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Castration-Resistant Prostate Cancer: Mechanisms, Targets, and Treatment  [PDF]
Teresa Maria Santos Amaral,Daniela Macedo,Isabel Fernandes,Luis Costa
Prostate Cancer , 2012, DOI: 10.1155/2012/327253
Abstract: Patients with castration-resistant prostate cancer (CRPC), who progress after docetaxel therapy, had until very recently, only a few therapeutic options. Recent advances in this field brought about new perspectives in the treatment of this disease. Molecular, basic, and translational research has given us a better understanding on the mechanisms of CRPC. This great investment has turned into a more rational approach to the development of new drugs. Some of the new treatments are already available to our patients outside clinical trials and may include inhibitors of androgen biosynthesis; new chemotherapy agents; bone-targeted therapy; and immunotherapy. This paper aims to review the mechanisms of prostate cancer resistance, possible therapeutic targets, as well as new options to treat CRPC. 1. Introduction Prostate cancer is the most common malignancy in males in Western countries, representing the second leading cause of cancer death [1]. Advances in screening and diagnosis have allowed detection of the disease in early stages (approximately 85% of cases diagnosed), stages at which the therapeutic options are curative and include surgery, radiation and, in some cases, active surveillance only [2–4]. However, for late-stage disseminated disease, current therapies are merely palliative. In 1941, a study of Huggins and Hodges showed the close relationship of androgens with prostate tumor growth and androgen-deprivation therapy (castration) became the key treatment for these stages in monotherapy or in combination with other methods [2, 4, 5]. Initial responses to castration therapy are quite favorable, with a significant clinical regression and rapid biochemical responses, as assessed by decline in levels of serum marker, prostate-specific antigen (PSA) in 80–90% of patients with metastatic disease [2, 4, 6]. Despite a good initial response, remissions last on average 2-3 years, with eventual progression occurring despite castration [4, 5, 7]. In these cases prostate cancer will progress to a castration-insensitive phase of disease (Castration-Resistant Prostate Cancer—CRPC) which carries a worse prognosis and translates into a survival time of 16–18 months in average from the beginning of progression [2, 4–6]. Systemic therapies have also been an option in the management to these patients. However, chemotherapy is not well tolerated by all CRPC patients, who were often elderly men with limited bone marrow reserve and concurrent medical conditions [8]. In 2004 the result of two major phase 3 clinical trials established docetaxel as the first-line
Castration-resistant prostate cancer: potential targets and therapies
Parray A, Siddique HR, Nanda S, Konety BR, Saleem M
Biologics: Targets and Therapy , 2012, DOI: http://dx.doi.org/10.2147/BTT.S23954
Abstract: stration-resistant prostate cancer: potential targets and therapies Review (2207) Total Article Views Authors: Parray A, Siddique HR, Nanda S, Konety BR, Saleem M Published Date August 2012 Volume 2012:6 Pages 267 - 276 DOI: http://dx.doi.org/10.2147/BTT.S23954 Received: 28 June 2012 Accepted: 13 July 2012 Published: 17 August 2012 Aijaz Parray,1 Hifzur R Siddique,1 Sanjeev Nanda,1,2 Badrinath R Konety,3 Mohammad Saleem1,3,4 1Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, Austin, 2Department of Internal Medicine, Mayo Clinic Health Systems, Austin, 3Department of Urology, University of Minnesota, Minneapolis, 4Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA Abstract: The treatment landscape for patients with castration-resistant prostate cancer (CRPC) is undergoing significant changes with the advent of new therapies and multidisciplinary efforts by scientists and clinicians. As activation of multiple molecular pathways in the neoplastic prostate makes it impossible for single-target drugs to be completely effective in treating CRPC, this has led to combination therapy strategy, where several molecules involved in tumor growth and disease progression are targeted by a therapeutic regimen. In the present review, we provide an update on the molecular pathways that play an important role in the pathogenesis of CRPC and discuss the current wave of new treatments to combat this lethal disease.
Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer
Rehman Y, Rosenberg JE
Drug Design, Development and Therapy , 2012, DOI: http://dx.doi.org/10.2147/DDDT.S15850
Abstract: biraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer Review (5304) Total Article Views Authors: Rehman Y, Rosenberg JE Published Date January 2012 Volume 2012:6 Pages 13 - 18 DOI: http://dx.doi.org/10.2147/DDDT.S15850 Received: 30 September 2011 Accepted: 14 December 2011 Published: 16 January 2012 Yasser Rehman1, Jonathan E Rosenberg2 1Division of Hospital Medicine, UMass Memorial Healthcare, Worcester, MA, USA; 2Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Abstract: Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC), which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17). This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.
