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Castration-resistant prostate cancer

Alastair Davies, Vincenza Conteduca, Amina Zoubeidi, Himisha Beltran
CONTEXT: Recent studies focused on the molecular characterization of metastatic prostate cancer have identified genomic subsets and emerging resistance patterns. Detection of these alterations in patients has potential implications for therapy selection and prognostication. OBJECTIVE: The primary objective is to review the current landscape of clinical and molecular biomarkers in advanced prostate cancer and understand how they may reflect underlying tumor biology...
February 13, 2019: European Urology Focus
Shimiao Zhu, Hao Tian, Xiaodan Niu, Jiang Wang, Xing Li, Ning Jiang, Simeng Wen, Xuanrong Chen, Shancheng Ren, Chuanliang Xu, Chawnshang Chang, Amilcar Flores-Morelas, Zhiqun Shang, Yinghao Sun, Yuanjie Niu
Castration-resistant prostate cancer (CRPC) with neuroendocrine differentiation (NED) is a lethal disease for which effective therapies are urgently needed. The mechanism underlying development of CRPC with NED, however, remains largely uncharacterized. In this study, we explored and characterized the functional role of neurotensin (NTS) in cell line and animal models of CRPC with NED. NTS was acutely induced by androgen deprivation in animal models of prostate cancer (PCa) and activated downstream signaling leading to NED through activation of neurotensin receptor 1 (NTSR1) and neurotensin receptor 3 (NTSR3), but not neurotensin receptor 2 (NTSR2)...
February 15, 2019: Oncogene
Naoki Terada, Toshiyuki Kamoto, Hiromasa Tsukino, Shoichiro Mukai, Shusuke Akamatsu, Takahiro Inoue, Osamu Ogawa, Shintaro Narita, Tomonori Habuchi, Shinichi Yamashita, Koji Mitsuzuka, Yoichi Arai, Shuya Kandori, Takahiro Kojima, Hiroyuki Nishiyama, Yoshiaki Kawamura, Yuki Shimizu, Toshiro Terachi, Motohiko Sugi, Hidefumi Kinoshita, Tadashi Matsuda, Yusuke Yamada, Shingo Yamamoto, Hiromi Hirama, Mikio Sugimoto, Yoshiyuki Kakehi, Toshihiko Sakurai, Norihiko Tsuchiya
BACKGROUND: We analyzed the efficacy and toxicity of cabazitaxel (CBZ) at high and low initial doses in Japanese patients with docetaxel-resistant castration-resistant prostate cancer (CRPC). METHODS: We retrospectively evaluated 118 patients who received CBZ for docetaxel-resistant CRPC in 10 university hospitals in Japan between 2014 and 2016. The rate of decrease of prostate-specific antigen (PSA), adverse events, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving initially high (≥22...
February 15, 2019: BMC Cancer
Andrew W Hahn, David D Stenehjem, Anitha B Alex, David M Gill, Heather H Cheng, Elizabeth R Kessler, Namita Chittoria, Przemyslaw Twardowski, Ulka Vaishampayan, Neeraj Agarwal
PURPOSE: Contemporary treatment for metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) plus abiraterone or docetaxel. While these intensified regimens have improved efficacy, they are also associated with increased cost and toxicities. Not all men with mHSPC may be candidates for these intensified regimens, yet there are no clinical models or biomarkers used to optimize treatment selection. Herein, we hypothesized that longer time from prior definitive therapy (DT), either radical prostatectomy, definitive radiotherapy, or both, to onset of metastatic disease is associated with improved survival outcomes in men with newly diagnosed mHSPC...
February 13, 2019: Urologic Oncology
Bertrand Tombal, Fred Saad, David Penson, Maha Hussain, Cora N Sternberg, Robert Morlock, Krishnan Ramaswamy, Cristina Ivanescu, Gerhardt Attard
BACKGROUND: In the PROSPER trial, enzalutamide significantly improved metastasis-free survival in patients with non-metastatic, castration-resistant prostate cancer. Here, we report the results of patient-reported outcomes of this study. METHODS: In the randomised, double-blind, placebo-controlled, phase 3 PROSPER trial, done at 254 study sites worldwide, patients aged 18 years or older with non-metastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of up to 10 months were randomly assigned (2:1) via an interactive voice web recognition system to receive oral enzalutamide (160 mg per day) or placebo...
February 12, 2019: Lancet Oncology
Daniel Worroll, Giuseppe Galletti, Ada Gjyrezi, David Nanus, Scott T Tagawa, Paraskevi Giannakakou
Androgen receptor (AR) signaling drives prostate cancer (PC) progression and remains active upon transition to castration resistant prostate cancer (CRPC). Active AR signaling is achieved through the nuclear accumulation of AR following ligand binding and through expression of ligand-independent, constitutively active AR splice variants, such as AR-V7, which is the most commonly expressed variant in metastatic CRPC patients. Most currently approved PC therapies aim to abrogate AR signaling and activity by inhibiting this ligand-mediated nuclear translocation...
