Chemoprevention of prostate cancer. Focus on key opportunities and clinical trials

By 2004-2005, the final results of the Prostate Cancer Prevention Trial should be available. Within several years thereafter, results of the SELECT should be available. The growing list of potential agents for prostate cancer prevention continues to grow and includes COX-2 inhibitors, vitamin D, dietary interventions (soy, isoflavenoids, low-fat diet), and many others. As prospective trials are completed and molecular genetic correlations are developed, it is almost certain that specific recommendations, tailored to the individual patient, will be developed. Ultimately, through these efforts, it can be anticipated that the primary focus for control of prostate cancer will shift from early detection and treatment to prevention.     

Elevated levels of the mismatch repair protein PMS2 are associated with prostate cancer

BACKGROUND: Defects in mismatch repair (MMR) proteins have been identified in various types of cancer. However, an association with prostate cancer has been controversial. Defective MMR results in genome instability with detrimental consequences that significantly contribute to tumorigenesis. This study determined alterations in key MMR protein levels in prostate cancer with the goal to identify prognostic markers. METHODS: Prostatectomy samples were immunohistochemically stained and the relative presence or absence of key proteins MSH2, MLH1, and PMS2 determined. Cancer tissue of distinct grades was compared with the normal surrounding tissue. Microsatellite instability (MSI) in altered tissues was determined according to NCI guidelines. RESULTS: In contrast to reports that associate a lack of individual MMR proteins with tumorigenesis, a significant increase in PMS2 levels was identified in PIN lesions and prostate cancer tissue. This elevation in PMS2 was independent of changes in levels in its heterodimeric partner, MLH1. Prostate tumors with elevated levels of PMS2 were genetically unstable, which was corrected by MLH1 co-elevation. CONCLUSIONS: This is the first documentation of detrimental consequences associated with the increase in a MMR protein in human cancer. This study recognizes PMS2 elevation as a prognostic marker in pre-neoplastic and prostate cancer lesions. This result has significant implications for future diagnostic and treatment measures.     

SELECT: the next prostate cancer prevention trial. Selenum and Vitamin E Cancer Prevention Trial

PURPOSE: Growing evidence implies that selenium and vitamin E may decrease the risk of prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a randomized prospective double-blind study designed to determine whether selenium and vitamin E decrease the risk of prostate cancer in healthy men. MATERIALS AND METHODS: The preclinical and epidemiological evidence regarding chemoprevention with selenium and vitamin E were reviewed. Secondary analyses from randomized trials of the 2 agents were included in the current analysis. Data from these analyses as well as evidence from the Prostate Cancer Prevention Trial were used to develop the SELECT schema. RESULTS: Preclinical, epidemiological and phase III data imply that selenium and vitamin E have potential efficacy for prostate cancer prevention. The experience of the Prostate Cancer Prevention Trial shows the interest and dedication of healthy men to long-term studies of cancer prevention. A total of 32,400 men are planned to be randomized in SELECT. CONCLUSIONS: SELECT is the second large-scale study of chemoprevention for prostate cancer. Enrollment in the study is planned to begin in 2001 with final results anticipated in 2013.     

An update on chemoprevention strategies in prostate cancer for 2006

PURPOSE OF REVIEW: An increasing volume of research has been directed at the prevention of prostate cancer. This review proposes to summarize the large trials, novel approaches and molecular mechanisms of effect published in 2004 and 2005. RECENT FINDINGS: The impact of the Prostate Cancer Prevention Trial continues and subsequent articles have addressed the increase of high-grade prostate cancers detected in the finasteride arm of the trial, as well as the potential costs and benefits of extrapolating the findings to a public health campaign. Studies of risk have been published warning of excessive vitamin E and cyclooxygenase-2 inhibitor use in chemoprevention. Growing evidence supports the concept of chemopreventative agent combinations and further data on the roles of selenium, lycopene, soy, green tea, anti-inflammatories and statins in prostate-cancer prevention are presented. SUMMARY: Level one evidence exists for the preventative effects of finasteride in prostate cancer. The evidence for other agents is less conclusive but a number of large-scale, appropriately designed trials will hopefully address some of the relevant issues in prostate-cancer prevention over the next decade.     

