Download or read book Targeting Hormone Refractory Prostate Cancer by Inhibition of the Androgen Receptor written by Derek Stuart Welsbie and published by . This book was released on 2006 with total page 294 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Strategies to Overcome Progression of Androgen Refractory Prostate Cancer Targeting Bcl xL and Androgen Receptor written by Chih-Cheng Yang and published by . This book was released on 2007 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: A major challenge in the management of patients with prostate cancer is the treatment of hormone refractory tumors (HRPC), a hallmark of incurable and lethal prostate cancer progression. Novel strategies are needed to improve the treatment of prostate cancer and ultimately increase the survival of prostate cancer patients. Troglitazone, a peroxisome proliferators-activated receptor gamma (PPARgamma) agonist, has been reported to repress PSA expression and induce apoptosis in prostate cancer cells. Our data indicated that troglitazone has potential to inhibit the function of AR and Bcl-xL/Bcl-2, which are both critical survival signals involved in the progression of HRPC. In this study, we start from demonstrating that downregulate of androgen-stimulated PSA expression by troglitazone is through a PPARgamma independent mechanism. The evidence showed that the inhibition of PSA expression is mediated primarily through the interference of AR recruitment to the AREI and AREII within the PSA promoter region. Although the effect of down-regulation of PSA didn't contribute to the antitumor activity, it is noteworthy that troglitazone and delta2TG at doses higher than 30 uM were able to inhibit AR expression and induced apoptosis in LNCaP cells. By screening against a thiazolidinedione-based library, we identified a PPARgamma inactive derivative, STG28, which exhibited higher potency on AR repression. Evidence indicates that these troglitazone derivatives mediated transcriptional repression of AR by facilitating ubiquitin-dependent proteasomal degradation of the transcriptional factor Sp1. Furthermore, we have demonstrated that Bcl-xL overexpression provides a distinctive survival mechanism that protects PC-3 cells from apoptosis signals emanating from PI3K inhibition. Considering the pivotal role of Bcl-xL and Bcl-2 in the development of androgen independent prostate cancer, we discovered that troglitazone has ability to inhibit the function of Bcl-xL and Bcl-2 by disrupting the BH3 domain-mediated interactions with pro-apoptotic Bcl-2 members. Troglitazone derivatives that lack activity in PPARgamma activation have been utilized to demonstrate the proof of principle and modified to design more potent agents on inhibition of Bcl-xL/Bcl-2. Together, we have developed two novel class small molecules inhibitors against AR and Bcl-xL/Bcl-2, which are potential targets to inhibit the progression of hormone refractory prostate cancer.
Download or read book Androgen Action in Prostate Cancer written by Donald Tindall and published by Springer Science & Business Media. This book was released on 2009-04-20 with total page 782 pages. Available in PDF, EPUB and Kindle. Book excerpt: Androgens are critical regulators of prostate differentiation and function, as well as prostate cancer growth and survival. Therefore, androgen ablation is the preferred systemic treatment for disseminated prostate cancer. Androgen action is exerted in target tissues via binding the androgen receptor (AR), a nuclear receptor transcription factor. Historically, the gene expression program mediated by the AR has been poorly understood. However, recent gene expression profiling and more traditional single-gene characterization studies have revealed many androgen-regulated genes that are important mediators of androgen action in both normal and malignant prostate tissue. This book will focus on the androgen-regulated gene expression program, and examine how recently identified androgen-regulated genes are likely to contribute to the development and progression of prostate cancer. Recent studies that have attempted to unravel how these genes are deregulated in androgen depletion independent prostate cancer will be included
Download or read book Hormone Therapy and Castration Resistance of Prostate Cancer written by Yoichi Arai and published by Springer. This book was released on 2018-05-11 with total page 433 pages. Available in PDF, EPUB and Kindle. Book excerpt: This comprehensive reference expounds the current state of hormone therapy and castration resistance of prostate cancer (PCa). Previously, the incidence of PCa in Asian countries was relatively low, but it has been increasing dramatically in recent years. Although most of the new cases are diagnosed in early stages, a significant proportion of patients receive hormone therapy for metastatic disease or for relapse after local treatment. Thus the situation has gradually changed toward earlier and longer use of hormone therapy. The malignancy finally forms castration-resistant prostate cancer (CRPC) despite the lack of testicular androgen. With advances in understanding of the molecular basis of hormone dependence and CRPC, many new androgen receptor-targeted agents have emerged. During the last decade, much evidence on hormone therapy has been accumulated in Japan. Interestingly, some of these findings are different from those reported from Western countries, suggesting ethnic variation in the outcome of hormone therapy. In the chapters of this book, expert authors provide exhaustive interpretations of the evidence recently reported from Japan and provide important Asian perspectives on hormone therapy for PCa. This work benefits not only Asian urologists but also their Western counterparts and all physicians and medical personnel who are involved in the treatment of PCa.
