Castration Induces Up-Regulation of Intratumoral Androgen Biosynthesis and Androgen Receptor Expression in an Orthotopic VCaP Human Prostate Cancer Xenograft Model

Knuuttila, Matti; Yatkin, Emrah; Kallio, Johanna; Savolainen, Saija; Laajala, Teemu D.; Aittokallio, Tero; Oksala, Riikka; Häkkinen, Merja R.; Keski‐Rahkonen, Pekka; Auriola, Seppo; Poutanen, Matti; Mäkelä, Sari

doi:10.1016/j.ajpath.2014.04.010

Cited by 55 publications

(71 citation statements)

References 48 publications

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“…Unlike ARV7-expressing LNCaP xenografts, ARV1-expressing LNCaP xenografts were not significantly larger than control xenografts in pre-castrated mice, indicating that ARV1 does not promote tumor growth in vivo [53]. Using a different in vivo xenografting method, one study established orthotopic xenografts by combining VCaP cells with medium and injecting the mixture into the dorsolateral prostate of immunocompromised mice [65]. Unfortunately, the authors did not accurately measure tumor size using imaging methods, such as with MRI , but monitored tumor progression using serum PSA measurements only [65,66].…”

Section: Ar Splice Variants In Pre-clinical Models Of Prostate Cancermentioning

confidence: 99%

Androgen receptor splice variants and prostate cancer: From bench to bedside

2017

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Therapeutic interventions for advanced prostate cancer (PCa) center on inhibiting androgen receptor (AR) and downstream signaling pathways. Resistance to androgen deprivation therapy and/or AR antagonists is inevitable and molecular mechanisms driving castration-resistant PCa (CR-PCa) primarily involve alterations in AR expression and activity. Detailed molecular biology work over the past decade, discussed at length in this review article, has revealed several AR transcripts that result from alternative splicing. These AR splice variants are increased in cell and mouse models of CR-PCa and in CR-PCa tumors. Several AR variants lack the ligand binding domain, but retain their ability to bind DNA and activate transcriptionlinking constitutive AR function and therapeutic failure. ARV7 is the only variant endogenously detected at the protein level and thus has undergone more thorough molecular characterization. Clinical trials in PCa are currently investigating ARV7 utility as a biomarker and new therapeutics that inhibit ARV7 . Overall, this review will illustrate the historical perspectives of AR splice variant discovery using fundamental molecular biology techniques and how it changed the clinical approach to both therapeutic decisions and strategy. The body of work investigating AR splice variants in PCa represents a true example of translational research from bench to bedside.

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Section: Ar Splice Variants In Pre-clinical Models Of Prostate Cancermentioning

confidence: 99%

Androgen receptor splice variants and prostate cancer: From bench to bedside

2017

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“…The androgen receptor (AR) signalling axis is the most clinically targeted pathway in patients with both untreated prostate cancer (who are castration-sensitive) and in those with CRPC. Lowering serum testosterone levels, or more specifically, dihydrotestosterone (DHT) levels, activates a feedback loop that increases transcription of the AR in prostate cancer cells(19, 20). This paradoxical increase in AR expression and signalling is hypothesized to lead to DNA strand breaks, which might be responsible for the resulting AR amplifications seen in 20–55% of CRPC samples, which is the most common mechanism of developing CRPC(21, 22).…”

Section: Androgen Signalingmentioning

confidence: 99%

Translational and clinical implications of the genetic landscape of prostate cancer

et al. 2016

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Over the past several years, analyses of data from high-throughput studies have elucidated many fundamental insights into prostate cancer biology. These insights include the identification of molecular alterations and subtypes that drive tumour progression, recurrent aberrations in signalling pathways, the existence of substantial intertumoural and intratumoural heterogeneity, Darwinian evolution in response to therapeutic pressures and the complicated multidirectional patterns of spread between primary tumours and metastatic sites. However, these concepts have not yet been fully translated into clinical tools to improve prognostication, prediction and personalization of treatment of patients with prostate cancer. The current and future clinical implications of ‘omics’ level knowledge is not only revolutionizing our understanding of prostate cancer biology, but is also shaping ongoing, and future clinical investigations and practice. In this Review, these advances are summarized, and the remaining challenges surrounding tumour heterogeneity and the ability to overcome treatment resistance are described.

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“…Recent autopsy studies and tissue biopsy studies have demonstrated high levels of androgens in tumor tissue of men with CRPC [13,14]. This is thought to result from conversion of weak androgens to potent androgens such as dihydrotestosterone (DHT), or de novo production of androgens from cholesterol within the tumor tissue itself [15,16]. The role of intratumoral androgens driving CRPC cancer growth is buttressed by the results of clinical trials testing testosterone concentrations in patient tumor biopsies and in clinical trials targeting the AR axis with novel anti-hormonal therapies.…”

Section: Mechanisms Of Androgen Resistancementioning

confidence: 99%

Androgen pathway resistance in prostate cancer and therapeutic implications

Maughan

Antonarakis

2015

Expert Opinion on Pharmacotherapy

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Introduction Metastatic prostate cancer is an incurable disease that is treated with a variety of hormonal therapies targeting various nodes of the androgen receptor (AR) pathway. Invariably patients develop resistance and become castration resistant. Common treatments for castration-resistant disease include novel hormonal therapies, such as abiraterone and enzalutamide, chemotherapy, immunotherapy and radiopharmaceuticals. As this disease generally remains incurable, understanding the molecular underpinnings of resistance pathways is critical in designing therapeutic strategies to delay or overcome such resistance. Areas covered This review will explore the resistance mechanisms relevant to hormonal agents, such as AR-V7 expression and others, as well as discussing new approaches being developed to treat patients with castration-resistant prostate cancer that take advantage of these new insights. A literature search was performed to identify all published clinical trials related to androgen therapy mechanisms of drug resistance in metastatic castration-resistant prostate cancer. Expert opinion Androgen therapy resistance mechanisms are varied, and include modification of all nodes in the androgen signaling pathway. The optimal treatment for men with relapsed metastatic castration-resistant prostate cancer is uncertain at this time. The authors recommend using available clinical data to guide treatment decision making until more specific biomarkers are clinically available.

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Castration Induces Up-Regulation of Intratumoral Androgen Biosynthesis and Androgen Receptor Expression in an Orthotopic VCaP Human Prostate Cancer Xenograft Model

Cited by 55 publications

References 48 publications

Androgen receptor splice variants and prostate cancer: From bench to bedside

Androgen receptor splice variants and prostate cancer: From bench to bedside

Translational and clinical implications of the genetic landscape of prostate cancer

Androgen pathway resistance in prostate cancer and therapeutic implications

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