SELECT: the selenium and vitamin E cancer prevention trial

PURPOSE: Growing evidence suggests that both selenium and vitamin E may reduce the risk of prostate cancer. SELECT is a randomized, prospective, double-blind study designed to determine if selenium and vitamin E can reduce the risk of prostate cancer among healthy men. MATERIALS AND METHODS: The preclinical and epidemiologic evidence regarding chemoprevention with selenium and vitamin E were reviewed. Secondary analyses from randomized trials of both agents were included in the analysis. Data from these analyses as well as evidence from the Prostate Cancer Prevention Trial were used to develop the schema of SELECT. RESULTS: Preclinical, epidemiologic, and Phase III data suggest that both selenium and vitamin E have potential efficacy in prostate cancer prevention. The experience of the Prostate Cancer Prevention Trial and the rapid accrual of SELECT during its first year demonstrate the interest and dedication of healthy men to long-term studies of cancer prevention. A total of 32,400 men are planned to be randomized in SELECT. CONCLUSIONS: SELECT is the second large-scale study of chemoprevention for prostate cancer. Enrollment began in 2001 with final results anticipated in 2013.     

In vitro human cell culture models for the study of prostate cancer

Prostate cancer is the most commonly diagnosed malignancy in the American men and the second leading cause of male cancer death in the United States. Despite its high incidence, the molecular and genetic events involved in prostate cancer progression remain poorly understood. A hurdle in understanding the molecular genetic changes in prostate cancer has been the difficulty in establishing premalignant lesions and primary prostate tumors as in vitro cell cultures. Primary epithelial cells grow for a finite life span and then senesce. Immortalization is defined by continuous growth of otherwise senescing cells and is believed to represent an early stage in tumor progression. In order to examine these early stages, we and others have developed in vitro models of prostate epithelial cell immortalization. Because prostate cancer is a multistep, progressive disease with a typical onset later in life and with an unusually high number of latent cases that do not develop into clinically manifest cancer, the steps in the progression to malignancy are of particular interest. To understand the many factors that are suspected to contribute to the development of this malignancy, there is a need for an in vitro multistep human prostate epithelial (HPE) culture system. These models have been extremely important in identifying genetic and molecular changes involved in prostate cancer progression. Prostate Cancer and Prostatic Diseases (2000) 3, 229-235     

Prostate Cancer – To screen, or not to screen, is that the question?

There continues to be controversy regarding serum Prostate-Specific Antigen (PSA) and prostate cancer screening. We anxiously await the results of two large prospective randomized clinical trials (Prostate, Lung, Colon, and Ovary-PCLO screening trial in the US and European Randomized Study of Screening for Prostate Cancer-ERSPC in Europe) assessing the benefits of prostate cancer screening. However the true question to answer may be which cancer to treat and when should we treat it.     

Anti-EGF receptor therapy

The epidermal growth factor receptor (EGFR) signalling pathway contributes to a number of processes important to tumour progression, including cell proliferation, apoptosis, angiogenesis and metastatic spread. EGFR signalling is thought to be an important cell survival mechanism in hormone-resistant prostate cancer. ZD1839 ('Iressa') is an orally active, selective EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks signal transduction pathways implicated in promoting cancer growth. In preclinical studies, ZD1839 alone, and in combination with cytotoxic agents, produced reversible growth inhibition and growth delay in a wide range of tumour cell lines and human tumour xenografts. Preliminary results from phase I trials in patients with advanced disease suggest that ZD1839 has an acceptable tolerability profile and promising clinical efficacy in patients with a variety of tumour types, including hormone-resistant prostate cancer, where new treatment strategies are needed. Prostate Cancer and Prostatic Diseases (2000) 3, 296-302     

What’s new in the field of prostate cancer chemoprevention?

Chemoprevention trials for several malignancies are completed, planned, or underway. Prostate cancer is one of the most common forms of cancer and understandably has received considerable recent attention as a potential target for chemoprevention. This article examines chemoprevention trials for prostate cancer, including the Prostate Cancer Prevention Trial, Selenium and Vitamin E Cancer Prevention Trial, and cyclooxygenase inhibitors in the prevention of prostate cancer.     

