Journal ArticleDOI
Resistance to second-generation androgen receptor antagonists in prostate cancer.
TLDR
The use of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy as mentioned in this paper.Abstract:
The introduction of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy. SG-ARAs provide similar therapeutic benefit to abiraterone, a potent CYP17 inhibitor, and do not require the co-administration of prednisone. Despite considerable improvements in clinical outcomes in the settings of both castration sensitivity and castration resistance, the durability of clinical response to the SG-ARAs enzalutamide, apalutamide and darolutamide, similar to abiraterone, is limited by inevitable acquired resistance. Genomic aberrations that confer resistance to SG-ARAs or provide potential alternative treatment modalities have been identified in numerous studies, including alterations of the androgen receptor, DNA repair, cell cycle, PI3K-AKT-mTOR and Wnt-β-catenin pathways. To combat resistance, researchers have explored approaches to optimizing the utility of available treatments, as well as the use of alternative agents with a variety of targets, including AR-V7, AKT, EZH2 and HIF1α. Ongoing research to establish predictive biomarkers for the treatment of tumours with resistance to SG-ARAs led to the approval of the PARP inhibitors olaparib and rucaparib in pre-treated metastatic castration-resistant prostate cancer. The results of ongoing studies will help to shape precision medicine in prostate cancer and further optimize treatment paradigms to maximize clinical outcomes.read more
Citations
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Journal ArticleDOI
Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance
TL;DR: In this article , the authors discuss how nongenetic factors contribute to heterogeneity of prostate cancer and summarize the challenges targeting the tumor environments, and emphasize that continued exploration of tumor heterogeneity is needed in order to offer a personalized therapy for advanced prostate cancer patients.
Journal ArticleDOI
Second generation androgen receptor antagonists and challenges in prostate cancer treatment
TL;DR: In this paper , the authors summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.
Journal ArticleDOI
Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer
Safae Terrisse,Anne-Gaëlle Goubet,Kousuke Ueda,Andrew Maltez Thomas,Valentin Quiniou,Cassandra Thelemaque,Garett Dunsmore,Emmanuel Clave,Melissa Gamat-Huber,Satoru Yonekura,Gladys Ferrere,Conrad Rauber,Hang-Phuong Pham,Jean-Eudes Fahrner,Eugenie Pizzato,Pierre Ly,Marine Fidelle,Marine Mazzenga,Carolina Alves Costa Silva,Federica Armanini,Federica Pinto,Francesco Asnicar,Romain Daillère,Lisa Derosa,Corentin Richard,Pierre Blanchard,Bertrand Routy,Stéphane Culine,Paule Opolon,Aymeric Silvin,Florent Ginhoux,Antoine Toubert,Nicola Segata,Douglas G. McNeel,Karim Fizazi,Guido Kroemer,Laurence Zitvogel +36 more
TL;DR: The potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients is suggested, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs.
Journal ArticleDOI
Unravelling the molecular mechanisms of prostate cancer evolution from genotype to phenotype.
TL;DR: The identification of canonical genetic alterations and signaling pathway activation in prostate cancer has shed more insight into genetic background, molecular subtype and disease landscape of PC evolution, resulting in a more flexible role of individual therapies targeting diverse genotype and phenotype presentation as discussed by the authors.
Journal ArticleDOI
Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer.
TL;DR: In this paper, the role of the androgen/androgen receptor (AR) axis in prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is analyzed.
References
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Journal ArticleDOI
AR Signaling and the PI3K Pathway in Prostate Cancer.
TL;DR: The role of the PI3K pathway in prostate cancer and, in particular, its association with androgen receptor signaling in the pathogenesis and evolution of prostate cancer is outlined, as well as a review of the clinical utility ofPI3K targeting.
Journal ArticleDOI
The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact
Lisanne F. van Dessel,Job van Riet,Minke Smits,Yanyun Zhu,Paul Hamberg,Michiel S. van der Heijden,Andries M. Bergman,Inge M. van Oort,Ronald de Wit,Emile E. Voest,Neeltje Steeghs,Takafumi N. Yamaguchi,Julie Livingstone,Paul C. Boutros,John W.M. Martens,Stefan Sleijfer,Edwin Cuppen,Wilbert Zwart,Wilbert Zwart,Harmen J.G. van de Werken,Niven Mehra,Martijn P. Lolkema +21 more
TL;DR: In this paper, the authors presented the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients, using unsupervised clustering based on genomic features, defined eight distinct genomic clusters.
Journal ArticleDOI
The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy.
Martin Puhr,Julia Hoefer,Andrea Eigentler,Christian Ploner,Florian Handle,Georg Schaefer,Jan Kroon,Angela Leo,Isabel Heidegger,Iris E. Eder,Zoran Culig,Gabri van der Pluijm,Helmut Klocker +12 more
TL;DR: GR upregulation seems to be a common mechanism during antiandrogen treatment and supports the notion that targeting the GR pathway combined with anti androgen medication may further improve prostate cancer therapy.
Journal ArticleDOI
Generation 2.5 Antisense Oligonucleotides Targeting the Androgen Receptor and Its Splice Variants Suppress Enzalutamide-Resistant Prostate Cancer Cell Growth
Yoshiaki Yamamoto,Yohann Loriot,Eliana Beraldi,Fan Zhang,Alexander W. Wyatt,Nader Al Nakouzi,Fan Mo,Tianyuan Zhou,Youngsoo Kim,Brett P. Monia,A. Robert MacLeod,Ladan Fazli,Yuzhuo Wang,Colin Collins,Amina Zoubeidi,Martin E. Gleave +15 more
TL;DR: These data identify the AR as an important driver of ENZ resistance, and while the contributions of ARFL and AR-Vs can vary across cell systems, ARFL is the key driver in the ENZ-R LNCaP model.
Journal ArticleDOI
CDK12-altered prostate cancer: Clinical features and therapeutic outcomes to standard systemic therapies, poly (ADP-ribose) polymerase inhibitors, and PD-1 inhibitors
Emmanuel S. Antonarakis,Pedro Isaacsson Velho,Wei Fu,Hao Wang,Neeraj Agarwal,Victor Sacristan Santos,Benjamin L. Maughan,Roberto Pili,Nabil Adra,Cora N. Sternberg,Panagiotis J. Vlachostergios,Scott T. Tagawa,Alan H. Bryce,Andrea McNatty,Zachery R. Reichert,Robert Dreicer,Oliver Sartor,Tamara L. Lotan,Maha Hussain +18 more
TL;DR: CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors, which implicates CDK12 deficiency in immunotherapy sensitivity.