February 14, 2019: Physical Biology
Tobias A Mattei, Carlos R Goulart, Shawn S Rai, Azeem A Rehman, Michelle Williams, Ehud Mendel
BACKGROUND: Previous studies have described the association of spinal epidural lipomatosis with several conditions including chronic steroid therapy, Cushing's syndrome, obesity, Paget's disease, and hypothyroidism. We present a report of rapid development of spinal epidural lipomatosis after treatment with second-generation anti-androgen therapy, a new strategy for treatment of metastatic castration-resistant prostate cancer which has been increasingly employed in the past few years...
February 11, 2019: World Neurosurgery
Niranjan J Sathianathen, Yiannis A Philippou, Gretchen M Kuntz, Badrinath R Konety, Shilpa Gupta, Alastair D Lamb, Philipp Dahm
OBJECTIVES: Androgen deprivation therapy (ADT) has historically been the main management option for men with metastatic, hormone-sensitive prostate cancer. Over the last two decades, a number of agents have demonstrated a benefit in castration-resistant disease[1] and there has been interest to employ these drugs earlier in the disease course when the cancer is hormone-sensitive. Taxane-based chemotherapy has been utilized in such a manner and we aimed to assess the effects of early taxane-based chemohormonal therapy for newly diagnosed, metastatic, hormone-sensitive prostate cancer...
February 14, 2019: BJU International
Karim Fizazi, Neal Shore, Teuvo L Tammela, Albertas Ulys, Egils Vjaters, Sergey Polyakov, Mindaugas Jievaltas, Murilo Luz, Boris Alekseev, Iris Kuss, Christian Kappeler, Amir Snapir, Toni Sarapohja, Matthew R Smith
BACKGROUND: Darolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis and death in men with nonmetastatic, castration-resistant prostate cancer. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less...
February 14, 2019: New England Journal of Medicine
Rui Zhu, Bill Poland, Russ Wada, Qi Liu, Luna Musib, Daniel Maslyar, Eunpi Cho, Wei Yu, Han Ma, Jin Yan Jin, Nageshwar Budha
The aims of this work were to characterize ipatasertib exposure-response (E-R) relationships in a phase II study and to quantitatively assess benefit-risk using a clinical utility index (CUI) approach to support ipatasertib phase III dose selection in patients with metastatic castration-resistant prostate cancer (mCRPC). Logistic regression and Cox proportional-hazards models characterized E-R relationships for safety and efficacy endpoints, respectively. Exposure metrics with and without considering dose interruptions/reductions (modifications) were tested in the E-R models...
February 14, 2019: CPT: Pharmacometrics & Systems Pharmacology
Cong Wang, Ziying Liu, Yuepeng Ke, Fen Wang
Advanced castrate-resistant prostate cancer (CRPC) is a poorly prognostic disease currently lacking effective cure. Understanding the molecular mechanism that underlies the initiation and progression of CRPC will provide new strategies for treating this deadly disease. One candidate target is the fibroblast growth factor (FGF) signaling axis. Loss of the intrinsic FGF7/FGF10-type 2 FGF receptor (FGFR2) pathway and gain of the ectopic type 1 FGF receptor (FGFR1) pathway are associated with the progression to malignancy in prostate cancer (PCa) and many other epithelial originating lesions...
2019: Frontiers in Genetics
Anthony Atala
No abstract text is available yet for this article.
March 2019: Journal of Urology
Anna Sarnelli, Maria Luisa Belli, Valentina Di Iorio, Emilio Mezzenga, Monica Celli, Stefano Severi, Elisa Tardelli, Silvia Nicolini, Devil Oboldi, Licia Uccelli, Corrado Cittanti, Manuela Monti, Mahila Ferrari, Giovanni Paganelli
Radio-ligand therapy (RLT) with177 Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate-cancer (mCRPC). A prospective phase-II study (EUDRACT/RSO,2016-002732-32) on mCRPC is ongoing at IRST (Meldola, Italy). A total of 9 patients (median age: 68 y, range: 53⁻85) were enrolled for dosimetry evaluation of parotid glands (PGs), kidneys, red marrow (RM) and whole body (WB). Folic polyglutamate tablets were orally administered as PGs protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake...
February 11, 2019: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Shivashankar Damodaran, Joshua M Lang, David F Jarrard
PURPOSE: Androgen deprivation therapy(ADT) alone has been the standard of care for metastatic hormone sensitive prostate cancer(mHSPC) for the last 75 years. This review focuses on recent trials and mechanisms that highlight a new paradigm, combining ADT with other agents, changing the management of prostate cancer patients with advanced disease. METHODS: A PubMed and Web of Science database search on peer-reviewed literature was performed through January 2018 using the keywords "metastatic hormone sensitive prostate cancer", " metastatic castration sensitive prostate cancer", "docetaxel", "abiraterone" and "senescence in cancer"...