Chemoprevention using dutasteride: the REDUCE trial

PURPOSE OF REVIEW: This article will review the design and rationale of the dutasteride prostate cancer chemoprevention trial known as the REDUCE trial (Reduction by Dutasteride of Prostate Cancer Events) in the context of the recently completed Prostate Cancer Prevention Trial. RECENT FINDINGS: The Prostate Cancer Prevention Trial used the 5alpha-reductase inhibitor finasteride to prevent prostate cancer in a prospective randomized trial. The trial demonstrated a nearly 25% reduction in the prevalence of prostate cancer compared with placebo. Finasteride is a type 2-specific 5alpha-reductase inhibitor, whereas dutasteride is an inhibitor of both type 1 and type 2 5alpha-reductase. Recent evidence suggests that there may be increased expression of the type 1 5alpha-reductase in prostate cancer versus benign prostate tissue making dutasteride an attractive agent to study. SUMMARY: Proof of principle has been demonstrated by the Prostate Cancer Prevention Trial that a chemoprevention strategy using a hormonal agent such as a 5alpha-reductase inhibitor can be effective. The REDUCE trial will use the dual 5alpha-reductase inhibitor dutasteride in a group of men identified at increased risk of developing prostate cancer to determine if this will be an effective chemoprevention strategy.     

Intermittent androgen blockade in prostate cancer: rationale and clinical experience

Cancer of the prostate continues to be one of the most common malignancies in men in Europe, with a large number of patients presenting with advanced disease. The current standard treatment for metastatic cancer of the prostate, permanent androgen withdrawal, is palliative. Patients treated with permanent androgen blockade usually relapse and die secondary to prostate cancer's ability to progress to an androgen-independent state of growth. Based on experimental and preclinical studies, intermittent androgen blockade appears to be a potential alternative to permanent androgen blockade. Through the cycling of reversible androgen suppression, there appears to be recovery of apoptosis and subsequent slower progression to an androgen-independent state. In this paper experimental and preclinical studies concerning intermittent androgen blockade are reviewed. At present several prospective randomized trials are under way to test intermittent androgen blockade as an alternative treatment in various stages of cancer of the prostate. However, until the results of these trials are available, this approach remains experimental.     

Androgens and growth factors in prostate cancer: a transgenic perspective

With the advent of transgenic technology, novel animal models are being developed to facilitate prostate cancer research. The ability to perform genetic perturbation studies in a temporally and spatially restricted manner has established a new paradigm for investigations of the molecular mechanisms involved in the initiation, progression and metastogenesis of prostate cancer. Using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model we have begun to identify specific molecular events related to the emergence of the androgen-insensitive phenotype. In addition, a number of new models have recently been generated to characterize how the deregulation of stromal to epithelial interactions mediated by polypeptide growth factor signaling could facilitate transformation of the prostate. It is anticipated that these models and their successors will ultimately provide new molecular pathway-based strategies for the prevention, detection and treatment of prostate cancer. Prostate Cancer and Prostatic Diseases (2000) 3, 224-228     

Bipolar androgen therapy: The rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer

Androgen ablation is highly effective palliative therapy for metastatic prostate cancer but eventually all men relapse. New findings demonstrating that androgen receptor (AR) expression continues in androgen ablated patients has resulted in the classification “Castration Resistant Prostate Cancer” (CRPC) and has led to the development of new second‐line “anti‐ligand” hormonal agents. In this background is the paradoxical observation that the growth of some AR‐expressing “androgen sensitive” human prostate cancer cells can be inhibited by supraphysiologic levels of androgens. This response may be due to effects of high‐dose androgen on inhibiting re‐licensing of DNA in cells expressing high levels of AR. It may also be due to recently described effects of androgen in inducing double strand DNA breaks. Based on available preclinical data described in this review demonstrating the effects of supraphysiologic levels of testosterone on inhibition of growth of CRPC xenografts, we initiated a clinical trial in men with CRPC testing the effect of monthly treatments with an intramuscular (IM) depot injection of testosterone. This IM formulation achieves supraphysiologic levels of testosterone that cannot be achieved with standard testosterone gel‐based applications. The supraphysiologic testosterone level is followed by a rapid drop to castrate levels of testosterone with each cycle of therapy. This “bipolar androgen therapy” will not allow time for prostate cancer cells to adapt their AR expression in response to environmental conditions. The goal is to determine if a clinical response can be achieved through this non‐adaptive rapid cycling approach in men with CRPC. Prostate 70: 1600–1607, 2010. © 2010 Wiley‐Liss, Inc.     