Download or read book Drug Management of Prostate Cancer written by William D. Figg and published by Springer Science & Business Media. This book was released on 2010-09-14 with total page 421 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer is the most common noncutaneous prostate cancer. Research has revealed several distinct malignancy and the second leading cause of cancer mechanisms of castration-resistant disease that may deaths among men in the United States. It is a critical converge in patients with disease progression on public health problem and remains incurable in the ADT. Many approaches are currently being evaluated metastatic setting with mortality that usually occurs as to improve the treatment of this condition and these a result of castration-resistant disease. fndings have identifed several potential targets for Since Huggins and Hodges’ report of the dra- therapeutic intervention. These include drugs that are matic clinical effects of suppressing serum testos- more active or less toxic chemotherapy agents; drugs terone levels in men with advanced prostate cancer that induce androgen deprivation; drugs that target in 1941, hormone therapy (also called androgen the androgen receptor and/or androgen synthesis; deprivation therapy [ADT]) has become widely drugs that target specifc pathways, including ang- accepted as the mainstay of therapy for the treat- genesis and tyrosine kinase inhibitors, endothelin ment of advanced prostate cancer. ADT combined antagonists and matrix metalloproteinase inhibitors; with radiation therapy is a standard of care in the and immunologic approaches. Many of these agents treatment of men with locally advanced prostate seem promising and the rationale and effcacy of cancer on the basis of evidence that shows improved these emerging therapies remain to be validated in survival. The role of ADT in the management of future clinical trials.
Download or read book Hormones Genes and Cancer written by Brian E. Henderson and published by Oxford University Press. This book was released on 2003-03-13 with total page 467 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hormonal carcinogenesis is an important and controversial area of current research. In addition to accelerating existing cancers, can hormones play the role of primary carcinogens? How do genetic factors influence hormone-related cancer risk? Hormones, Genes, and Cancer addresses these questions. Over the past few decades, cancer research has focused on external environmental causes(e.g., tobacco smoke, viruses, asbestos). With the advent of new genetic sequencing techniques, we are just now beginning to understand how the body's internal environment(i.e., the hormones and growth factors that determine normal development) influences cancer etiology and prevention. From molecular insights to clinical analyses, this volume provides state-of-the-art information on the complex interactions between hormones and genes and cancer. The epidemiology and molecular endocrinology of prostate, breast, uterine, ovarian and testicular cancer are detailed in this timely treatise.
Download or read book Castration Resistant Prostate Cancer An Issue of Urologic Clinics E Book written by Adam S. Kibel and published by Elsevier Health Sciences. This book was released on 2012-11-01 with total page 240 pages. Available in PDF, EPUB and Kindle. Book excerpt: Castrate Resistant Prostate Cancer is advanced disease that has stopped responding to hormone therapy. This issue of the Urologic Clinics focuses on the various forms of therapy including immunotherapy, first line chemotherapy, and novel targeted agents. Articles on defining the diseae and palliative care are also included.