Role of Signaling Transduction Pathways in Development of Castration-Resistant Prostate Cancer  [PDF]
Takahiro Inoue,Osamu Ogawa
Prostate Cancer , 2011, DOI: 10.1155/2011/647987
Abstract: Almost all patients who succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard treatment for this disease and is associated with modest prolongation of survival, there is an urgent need for novel treatments for castration-resistant prostate cancer (CRPC). Great advances in our understanding of the biological and molecular mechanisms of prostate cancer progression have resulted in many clinical trials of numerous targeted therapies. In this paper, we review mechanisms of CRPC development, with particular focus on recent advances in the understanding of specific intracellular signaling pathways participating in the proliferation of CRPC cells. 1. Introduction Prostate cancer is the most common malignancy and the second leading cause of cancer death in the United States [1]. The American Cancer Society has estimated that 217,730 new cases will be diagnosed and 32,050 deaths will occur in the United States in 2010. However, in Japan, the incidence of prostate cancer was still lower than that of gastric and lung cancer in 2005 but has been markedly increasing, and it is predicted that the incidence will be second to lung cancer by 2020 [2]. In the early 1940s, Huggins demonstrated that the growth and survival of prostate cancer are dependent upon androgens [3]. Most patients with advanced prostate cancer initially respond to androgen ablation therapy. However, after an initial period of response to this therapy most of these patients finally relapse and develop castration-resistant prostate cancer (CRPC). CRPC cells mostly continue to express androgen-regulated genes, such as PSA, despite greatly reduced levels of androgens. In particular, androgen receptor (AR) expression is required for survival, and the AR signal axis is still activated in this state. Several possible mechanisms have been proposed, including: (a) the development of hypersensitive response due to increased AR levels or de novo production of endogenous androgens within the prostate; (b) promiscuous activation of AR due to mutation in ligand binding domain of AR; (c) altered transcriptional activity of AR due to changes in expression of coactivators and/or corepressors; (d) ligand-independent activation of AR through growth signaling activation [4, 5]. Alternatively, other models suggest that preexisting androgen-independent cancer cells infrequently occur within tumors and undergo clonal selection during androgen deprivation therapy, resulting in CRPC [4]. 2. PTEN-PI3K Signaling Pathway In 1997, the tumor suppressor gene PTEN was
Update on options for treatment of metastatic castration-resistant prostate cancer
Prakash Vishnu, Winston W Tan
OncoTargets and Therapy , 2010, DOI: http://dx.doi.org/10.2147/OTT.S5818
Abstract: ate on options for treatment of metastatic castration-resistant prostate cancer Review (5795) Total Article Views Authors: Prakash Vishnu, Winston W Tan Published Date March 2010 Volume 2010:3 Pages 39 - 51 DOI: http://dx.doi.org/10.2147/OTT.S5818 Prakash Vishnu, Winston W Tan Division of Hematology Oncology, Mayo Clinic, Jacksonville, FL, USA Background: Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA) testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC), the median survival is about 1–2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC. Recent findings: Since the two landmark trials (TAX-327 and Southwest Oncology Group 99–16) in CRPC, several newer cytotoxic drugs (epothilones, satraplatin), targeted agents (abiraterone, MDV3100) and vaccines have been tested in phase II and III setting with promising results. Conclusions: The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, ‘circulating tumor cells’, have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.
Update on options for treatment of metastatic castration-resistant prostate cancer  [cached]
Prakash Vishnu,Winston W Tan
OncoTargets and Therapy , 2010,
Abstract: Prakash Vishnu, Winston W TanDivision of Hematology Oncology, Mayo Clinic, Jacksonville, FL, USABackground: Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA) testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC), the median survival is about 1–2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC.Recent findings: Since the two landmark trials (TAX-327 and Southwest Oncology Group 99–16) in CRPC, several newer cytotoxic drugs (epothilones, satraplatin), targeted agents (abiraterone, MDV3100) and vaccines have been tested in phase II and III setting with promising results.Conclusions: The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, ‘circulating tumor cells’, have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.Keywords: castration-resistant prostate cancer, novel therapies, mechanisms of resistance, circulating tumor cells
Clinical Efficacy of TroVax in the Treatment of Progressive Castration-resistant Prostate Cancer
Robert J. Amato and Mika Stepankiw
Clinical Medicine Insights: Oncology , 2012, DOI: 10.4137/CMO.S7654
Abstract: With approximately 240,890 new cases expected in 2011, prostate cancer remains the leading cause of non-melanoma cancer deaths in men. Immunotherapies using viral vector-based delivery systems targeting tumor-specific antigens are being studied. Viral vector-based delivery systems present tumor-targeted antigens (TAAs) to the immune system while breaking self-tolerance. Modified vaccinia ankara has been combined with the oncofetal antigen 5T4 to create TroVax for the treatment of castration-resistant prostate cancer (CRPC). The 5T4 antigen is highly expressed in a large number of carcinomas, including prostate cancer, but is rarely expressed in healthy tissue. TroVax has been demonstrated to be safe and highly immunogenic, both as monotherapy and in combination with other standard of care therapies in colorectal, renal cell, and prostate cancer. With minimal side effects and the ability to produce a strong immunogenic response, TroVax (MVA-5T4) is a viable addition to the treatment of prostate cancer.