Prostate cancer chemoprevention agents exhibit selective activity against early stage prostate cancer cells

Preclinical models for the identification of prostate cancer chemoprevention agents are lacking. Based upon the notion that clinically useful chemoprevention agents should exhibit selective activity against early stage disease, studies were undertaken to assess whether chemoprevention agents selectively inhibited the growth of early stage prostate cancer, as compared to late stage cancer. First, a series of cell and molecular studies were performed, which, when taken together, validated the use of a panel of prostate cell lines as a model of the different stages of carcinogenesis. Next, therapeutic responsiveness to ten different cytotoxic or chemoprevention agents was evaluated. Chemoprevention agents exhibited selective activity against normal and early transformed prostate tissue, whereas cytotoxic agents were non-specific. Selective activity against early versus advanced prostate cancer cells is identified as a potential screening method for chemoprevention agents.Prostate Cancer and Prostatic Diseases (2001) 4, 81-91     

Evolving strategies for prostate cancer chemoprevention trials

Prostate cancer chemoprevention (CP) can be defined as the use of natural and synthetic agents that inhibit, reverse or regress precancer and delay progression to invasive cancer. During the past two decades several CP strategies have evolved. The first generation of CP trials tested the efficacy of antioxidants and vitamins including B-carotene, vitamin A, retinol, 13 cis retinoic acid, vitamins E, C and selenium. Although these trials were disappointing, provocative hypotheses were generated for selenium and vitamin E that set the stage for future prostate trials. In the 1990s, the NCI launched a second generation of large CP trials aimed at breast and prostate cancer. One of these trials is the PCPT, testing the efficacy of a 5 alpha-reductase inhibitor-finasteride to prevent prostate cancer in 18,000 men. Although PCPT is still in progress, the NCI recently launched a second large primary prostate CP trial called SELECT, testing the efficacy of selenium and vitamin E in 32,400 men. The Prostate Cancer Progress Report to the Director of NCI in 1998 challenged the research community to design more efficient CP trials for prostate cancer. In response, the NCI has evolved a third generation of CP trials. This involves pharmacologically driven translational science research including agents and their targets, biomarker endpoints, suitable clinical models for testing agents and efficient trial designs employing high risk cohorts and surrogate endpoints. In summary, a dual strategy for CP is being developed which includes public health measures and a medical intervention approach.     

The immunotherapy of prostate cancer

Advanced prostate cancer remains incurable with standard treatment options. Immunotherapy may be a realistic alternative given the growing evidence that the immune response can affect the growth of other solid tumours and the regulation of both specific and shared prostate cancer antigens. Early studies suggest that both non-specific and specific vaccines can effect relevant animal models and clinical trials based on these observations are now in progress. A number of other approaches including gene therapy with HSVtk are already undergoing clinical studies (Herman et al. Hum Gene Ther 1999; 10: 1239-1249). Prostate Cancer and Prostatic Diseases (2000) 3, 303-307     

Etablierung von interdisziplin?ren Prostatakrebszentren nach den Empfehlungen der DKG

The introduction of prostate cancer treatment centers according to the criteria of the German Cancer Society ("Deutsche Krebsgesellschaft", DKG) aims at improving the quality of care for patients with prostate cancer. Systematic analyses of the effects and costs are lacking as yet. Three years after certification of the Interdisciplinary Prostate Cancer Center at the Charité Hospital Berlin we observed a decrease in the rate of positive surgical margins (tumor stage pT2), but other parameters of treatment quality including patient satisfaction remained unchanged. A survey among urologists of the region showed a high acceptance of prostate cancer centers in general. The majority of participating urologists appreciated the work of the Charité center, in particular the treatment recommendations given by the center were mostly followed and the majority of urologists regularly use educational activities of the center. However, only 30% of the participating urologists confirmed short-term improvements in the quality of patient care. Yearly additional costs for the Charité prostate cancer center are estimated at 205,000 euro (precertification phase and certification) and 138,000 euro (monitoring phase), despite the initial drop in mean treatment costs per case (radical prostatectomy). The introduction of prostate cancer treatment centers certified by the DKG is cost intensive, increases in treatment efficiency notwithstanding. