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Castrate resistent

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
John Esther, Benjamin L Maughan, Neysi Anderson, Neeraj Agarwal, Andrew W Hahn
Nonmetastatic castration-resistant prostate cancer (nmCRPC) comprises a relatively narrow niche of advanced prostate cancer, but the treatment landscape for men with nmCRPC has drastically changed over the past year. Prior to the SPARTAN and PROSPER trials, men with nmCRPC were commonly treated with first-generation androgen receptor antagonists, such as bicalutamide or flutamide, or with estrogens or ketoconazole, none of which were associated with any proven survival benefit. The SPARTAN trial evaluated apalutamide versus placebo for men with nmCRPC and found that apalutamide significantly improved metastasis-free survival (MFS), the primary endpoint of this trial...
February 11, 2019: Current Treatment Options in Oncology
C Duarte, A Jimeno, E R Kessler
Prostate cancer is one of the most common cancers in the United States, with an estimated incidence of 164,690 cases, accounting for 9.5% of all new cancer diagnoses. The mainstay of therapy for metastatic prostate cancer involves suppressing testosterone production through androgen deprivation therapy. However, nearly all patients on androgen deprivation therapy will develop resistance to hormone therapy. An improved understanding of the biology of castration resistance has allowed for the development of novel inhibitors of the androgen axis...
January 2019: Drugs of Today
Hideaki Miyake, Yuto Matsushita, Hiromitsu Watanabe, Keita Tamura, Daisuke Motoyama, Toshiki Ito, Takayuki Sugiyama, Atsushi Otsuka
BACKGROUND: To compare the prognostic outcomes between first-generation antiandrogen (FGA) and novel androgen-receptor-axis-targeted agent (ARATA) as first-line therapy in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). METHODS: This study retrospectively included a total of 103 consecutive nmCRPC patients consisting of 47 (45.6%) and 56 (54.4%) who received FGA (bicalutamide or flutamide) and ARATA (abiraterone acetate or enzalutamide), respectively, as the first-line agent after the failure of primary androgen deprivation therapy (ADT)...
February 9, 2019: International Journal of Clinical Oncology
Matthew Smith, Chris Parker, Fred Saad, Kurt Miller, Bertrand Tombal, Quan Sing Ng, Martin Boegemann, Vsevolod Matveev, Josep Maria Piulats, Luis Eduardo Zucca, Oleg Karyakin, Go Kimura, Nobuaki Matsubara, William Carlos Nahas, Franco Nolè, Eli Rosenbaum, Axel Heidenreich, Yoshiyuki Kakehi, Amily Zhang, Heiko Krissel, Michael Teufel, Junwu Shen, Volker Wagner, Celestia Higano
BACKGROUND: Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries...
February 6, 2019: Lancet Oncology
Marcello Tucci, Orazio Caffo, Consuelo Buttigliero, Carla Cavaliere, Carmine D'aniello, Massimo Di Maio, Stefania Kinspergher, Francesca Maines, Mimma Rizzo, Sabrina Rossetti, Antonello Veccia, Giorgio Vittorio Scagliotti, Gaetano Facchini
In few years the scenario of metastatic prostate carcinoma treatment has radically changed due to improved knowledge of those mechanisms responsible of prostatic cancer cells survival and proliferation. Five new therapeutic agents (abiraterone acetate, enzalutamide, cabazitaxel, radium-223, sipuleucel-T), all able to improve overall survival, have been introduced in the management of metastatic castration-resistant prostate cancer. Moreover, recent evidences showed that adding docetaxel chemotherapy or abiraterone acetate to androgen deprivation therapy significantly increases overall survival of de novo castration-sensitive metastatic prostate cancer patients...
January 7, 2019: Cancer Treatment Reviews
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