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Chawnshang Chang – One of the best experts on this subject based on the ideXlab platform.

  • adt with Antiandrogens in prostate cancer induces adverse effect of increasing resistance neuroendocrine differentiation and tumor metastasis
    Cancer Letters, 2018
    Co-Authors: Yuanjie Niu, Chawnshang Chang, Shuyuan Yeh, Changcheng Guo, Simeng Wen, Jing Tian, Jie Luo, Keliang Wang, Hao Tian

    Abstract:

    Prostate cancer (PCa) is the most common cancer and the 2nd leading cause of cancer-related deaths among men in the United States. Androgen-deprivation-therapy (ADT) with Antiandrogens to target the androgens/androgen receptor (AR) signals remains the standard therapy for advanced PCa. However, most of the PCa patients who received ADT with Antiandrogens, including the recently developed Enzalutamide (Enz) that might extend PCa patients survival an extra 4.8 months, will still develop the castration (or antiandrogen) resistance. Mechanism dissection studies suggest these antiandrogen resistances may involve the induction of AR splicing variants and/or AR mutants. Further preclinical in vitro/in vivo studies suggest ADT-Antiandrogens may also enhance the neuroendocrine differentiation (NED) and PCa cell invasion, and these unwanted side-effects may function through various mechanisms including altering the infiltrating inflammatory cells within the prostate tumor microenvironment. This review summarizes these unwanted ADT-induced side-effects and discusses multiple approaches to overcome these side-effects to better suppress the PCa at the castration resistant stage.

  • reducing the agonist activity of Antiandrogens by a dominant negative androgen receptor coregulator ara70 in prostate cancer cells
    Journal of Biological Chemistry, 2003
    Co-Authors: Mujib Rahman, Hiroshi Miyamoto, Shuyuan Yeh, Saleh Altuwaijri, Hiroshi Takatera, Chawnshang Chang

    Abstract:

    Abstract Although the progression of prostate cancer initially is dependent on androgens, tumor progression to an androgen-independent growth eventually occurs in most of patients treated with androgen ablation and/or antiandrogen therapy. After the initial response, Antiandrogens lose their efficacy and eventually act as agonists to promote androgen receptor (AR)-mediated growth of prostate cancer cells. An aberrant regulation of AR activity, presumably by AR coregulators, may contribute to this acquired agonist activity of Antiandrogens. Using an in vitro mutagenesis and a double-negative selection in yeast two-hybrid screening, we have identified a dominant-negative AR coregulator ARA70 (dARA70N), which can inhibit AR transcriptional activity by inactivating the normal function of ARA70 in the LNCaP cells. Whereas ARA70 in oligomeric form interacts with AR and enhances its transcriptional activity, dARA70N lacks AR interaction and might retain the ability to form a non-functional heteromer with ARA70 and interrupt AR transcriptional activity without a change in AR protein itself. The addition of dARA70N reduces the agonist activity and rescues the normal function of Antiandrogens in prostate cancer cells. RNA-interference-mediated silencing of ARA70 gene further confirms these observations. Taken together, these findings indicate that ARA70 may contribute to the acquired agonist activity of Antiandrogens and plays an important role in making prostate cancer cells resistant to androgen ablation and/or antiandrogen therapy. ARA70 may, thus, be a critical target for developing therapeutic agents against AR-mediated progression of prostate cancer.

  • inactivation of androgen receptor coregulator ara55 inhibits androgen receptor activity and agonist effect of Antiandrogens in prostate cancer cells
    Proceedings of the National Academy of Sciences of the United States of America, 2003
    Co-Authors: Mujib Rahman, Hiroshi Miyamoto, Henry A Lardy, Chawnshang Chang

    Abstract:

    Antiandrogens given to antagonize androgen receptor (AR) activity gradually lose their efficacy as antagonists and eventually function as agonists to promote (instead of block) AR-mediated growth of prostate cancer cells. The mechanisms of how Antiandrogens acquire this agonist activity during hormonal therapy are largely unknown. Here, we report that expression of a dominant-negative AR-associated protein 55 (dARA55) coregulator, inhibits AR transcriptional activity and reduces the agonist activity of Antiandrogens. Inducibly expressed dARA55 inhibits prostate-specific antigen and cell growth in prostate cancer cells. Further dissection of the molecular mechanism shows dARA55 can selectively suppress endogenous AR-associated protein 55 (ARA55) enhanced AR transactivation by means of interruption of dimerization between ARA55 and ARA55. These results were confirmed by using RNA interference-mediated silencing of the ARA55 gene. These results therefore provide evidence that AR function could be suppressed without mutation or change in AR itself. Taken together, these findings not only demonstrate the important roles of the ARA55 coregulator in the AR-mediated growth of prostate cancer, they also may provide a critical target for developing therapeutic agents for the antiandrogen therapy that almost always fails in the treatment of hormone-refractory prostate cancer.

Peter T. Nieh – One of the best experts on this subject based on the ideXlab platform.