Download or read book Management of Castration Resistant Prostate Cancer written by Fred Saad and published by Springer. This book was released on 2014-08-20 with total page 336 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume provides new data about the molecular biology of CRPC and a review of the definition, staging and prognostic factors that define CRPC. The book features an in depth review of proven therapeutic options, including bone targeted therapies, immunotherapy, chemotherapy and hormonal based therapies. Combination therapy as well as novel targeted approaches presently under investigations are also reviewed. The text provides up to date guidelines and algorithms for the management of CRPC based on international guidelines presently available as well as evidence based medicine. As a concise yet comprehensive summary of the current status of the field, Management of Castration Resistant Prostate Cancer serves as a very useful resource for physicians and researchers dealing with this challenging malignancy.
Download or read book The Role of Androgen Receptor Phosphorylation in Hormone Refractory Prostate Cancer Growth written by Andrew Yong-Moon Kwon and published by . This book was released on 2008 with total page 178 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Combinatorial Targeting of the Androgen Receptor for Prostate Cancer Therapy written by Sarah Louise Carter and published by . This book was released on 2015 with total page 430 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer is one of the most commonly diagnosed cancers in Australian men and is the second leading cause of death from cancer. Since the advent of prostate specific antigen (PSA) testing, more men are being diagnosed with early-stage or organ-confined prostate cancer. At this stage of the disease, surgical removal of the prostate and/or radiotherapy is potentially curative. However, approximately 10-30% of men will progress with metastatic disease despite an initial diagnosis of organ-confined cancer, and 5-10% of men are diagnosed in the first instance with metastatic disease. Given that prostate cancer is dependent on androgens for growth and survival, the current standard of treatment for these men is androgen deprivation therapy (ADT). Despite an initial positive response to this treatment, it is not curative and relapse generally occurs within 5 years. At this stage of the disease, further hormonal manipulations or chemotherapy do not typically significantly prolong survival. It is now well accepted that this relapse is due to mechanisms by which the prostate cancer continues to rely on androgen signalling through the androgen receptor, despite the efficacy of androgen deprivation. Our laboratory and others have shown that clinical agents and molecular methods that target the androgen receptor (AR), as opposed to the androgen, are effective at suppressing growth and inducing death in prostate cancer cells. The objective of this thesis was to characterise the effects of combining clinically different drugs that modulate levels and/or activity of the AR. The histone deacetylase inhibitor vorinostat and the hsp90 inhibitor 17-AAG were investigated in combination with bicalutamide, an AR antagonist currently in clinical use. Both combinations proved to be significantly effective at synergistically suppressing growth and inducing death in prostate cancer cells in vitro, using concentrations of the drugs that are individually sub-effective. Due to factors beyond control, in vivo testing did not result in a definitive answer regarding efficacy in a mouse model of prostate cancer. Microarray profiling revealed a mechanism for the synergistic interaction between vorinostat and bicalutamide, implicating loss of the gene NFKBIA as a cause of prostate cancer cell death. Furthermore, microarray analysis showed that combining 17-AAG with bicalutamide reduces the characteristic and undesirable heat shock response associated with 17-AAG, but also implicated NFKBIA in the prostate cancer cell death caused by this combination. These insights provide a basis for further investigation into the role that manipulation of NFKBIA could play in future therapeutics, and the potential for the use of 17-AAG in a clinical setting despite the development of new generation hsp90 inhibitors. Overall, the information presented in this thesis builds on the pre-clinical characterisation of two different combinations targeting the AR for prostate cancer treatment, and facilitates clinical testing of these treatment options.
Download or read book Advances in Rapid Sex Steroid Action written by Gabriella Castoria and published by Springer Science & Business Media. This book was released on 2011-12-15 with total page 271 pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast and prostate cancers are both hormone-dependent, at least in some stages of their progression. Hormonal manipulation represents an important therapeutic approach. Although most of breast and prostate cancers initially respond to hormone therapy, most tumors reinitiate to growth. Finally, hormone-resistant and metastatic breast and prostate cancers may develop. Thus, the challenge is the dissection of mechanisms by which steroid receptor signaling pathways continue to influence cell growth and invasiveness. Compelling evidence indicates that steroid hormones elicit non-genomic responses in extra-nuclear compartment of target cells. In this cellular location, steroid-coupled receptors rapidly recruit signaling effectors or scaffold proteins and activate multiple pathways leading to proliferation, survival, migration and invasiveness. The immediate challenge is the dissection of key events regulating the steroid response of target tissues to prevent progression and improve treatment of breast and prostate cancers.
