Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a key signaling pathway that has been linked to both tumorigenesis and resistance to therapy in prostate cancer and other solid tumors. Given the significance of the PI3K/Akt/mTOR pathway in integrating cell survival signals and the high prevalence of activating PI3K/Akt/mTOR pathway alterations in prostate cancer, inhibitors of this pathway have great potential for clinical benefit. Here, we review the role of the PI3K/Akt/mTOR pathway in prostate cancer and discuss the potential use of pathway inhibitors as single agents or in combination in the evolving treatment landscape of castration-resistant prostate cancer.

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The role of microbiota in driving castration-resistant prostate cancer

10.26226/morressier.5f69edb69b74b699bf38c5cf ◽

2020 ◽

Author(s):

Arianna Calcinotto

Keyword(s):

Prostate Cancer ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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AR Copy Number and AR Signaling-directed Therapies in Castrationresistant Prostate Cancer

Current Cancer Drug Targets ◽

10.2174/1568009617666171122145852 ◽

2018 ◽

Vol 18 (9) ◽

pp. 869-876

Author(s):

Samanta Salvi ◽

Vincenza Conteduca ◽

Cristian Lolli ◽

Sara Testoni ◽

Valentina Casadio ◽

...

Keyword(s):

Prostate Cancer ◽

Copy Number ◽

Clinical Trial Design ◽

Complete Information ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Anti Cancer ◽

Hormone Sensitive ◽

Predictive And Prognostic Biomarker

Background: Adaptive upregulation of Androgen Receptor (AR) is the most common event involved in the progression from hormone sensitive to Castration-Resistant Prostate Cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. Objective: In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR Copy Number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Conclusion: Outcomes of CRPC patients are reported to be highly variable as the consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20092066 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2066 ◽

Cited By ~ 12

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.

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Prognostic role of the duration of response to androgen deprivation therapy in patients with metastatic castration resistant prostate cancer treated with enzalutamide or abiraterone acetate

Prostate Cancer and Prostatic Diseases ◽

10.1038/s41391-021-00336-1 ◽

2021 ◽

Author(s):

Rosario F. Di Stefano ◽

Marcello Tucci ◽

Fabio Turco ◽

Alessandro Samuelly ◽

Maristella Bungaro ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Deprivation Therapy ◽

Abiraterone Acetate ◽

Androgen Deprivation ◽

Castration Resistant Prostate Cancer ◽

Prognostic Role ◽

Castration Resistant ◽

Duration Of Response

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Changing the History of Prostate Cancer with New Targeted Therapies

Biomedicines ◽

10.3390/biomedicines9040392 ◽

2021 ◽

Vol 9 (4) ◽

pp. 392

Author(s):

Susana Hernando Polo ◽

Diana Moreno Muñoz ◽

Adriana Carolina Rosero Rodríguez ◽

Jorge Silva Ruiz ◽

Diana Isabel Rosero Rodríguez ◽

...

Keyword(s):

Prostate Cancer ◽

Targeted Therapies ◽

Synthetic Lethality ◽

Castration Resistant Prostate Cancer ◽

Phosphatidylinositol 3 Kinase ◽

Castration Resistant ◽

Therapeutic Landscape ◽

Important Benefit ◽

History Of ◽

Repair Genes

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is changing due to the emergence of new targeted therapies for the treatment of different molecular subtypes. Some biomarkers are described as potential molecular targets different from classic androgen receptors (AR). Approximately 20–25% of mCRPCs have somatic or germline alterations in DNA repair genes involved in homologous recombination. These subtypes are usually associated with more aggressive disease. Inhibitors of the enzyme poly ADP ribose polymerase (PARPi) have demonstrated an important benefit in the treatment of these subtypes of tumors. However, tumors that resistant to PARPi and wildtype BRCA tumors do not benefit from these therapies. Recent studies are exploring drug combinations with phosphatidylinositol-3-kinase (PI3K) or protein kinase B (AKT) inhibitors, as mechanisms to overcome resistance or to induce BRCAness and synthetic lethality. This article reviews various different novel strategies to improve outcomes in patients with prostate cancer.

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