  • Withdrawal phenomenon with the antiandrogen casodex.
    The Journal of Urology, 1995
    Co-Authors: Peter T. Nieh

    Abstract:

    Total androgen blockade with castration and Antiandrogens has become the primary therapy in metastatic prostate carcinoma. Several reports have been published on the flutamide withdrawal syndrome with a favorable response in patients with progression of disease after lengthy remission while taking combined hormone therapy. The experience with withdrawal of the experimental nonsteroidal antiandrogen casodext in 3 patients is reported. All patients received casodex monotherapy initially, then luteinizing hormone-releasing hormone analogues were added on progression of disease (bone scan and prostate specific antigen [PSAI) and eventually casodex was withdrawn on further progression of disease (PSA and bone scan). Two patients had declines in PSA levels of 42% and 75% sustained for 3 to 6 months, and 1 patient had a stable condition for 2 months. These responses were similar to those of withdrawal of flutamide, which were limited to patients who had received combination therapy at the onset of treatment. Thus, the observations in this report would suggest that the initial and sustained exposure to an antiandrogen is the more important factor in the withdrawal phenomenon rather than the low androgen environment alone that occurs with initial luteinizing hormone-releasing hormone analogue monotherapy, orchi&my or combination luteinizing hormone-releasing hormone anaTotal androgen blockade with combined surgical or medical castration and Antiandrogens has become the mainstay of therapy for patients with stage D2 carcinoma of the prostate. Several recent reports have been published of favorable clinical and prostate specific antigen (PSA) responses to the withdrawal of the antiandrogen flutamide in patients with progression of disease &r lengthy remission while taking combined hormone therapy for metastatic carcinoma of the prostate. This paradoxical response may contribute to some of those reported with various second line treatments. Experience with withdrawal of the experimental nonsteroidal antiandrogen casodex in 3 patients is reported. MATERIALS AND METHODS All patients were enrolled into the casodex monotherapy trial for metastatic stage D2 carcinoma of the prostate, which compared results with the antiandrogen casodex with castration (either orchiectomy or medical castration using a goserelin acetate implant). These 3 patients were randomized to receive 50 mg. casodex daily and demonstrated excellent responses for the first year. At the time of progression of clinical disease with evidence of deterioration seen on bone scans and a considerable increase in PSA, luteinizing hormone-releasing hormone agonist therapy was added with improvement in symptoms, PSA and bone scan results. Eventually, when progression of disease recurred casodex was discontinued while the patients continued to take the luteinizing hormone-releasing hormone analogue.

  • Withdrawal phenomenon with the antiandrogen casodex. Commentaries
    The Journal of Urology, 1995
    Co-Authors: Peter T. Nieh, E. D. Crawford, Howard I. Scher, William Kevin Kelly

    Abstract:

    Total androgen blockade with castration and Antiandrogens has become the primary therapy in metastatic prostate carcinoma. Several reports have been published on the flutamide withdrawal syndrome with a favorable response in patients with progression of disease after lengthy remission while taking combined hormone therapy. The experience with withdrawal of the experimental nonsteroidal antiandrogen casodex in 3 patients is reported. All patients received casodex monotherapy initially, then luteinizing hormone-releasing hormone analogues were added on progression of disease (bone scan and prostate specific antigen [PSA]) and eventually casodex† was withdrawn on further progression of disease (PSA and bone scan). Two patients had declines in PSA levels of 42% and 75% sustained for 3 to 6 months, and 1 patient had a stable condition for 2 months. These responses were similar to those of withdrawal of flutamide, which were limited to patients who had received combination therapy at the onset of treatment. Thus, the observations in this report would suggest that the initial and sustained exposure to an antihydrogen is the more important factor in the withdrawal phenomenon rather than the low androgen environment alone that occurs with initial luteinizing hormone-releasing hormone analogue monotherapy, orchiectomy or combination luteinizing hormone-releasing hormone analogue and antiandrogen

Joerg J Meerpohl – One of the best experts on this subject based on the ideXlab platform.

  • non steroidal antiandrogen monotherapy compared with luteinizing hormone releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer a cochrane systematic review
    BJUI, 2015
    Co-Authors: Frank Kunath, Henrik R Grobe, Gerta Rucker, Edith Motschall, Gerd Antes, Philipp Dahm, Bernd Wullich, Joerg J Meerpohl

    Abstract:

