Androgen Receptor Gene Amplification at Primary Progression Predicts Response to Combined Androgen Blockade as Second Line Therapy for Advanced Prostate Cancer

Palmberg, Christian; Koivisto, Pasi A.; Kakkola, Laura; Tammela, Teuvo L.J.; Kallioniemi, Olli; Visakorpi, Tapio

doi:10.1016/s0022-5347(05)66935-2

Cited by 134 publications

(44 citation statements)

References 18 publications

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“…23 AR amplification may also sensitize AR to activation by low levels of precursor adrenal androgens. 24 Moreover, in tumor cells overexpressing AR coactivators SRC-1 and TIF2, higher the AR activities were measured after treatment with precursor adrenal androgens. 25 Such data suggest that precursor adrenal androgens participate in the transition to androgen independency via mechanisms that relate to AR hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer

Suzuki

Nishiyama

Hara

et al. 2007

Prostate Cancer Prostatic Dis

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The metabolic pathways of androgens and processes by which androgens induce re-growth after androgen deprivation therapy in prostate cancer have not been fully elucidated. In this study, finasteride decreased PSA secretion in medium containing testosterone, androstenedione, androstenediol and dehydroepiandrosterone, whereas dihydrotestosterone (DHT)-and hydroxyflutamide-induced PSA production was not inhibited by finasteride in LNCaP-FGC cells. The present data show that adrenal androgen precursors do not directly interact with androgen receptors (ARs) but are converted to DHT via the intraprostatic metabolic pathways, resulting in the induction of LNCaP activity. This is the first report confirming this mechanism experimentally and also suggest the use of combined therapies that target ARs and prevent the formation of DHT within prostate cancer cells to achieve optimal therapeutic efficacy.

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Section: Discussionmentioning

confidence: 99%

Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer

Suzuki

Nishiyama

Hara

et al. 2007

Prostate Cancer Prostatic Dis

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“…It was seen that amplification positively correlated with increase in PSA in one study 20 but not in the others. 18,19,26 Furthermore, Ford et al 18 showed that there was no difference in the survival of the patients with or without amplification. In addition, studies show that amplification is not a common feature of all HR tumors.…”

Section: Amplification Of the Armentioning

confidence: 99%

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Rubin

2008

Modern Pathology

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The clinical dilemma today in the management of prostate cancer (PCA) is to distinguish men who need definitive treatment from men who have indolent disease. As demonstrated most recently by the randomized Scandinavian trial evaluating the benefit of prostatectomy over Watchful Waiting, surgery significantly decreased the risk of death from PCA. However, this same study also suggests that 19 men need to be treated to benefit one man. Given the high prevalence of the disease, the aging of the population, and the potential morbidity of treatment, the ability to distinguish aggressive from indolent forms of PCA is critical. Treatment for advanced PCA begins with androgen ablation, but eventually hormone-refractory (HR) PCA emerges. Novel therapies are in various stages of clinical trials, including kinase inhibitors, antisense oligonucleotides, and inhibitors of heat-shock proteins. The discovery of novel therapeutic approaches is an active area of clinical research. Eliminating HR PCA before it advances is a high priority in the biomarker field. Therefore, the development of molecular signatures of lethal PCA are critical. In addition, the recent discovery that a significant percentage of PCAs harbor a TMPRSS2-ETS gene fusion suggests that targeting either the ETS transcription factors or the fusion product may offer a novel approach to therapy. However, in 2007, the mainstay of treatment for advanced PCA remains androgen ablation therapy as originally introduced in the early 1940s.

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“…However, almost all of the patients whose tumors overexpressed ARs underwent androgen-deprivation monotherapy without the administration of anti-androgens. Another report by Palmberg et al (2000) evaluated whether AR gene amplification at the primary progression of prostate cancer is associated with a response to a second-line maximum androgen blockade (MAB). Patients with AR gene amplification also had a decrease in serum prostate-specific antigen (PSA) more often after MAB than those with no amplification (P = 0.079).…”

Section: Loss Of Hormone Sensitivity In Prostate Cancermentioning

confidence: 99%

Androgen receptor involvement in the progression of prostate cancer.

Suzuki¹,

Ueda²,

Ichikawa³

et al. 2003

Endocrine-Related Cancer

156

116

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Since the growth of prostate cancer is androgen-sensitive, metastatic disease has been treated by hormonal therapy. Almost all prostate cancer patients initially respond to hormonal therapy, but the majority gradually develop resistance. The mechanism of the change in tumors from being androgen-responsive to androgen-unresponsive is generally explained by clonal selection, adaptation, an alternative pathway of signal transduction and androgen receptor (AR) involvement. Since androgen action is mediated by ARs, abnormalities in ARs are believed to play an important role in the progression of prostate cancer. Hyperactivated AR gene mutations have been detected in 20-30% of hormone-refractory tumors and functional analyses have demonstrated a wide responsiveness to estrogens, progesterone and anti-androgens as well as to androgens. The AR is highly amplified in 30% of patients with hormone-refractory prostate cancer that has been treated by castration without anti-androgens. Immunohistochemical studies of ARs in hormone-refractory prostate cancer specimens have shown that AR protein is down-regulated. DNA hypermethylation of the AR promoter region leading to AR down-regulation has been identified in 30% of hormone-refractory prostate cancers. The AR N-terminal domain in the LNCaP cell line model is activated by interleukin-6 via mitogen-activated protein kinase and single transducers and activators of transcription 3. Epidemiological observations have shown that short CAG repeats are more frequently associated with higher transactivational function in the African-American population, which may explain racial differences in the incidence of prostate cancer. Among Japanese, a short CAG repeat appears to predict a response to hormonal therapy, indicating a positive prognostic value and good prognosis at the metastatic stage of prostate cancer. Several co-factors between ARs and the transcriptional complex have been cloned and reports indicate that steroid receptor co-activator 1 is correlated with the hormone-refractory progression of prostate cancer.Thus, ARs plays an important role in the progression of prostate cancer. Based on the findings described above, genetic diagnosis and/or molecular-targeted therapy via AR pathways can be developed for hormone-refractory states.

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Androgen Receptor Gene Amplification at Primary Progression Predicts Response to Combined Androgen Blockade as Second Line Therapy for Advanced Prostate Cancer

Cited by 134 publications

References 18 publications

Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer

Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Androgen receptor involvement in the progression of prostate cancer.

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