February 7, 2019: Journal of Urology
Eugenio Zoni, Letizia Astrologo, Charlotte K Y Ng, Salvatore Piscuoglio, Janine Melsen, Joel Grosjean, Irena Klima, Lanpeng Chen, Ewa B Snaar-Jagalska, Kenneth Flanagan, Gabri van der Pluijm, Peter Kloen, Marco G Cecchini, Marianna Kruithof-de-Julio, George N Thalmann
Prostate Cancer (PCa) is the most common cancer and the second leading cause of cancer-related death in males. When PCa acquires castration resistance, incurable metastases, primarily in the bone, occur. The aim of this study is to test the applicability of targeting MCAM (CD146) with a monoclonal antibody for the treatment of lytic PCa bone metastasis. We evaluated the effect of targeting MCAM using in vivo preclinical bone metastasis models and an in vitro bone niche co-culture system. We utilized FACS, cell proliferation assays, and gene expression profiling to study the phenotype and function of MCAM knockdown in vitro and in vivo...
February 11, 2019: Molecular Cancer Research: MCR
Andrew W Hahn, David Stenehjem, Roberto Nussenzveig, Emma Carroll, Erin Bailey, Julia Batten, Benjamin L Maughan, Neeraj Agarwal
BACKGROUND: Targeted therapies have shown promise for men with metastatic castration-resistant prostate cancer (mCRPC). Due to the difficulty with obtaining tumor tissue in bony metastases, liquid biopsies are a promising alternative to guide treatment selection. While concurrent tissue next-generation sequencing (tNGS) and liquid biopsy has high concordance, it is unknown whether the genomic landscape of metastatic prostate cancer (mPC) changes over time or treatment. Herein, we hypothesize that the genomic landscape of mPC evolves with new treatments and/or time between tests...
February 6, 2019: Cancer Treatment and Research Communications
Ronald D Ennis, Anish B Parikh, Mark Sanderson, Mark Liu, Luis Isola
PURPOSE: The Oncology Care Model (OCM) must be clinically relevant, accurate, and comprehensible to drive value-based care. METHODS: We studied OCM data detailing observed and expected expenses for 6-month-long episodes of care for patients with prostate cancer. We constructed seven disease state-treatment dyads into which we grouped each episode on the bases of diagnoses, procedures, and medications in OCM claims data. We used this clinical-administrative stratification model to facilitate a comparative cost analysis, and we evaluated emergency department and hospital utilization and drug therapy as potential drivers of cost...
February 11, 2019: Journal of Oncology Practice
Martina Pagliuca, Carlo Buonerba, Karim Fizazi, Giuseppe Di Lorenzo
Prostate cancer (PC) is a major health issue in developed countries, with, on the one hand, men suffering from sequelae related to unnecessary treatment of non-lethal PC, and, on the other hand, still dying because of advanced PC that progresses to castration-resistant disease. Systemic treatment is the mainstay of therapy of castration-resistant PC (CRPC). To date, a multitude of systemic agents have been tested and many of these have failed to provide a clinically meaningful benefit in CRPC, while others have been approved by the US Food and Drug Administration and/or the European Medicines Agency, including antiandrogen hormonal drugs (abiraterone, enzalutamide, apalutamide), chemotherapy (docetaxel and cabazitaxel), immunotherapy (Sipuleucel-T), and radiopharmaceutical (Radium-223) agents...
February 11, 2019: Drugs
A C Hepburn, R E Steele, R Veeratterapillay, L Wilson, E E Kounatidou, A Barnard, P Berry, J R Cassidy, M Moad, A El-Sherif, L Gaughan, I G Mills, C N Robson, R Heer
Stem cell characteristics have been associated with treatment resistance and poor prognosis across many cancer types. The ability to induce and regulate the pathways that sustain these characteristic hallmarks of lethal cancers in a novel in vitro model would greatly enhance our understanding of cancer progression and treatment resistance. In this work, we present such a model, based simply on applying standard pluripotency/embryonic stem cell media alone. Core pluripotency stem cell master regulators (OCT4, SOX2 and NANOG) along with epithelial-mesenchymal transition (EMT) markers (Snail, Slug, vimentin and N-cadherin) were induced in human prostate, breast, lung, bladder, colorectal, and renal cancer cells...
February 11, 2019: Oncogene
Taro Iguchi, Satoshi Tamada, Minoru Kato, Sayaka Yasuda, Taiyo Otoshi, Kosuke Hamada, Takeshi Yamasaki, Tatsuya Nakatani
BACKGROUND: Alternative anti-androgen therapy (AAT) with flutamide after combined androgen blockade (CAB) therapy with bicalutamide for metastatic prostate cancer is common. However, no studies have compared enzalutamide without AAT with enzalutamide after AAT with flutamide as treatment for castration-resistant prostate cancer (CRPC). We aimed to compare the efficacies of flutamide and enzalutamide for CRPC. METHODS: In our hospital, 55 patients were diagnosed with CRPC after CAB therapy and administered flutamide or enzalutamide between May 2014 and December 2017...
February 11, 2019: International Journal of Clinical Oncology
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