scholarly journals Understanding Mechanisms of Resistance in Metastatic Castration-resistant Prostate Cancer: The Role of the Androgen Receptor

2016 ◽  
Vol 2 (5) ◽  
pp. 499-505 ◽  
Author(s):  
Derya Tilki ◽  
Edward M. Schaeffer ◽  
Christopher P. Evans
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Castration Resistant Prostate Cancer ◽  
Mechanisms Of Resistance ◽  
Castration Resistant

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

scholarly journals Second-generation androgen receptor inhibitors in therapy of non-metastatic castration resistant prostate cancer: role of safety profile and effect on quality of life

2021 ◽  
Vol 67 (2) ◽  
pp. 217-226
Author(s):  
Elena Ushkalova ◽  
Sergey Zyryanov ◽  
Irina Gopienko
Keyword(s):  
Quality Of Life ◽  
Prostate Cancer ◽  
Androgen Receptor ◽  
Safety Profile ◽  
Second Generation ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Clinically Significant

The article discusses the role of second-generation androgen receptor inhibitors (ARi) in therapy of non-metastatic castration resistant prostate cancer (nmCRPC). The phase 3 trials PROSPER (enzalutamide), SPARTAN (apalutamide) and ARAMIS (darolutamide) showed that these medicines if used in combination with androgen deprivation therapy (ADT) make possible to significantly improve, as compared with placebo, metastasis-free survival and overall survival of patients with nmCRPC. An important role in choosing a certain medicine of the group is played by its safety profile, including its drug-drug interaction potential and effect on patient’s quality of life. In this respect, darolutamide has a number of advantages over apalutamide or enzlutamide. The frequency of CNS (cognitive, psychiatric, convulsive) and other adverse drug reactions that significantly worsen the patients’ quality of life (falls, fractures, hypertension, etc.) in therapy with darolutamide does not differ from that with placebo. Moreover, this medicine retains its antagonistic effects to all clinically significant androgen receptor mutations that develop resistance to enzalutamide and apalutamide.

scholarly journals Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

2016 ◽  
Vol 23 (12) ◽  
pp. T179-T197 ◽  
Author(s):  
Isabel Coutinho ◽  
Tanya K Day ◽  
Wayne D Tilley ◽  
Luke A Selth
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
The Novel ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Signaling Axis ◽  
Novel Therapeutic Strategies

The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in theARgene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

scholarly journals Role of Chemotherapy and Mechanisms of Resistance to Chemotherapy in Metastatic Castration-Resistant Prostate Cancer

2016 ◽  
Vol 10s1 ◽  
pp. CMO.S34535 ◽  
Author(s):  
Vipin Lohiya ◽  
Jeanny B. Aragon-Ching ◽  
Guru Sonpavde
Keyword(s):  
Prostate Cancer ◽  
Potential Role ◽  
Therapeutic Option ◽  
Cross Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Mechanisms Of Resistance ◽  
Castration Resistant ◽  
Phases Of Development ◽  
Resistance To Chemotherapy

Chemotherapy using the taxanes, docetaxel and cabazitaxel, remains an important therapeutic option in metastatic castration-resistant prostate cancer (CRPC). However, despite the survival benefits afforded by these agents, the survival increments are modest and resistance occurs universally. Efforts to overcome resistance to docetaxel by combining with biologic agents have heretofore been unsuccessful. Indeed, resistance to these taxanes is also associated with cross-resistance to the antiandrogen drugs, abiraterone and enzalutamide. Here, we discuss the various mechanisms of resistance to chemotherapy in metastatic CRPC and the potential role of emerging regimens and agents in varying clinical phases of development.

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