Download or read book Therapeutic Targeting of Stat5a b in Advanced Prostate Cancer written by David Timothy Hoang and published by . This book was released on 2016 with total page 544 pages. Available in PDF, EPUB and Kindle. Book excerpt: Progression of prostate cancer to the incurable and lethal castrate-resistant stage is accompanied by failure of therapies targeting the androgen receptor (AR) signaling axis, which inhibit AR-dependent proliferation and survival pathways. Signal Transducer and Activator of Transcription 5a/b (Stat5a/b) has previously been identified and validated as a therapeutic target protein in prostate cancer. In this thesis, we demonstrate that Stat5a/b promotes growth of prostate cancer through both AR-independent and AR-dependent mechanisms. Regarding AR-independent mechanisms, we show that genetic knockdown or pharmacological inhibition of AR permits survival of a prostate cancer cell subpopulation which retains sensitivity to Stat5a/b inhibition. Mechanistically, Stat5a/b was found to regulate a component of prostate cancer cell viability independently of AR, and disruption of Stat5a/b signaling induces extensive apoptotic death of androgen-dependent as well as AR signaling-depleted cells. Stat5a/b inhibition also blocked growth of both androgen-dependent and castrate/antiandrogen-resistant prostate cancer xenograft tumors and clinical prostate cancers grown ex vivo. Our results suggest that combination or sequential therapy with antiandrogens and Stat5a/b inhibitors is superior to antiandrogen monotherapy in suppressing growth and viability of advanced prostate cancer in vitro and in vivo. Regarding AR-dependent mechanisms, we show that Stat5a/b protects AR liganded by antiandrogens from proteasomal degradation and physically interacts with AR, potentiating AR signaling in the presence of antiandrogen therapy. Active Stat5a/b enhances nuclear localization of unliganded and antiandrogen-liganded AR, occupancy of AR at an AR-regulated promoter and expression of AR-regulated genes. Both antiandrogen therapy and Stat5a/b genetic knockdown individually increased proteasomal degradation of AR, while combined inhibition of AR and Stat5a/b induced maximal loss of AR protein through the proteasome and suppression of prostate cancer cell growth. In conclusion, our findings suggest that therapeutic targetinc of Stat5a/b may provide a dual strategy to inhibit growth and viability of prostate cancer. Blockade of Stat5a/b signaling may present a novel therapeutic strategy to potentially improve efficacy of antiandrogens in primary prostate cancer and bypass continued AR signaling in advanced CRPC after onset of risistance to antiandrogens.
Download or read book Selective Androgen Receptor Down Regulators SARDs A New Prostate Cancer Therapy written by and published by . This book was released on 2006 with total page 27 pages. Available in PDF, EPUB and Kindle. Book excerpt: The androgen receptor (AR) plays a key role in the development and progression of prostate cancer Targeting the AR for down-regulation would be a useful strategy for treating prostate cancer, especially hormone-refractory or androgen independent prostate cancer (AIPC). In the present study we showed that the antiestrogen Fulvestrant (ICI 182,780, ICI) effectively suppressed AR expression in several human prostate cancer cells including androgen-independent cells In LNCaP cells, ICI (10 microM) treatment decreased AR mRNA expression by 43% after 24 hours and AR protein expression by approximately 50% after 48 hours We further examined the mechanism of AR down-regulation by ICI in LNCaP cells ICI did not bind to the T877A mutant AR present in the LNCaP cells nor did it promote proteasomal degradation of the AR ICI did not affect AR mRNA or protein half-life However, ICI decreased the activity of an AR promoter-luciferase reporter plasmid transfected into LNCaP cells, suggesting a direct repression of AR gene transcription. As a result of AR down-regulation by ICI, androgen induction of PSA mRNA and protein expression were substantially attenuated. Importantly, LNCaP cell proliferation was significantly inhibited by ICI treatment Following 6 days of ICI treatment a 70% growth inhibition was seen in androgen stimulated LNCaP cells. These data demonstrate that the antiestrogen ICI is a potent AR down-regulator that causes significant inhibition of prostate cancer cell growth. Our study suggests that AR down-regulation by ICI would be an effective strategy for the treatment of all prostate cancer, especially AR-dependent Al PC.
