Evans, Bertrand Tombal, Timothy C Thompson, Rodolfo Montironi, William B Isaacs
CONTEXT: Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC). OBJECTIVE: To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC...
March 2015: European Urology
Francesco Ricci, Giulia Buzzatti, Alessandra Rubagotti, Francesco Boccardo
INTRODUCTION: Antiandrogens are a treatment option in patients with prostate cancer, given either in combination with androgen deprivation or, in selected cases, as monotherapy. New-generation antiandrogens have been recently introduced in clinical practice (enzalutamide) or are under evaluation in clinical trials (ARN-509). AREAS COVERED: This review elucidates the safety profile of antiandrogens, in particular focusing on the tolerability profile of each drug either when employed in combination with castration or as monotherapy, in hormone-naive or in castration-resistant patients...
November 2014: Expert Opinion on Drug Safety
Won Kim, Charles J Ryan
The novel androgen receptor-directed therapies abiraterone acetate and enzalutamide, having demonstrated improved survival in randomized phase 3 studies of men with metastatic castration-resistant prostate cancer, have ushered in a new era in the treatment of this disease. Additional novel androgen receptor-directed therapies, such as ARN-509 and orteronel, are in various phases of clinical trials and development. However, the emergence of therapeutic resistance and clinical disease progression is inevitable...
February 1, 2015: Cancer
Eva Gupta, Troy Guthrie, Winston Tan
Recently, the standard of care for metastatic Castration Resistant Prostate Cancer (mCRPC) has changed considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen receptor gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens...
2014: BMC Urology
Matias Knuuttila, Emrah Yatkin, Jenny Kallio, Saija Savolainen, Teemu D Laajala, Tero Aittokallio, Riikka Oksala, Merja Häkkinen, Pekka Keski-Rahkonen, Seppo Auriola, Matti Poutanen, Sari Mäkelä
Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups...
August 2014: American Journal of Pathology
Marilena Manea, Marina Montagnani Marelli, Roberta M Moretti, Roberto Maggi, Monica Marzagalli, Patrizia Limonta
It is now well established that hormonal pathways are involved in the development of prostate cancer towards the castration resistant (CRPC) stage and can be effective molecular targets for novel treatment strategies. Most CRPC are sensitive to androgens and this can be due to the intratumoral production of androgens, androgen receptor (AR) amplification/ mutations and epigenetic modifications of AR expression/signaling. Based on these observations, potent agents targeting the AR axis were developed: 1) inhibitors of CYP17 (a key enzyme in the production of androgens), such as abiraterone and orteronel; 2) AR antagonists that bind to AR and impair AR activation, such as enzalutamide and ARN-509...
2014: Recent Patents on Anti-cancer Drug Discovery
N Agarwal, G Di Lorenzo, G Sonpavde, J Bellmunt
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand...
September 2014: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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