An update on TroVax for the treatment of progressive castration-resistant prostate cancer
Abern M, Kaufman HL, Latchamsetty K
OncoTargets and Therapy , 2011, DOI: http://dx.doi.org/10.2147/OTT.S14271
Abstract: n update on TroVax for the treatment of progressive castration-resistant prostate cancer Review (3098) Total Article Views Authors: Abern M, Kaufman HL, Latchamsetty K Published Date May 2011 Volume 2011:4 Pages 33 - 41 DOI: http://dx.doi.org/10.2147/OTT.S14271 Michael Abern1, Howard L Kaufman2, Kalyan Latchamsetty1 1Department of Urology, Rush University Medical Center, Chicago, IL, USA; 2Department of General Surgery and Immunology and Microbiology, Rush University Medical Center, Chicago, IL, USA Abstract: Prostate cancer is a common human malignancy with few effective therapeutic options for treating advanced castration-resistant disease. The potential therapeutic effectiveness of immunotherapy and vaccines, in particular, has gained popularity based on the identification of prostate-associated antigens, potent expression vectors for vaccination, and data from recent clinical trials. A modified vaccinia Ankara (MVA) virus expressing 5T4, a tumor-associated glycoprotein, has shown promise in preclinical studies and clinical trials in patients with colorectal and renal cell carcinoma. This review will discuss the rationale for immunotherapy in prostate cancer and describe preclinical and limited clinical data in prostate cancer for the MVA-5T4 (TroVax ) vaccine.
Castration-resistant prostate cancer: potential targets and therapies  [cached]
Parray A,Siddique HR,Nanda S,Konety BR
Biologics: Targets and Therapy , 2012,
Abstract: Aijaz Parray,1 Hifzur R Siddique,1 Sanjeev Nanda,1,2 Badrinath R Konety,3 Mohammad Saleem1,3,41Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, Austin, 2Department of Internal Medicine, Mayo Clinic Health Systems, Austin, TX, 3Department of Urology, University of Minnesota, Minneapolis, 4Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USAAbstract: The treatment landscape for patients with castration-resistant prostate cancer (CRPC) is undergoing significant changes with the advent of new therapies and multidisciplinary efforts by scientists and clinicians. As activation of multiple molecular pathways in the neoplastic prostate makes it impossible for single-target drugs to be completely effective in treating CRPC, this has led to combination therapy strategy, where several molecules involved in tumor growth and disease progression are targeted by a therapeutic regimen. In the present review, we provide an update on the molecular pathways that play an important role in the pathogenesis of CRPC and discuss the current wave of new treatments to combat this lethal disease.Keywords: chemoresistance, CRPC, molecular pathways, neoplastic prostate
Inhibition of Glycogen Synthase Kinase-3β Counteracts Ligand-Independent Activity of the Androgen Receptor in Castration Resistant Prostate Cancer  [PDF]
Stefanie V. Schütz,Andres J. Schrader,Friedemann Zengerling,Felicitas Genze,Marcus V. Cronauer,Mark Schrader
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0025341
Abstract: In order to generate genomic signals, the androgen receptor (AR) has to be transported into the nucleus upon androgenic stimuli. However, there is evidence from in vitro experiments that in castration-resistant prostate cancer (CRPC) cells the AR is able to translocate into the nucleus in a ligand-independent manner. The recent finding that inhibition of the glycogen-synthase-kinase 3β (GSK-3β) induces a rapid nuclear export of the AR in androgen-stimulated prostate cancer cells prompted us to analyze the effects of a GSK-3β inhibition in the castration-resistant LNCaP sublines C4-2 and LNCaP-SSR. Both cell lines exhibit high levels of nuclear AR in the absence of androgenic stimuli. Exposure of these cells to the maleimide SB216763, a potent GSK-3β inhibitor, resulted in a rapid nuclear export of the AR even under androgen-deprived conditions. Moreover, the ability of C4-2 and LNCaP-SSR cells to grow in the absence of androgens was diminished after pharmacological inhibition of GSK-3β in vitro. The ability of SB216763 to modulate AR signalling and function in CRPC in vivo was additionally demonstrated in a modified chick chorioallantoic membrane xenograft assay after systemic delivery of SB216763. Our data suggest that inhibition of GSK-3β helps target the AR for export from the nucleus thereby diminishing the effects of mislocated AR in CRPC cells. Therefore, inhibition of GSK-3β could be an interesting new strategy for the treatment of CRPC.
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