Download or read book Targeting the Androgen Receptor DNA Binding Domain in in Vitro Models of Castration resistant Prostate Cancer written by Elisabeth Ashlyn Messner and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer remains a leading contributor to overall cancer incidence and mortality worldwide. The androgen receptor (AR) plays a predominant role in prostate cancer pathology on the cellular level by driving a pro-tumorigenic transcriptional program. Androgen deprivation therapy (ADT) and AR signaling inhibitors (ASIs) can halt disease progression by inhibiting AR function through indirect or direct ligand binding domain (LBD) inhibition. These remedies are temporary, and upon relapse, the disease progresses into an incurable state of castration resistance that has limited therapeutic options. Mechanisms driving ADT and ASI treatment relapse and advancement to castration resistance can include the cellular production of alternatively spliced AR variants (AR-Vs), often translated into low molecular weight AR isoforms, or alternative oncogenic pathways that interact with the AR. AR-Vs often lack the LBD of the AR, rendering AR LBD-specific clinical therapies ineffective. To date, no small molecule that targets alternative AR domains is used in clinical practice. The DNA binding domain (DBD) is a prime target for inhibition as it performs necessary roles in AR transcriptional activity and is less susceptible to AR alternative splicing compared to the LBD. DBD inhibition would hinder AR-DNA interaction, AR-AR interaction, and AR localization to the nucleus to halt AR and AR-V tumorigenic activity and disease progression. This study examines the role of a series of novel compounds designed to inhibit AR-DNA interaction and induce cell death in castration-resistant prostate cancer cells. From 11 compounds, 4 are selected for further study on the basis of specificity and the ability to induce cell death. Two of these, C08 and C15, induce cell death, reduce PSA promoter activity and mRNA expression, reduce Akt and ERK phosphorylation, and bind to the AR DBD. Of the 11 compounds, C15, with limited off-target mechanisms of action, induces cell death in AR-positive prostate cells by physically binding the AR DBD and inhibiting both AR genomic and non-genomic activity to overcome common mechanisms of resistance.
Download or read book Inhibition of Androgen Independent Growth of Prostate Cancer by SiRNA Mediated Androgen Receptor Gene Silencing written by and published by . This book was released on 2005 with total page 47 pages. Available in PDF, EPUB and Kindle. Book excerpt: To develop a novel therapeutic approach for hormone-refractory prostate cancers, we proposed to knock down human androgen receptor (AR) gene using an RNAi-based technique. Based on our previous work, we generated a recombinant adeno-associated virus bearing a hairpin-structured small interfering RNA against the AR (ARHP8) for long-term expression of the AR siRNA. A control virus bearing the GFP gene only was also produced. We demonstrated that the resultant rAAV. ARHP8 knocked down the AR expression both in protein and mRNA levels in prostate cancer LNCaP cells. Next, we will use the virus to treat prostate cancer xenografts in a nude mice model.
Download or read book Targeting Tyrosine Kinases and Autophagy in Prostate Cancer written by Zhaoju Wu and published by . This book was released on 2010 with total page 274 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book The Androgen Receptor in Hormone refractory Prostate Cancer written by Marcus V. Cronauer and published by . This book was released on 2007 with total page 90 pages. Available in PDF, EPUB and Kindle. Book excerpt:
