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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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
A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer
TL;DR: The prevalence of DDR gene mutations in PC varied widely within somatic subgroups depending on study size, genetic screening techniques, DDR mutation definition and PC diagnosis; somatic and/or germline DDR mutation prevalence was in the range of 23-27% in PC.
Journal ArticleDOI
Clinical relevance of androgen receptor alterations in prostate cancer
TL;DR: This review will summarize AR alterations of clinical relevance for patients with CRPC, with focus on constitutively active AR variants, their possible association with AR amplification and structural rearrangements as well as their ability to predict patient resistance to AR targeting drugs.
Journal ArticleDOI
The effect of F877L and T878A mutations on androgen receptor response to enzalutamide
Stefan Prekovic,Martin E. van Royen,Arnout Voet,Bart Geverts,René Houtman,Diana Melchers,Kam Y. J. Zhang,Thomas Van den Broeck,Elien Smeets,Lien Spans,Adriaan B. Houtsmuller,Steven Joniau,Frank Claessens,Christine Helsen +13 more
TL;DR: Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity.
Journal ArticleDOI
Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide.
Dana E. Rathkopf,Matthew R. Smith,Charles J. Ryan,William R. Berry,N.D. Shore,Glenn Liu,Celestia S. Higano,Joshi J. Alumkal,Ralph J. Hauke,Ronald F. Tutrone,Mansoor N. Saleh,E. Chow Maneval,Shibu Thomas,Deborah Ricci,Margaret K. Yu,C. J. de Boer,A. Trinh,Thian Kheoh,Rajesh Bandekar,Howard I. Scher,Emmanuel S. Antonarakis +20 more
TL;DR: The overall frequency of detected mutations at baseline and progression using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide.
Journal ArticleDOI
Disrupting Androgen Receptor Signaling Induces Snail-Mediated Epithelial-Mesenchymal Plasticity in Prostate Cancer.
Lu Miao,Lin Yang,Lin Yang,Rui Li,Daniel Nava Rodrigues,Mateus Crespo,Jer Tsong Hsieh,Wayne D. Tilley,Johann S. de Bono,Luke A. Selth,Ganesh V. Raj +10 more
TL;DR: Findings demonstrate that de-repression of Snail and induction of EMP is an adaptive response to enzalutamide with implications for therapy resistance and elucidate a mechanism explaining the inverse relationship between AR and Snail.