    To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for treating advanced hormone-sensitive stages of prostate cancer. We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers. We included randomized controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced hormone-sensitive stages of prostate cancer. Two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, extracted data and assessed risk of bias as well as quality of evidence according to the GRADE working group guidelines. We used Review Manager 5.2 for data synthesis and the fixed-effect model as primary analysis (when heterogeneity was low with I(2) < 50%); we used a random-effects model when confronted with substantial or considerable heterogeneity (when I(2) ≥50%). A total of 11 studies involving 3060 randomly assigned participants were included in the present review. Use of non-steroidal Antiandrogens resulted in lower overall survival times (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.05-1.48, six studies, 2712 participants) and greater clinical progression (1 year: risk ratio [RR] 1.25, 95% CI 1.08-1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08-1.45, six studies, 2373 participants; 2 years: RR 1.14, 95% CI 1.04-1.25, three studies, 1336 participants), as well as treatment failure (1 year: RR 1.19, 95% CI 1.02-1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05-1.52, five studies, 1845 participants; 2 years: RR 1.14, 95% CI 1.05-1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Use of non-steroidal Antiandrogens increased the risk for treatment discontinuation as a result of adverse events (RR 1.82, 95% CI 1.13-2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79- 35.67, eight studies, 2670 participants) and gynaecomastia (RR 8.43, 95% CI 3.19-22.28, nine studies, 2774 participants) The risk of other adverse events, such as hot flushes (RR 0.23, 95% CI 0.19-0.27, nine studies, 2774 participants) was decreased when non-steroidal Antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flushes was rated as moderate according to GRADE. The effects of non-steroidal Antiandrogens on cancer-specific survival and biochemical progression remained unclear. Non-steroidal antiandrogen monotherapy compared with medical or surgical castration monotherapy for advanced prostate cancer is less effective in terms of overall survival, clinical progression, treatment failure and treatment discontinuation resulting from adverse events. Evidence quality was rated as moderate according to GRADE; therefore, further research is likely to have an important impact on results for patients with advanced but non-metastatic prostate cancer treated with non-steroidal antiandrogen monotherapy.

  • non steroidal antiandrogen monotherapy compared with luteinising hormone releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer
    Cochrane Database of Systematic Reviews, 2014
    Co-Authors: Frank Kunath, Henrik R Grobe, Gerta Rucker, Edith Motschall, Gerd Antes, Philipp Dahm, Bernd Wullich, Joerg J Meerpohl

    Abstract:

    Background
    Non-steroidal Antiandrogens and castration are the main therapy options for advanced stages of prostate cancer. However, debate regarding the value of these treatment options continues.

    Objectives
    To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinising hormone–releasing hormone agonists or surgical castration monotherapy for treating advanced stages of prostate cancer.

    Search methods
    We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers.

    Selection criteria
    We included randomised controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced stages of prostate cancer.

    Data collection and analysis
    One review author screened all titles and abstracts; only citations that were clearly irrelevant were excluded at this stage. Then, two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, assessed trial quality and extracted data. We contacted the study authors to request additional information. We used Review Manager 5 for data synthesis and used the fixed-effect model for heterogeneity less than 50%; we used the random-effects model for substantial or considerable heterogeneity.

    Main results
    Eleven studies involving 3060 randomly assigned participants were included in this review. The quality of evidence is hampered by risk of bias. Use of non-steroidal Antiandrogens decreased overall survival (hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.05 to 1.48, six studies, 2712 participants) and increased clinical progression (one year: risk ratio (RR) 1.25, 95% CI 1.08 to 1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08 to 1.45, six studies, 2373 participants; two years: RR 1.14, 95% CI 1.04 to 1.25, three studies, 1336 participants), as well as treatment failure (one year: RR 1.19, 95% CI 1.02 to 1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05 to 1.52, five studies, 1845 participants; two years: RR 1.14, 95% CI 1.05 to 1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Predefined subgroup analyses showed that use of non-steroidal Antiandrogens, compared with castration, was less favourable for overall survival, clinical progression (at one year, 70 weeks, two years) and treatment failure (at one year, 70 weeks, two years) in men with metastatic disease. Use of non-steroidal Antiandrogens also increased the risk for treatment discontinuation due to adverse events (RR 1.82, 95% CI 1.13 to 2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79 to 35.67, eight studies, 2670 participants), gynaecomastia (RR 8.43, 95% CI 3.19 to 22.28, nine studies, 2774 participants) and asthenia (RR 1.77, 95% CI 1.36 to 2.31, five studies, 2073 participants). The risk of other adverse events, such as hot flashes (RR 0.23, 95% CI 0.19 to 0.27, nine studies, 2774 participants), haemorrhage (RR 0.07, 95% CI 0.01 to 0.54, two studies, 546 participants), nocturia (RR 0.38, 95% CI 0.20 to 0.69, one study, 480 participants), fatigue (RR 0.52, 95% CI 0.31 to 0.88, one study, 51 participants), loss of sexual interest (RR 0.50, 95% CI 0.30 to 0.83, one study, 51 participants) and urinary frequency (RR 0.22, 95% CI 0.11 to 0.47, one study, 480 participants) was decreased when non-steroidal Antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flashes was rated as moderate according to GRADE. The effects of non-steroidal Antiandrogens on cancer-specific survival and biochemical progression remained unclear.

    Authors’ conclusions
    Currently available evidence suggests that use of non-steroidal antiandrogen monotherapy compared with medical or surgical castration monotherapy for advanced prostate cancer is less effective in terms of overall survival, clinical progression, treatment failure and treatment discontinuation due to adverse events. Evidence quality was rated as moderate according to GRADE. Further research is likely to have an important impact on results for patients with advanced but non-metastatic prostate cancer treated with non-steroidal antiandrogen monotherapy. However, we believe that research is likely not necessary on non-steroidal antiandrogen monotherapy for men with metastatic prostate cancer. Only high-quality, randomised controlled trials with long-term follow-up should be conducted. If further research is planned to investigate biochemical progression, studies with standardised follow-up schedules using measurements of prostate-specific antigen based on current guidelines should be conducted.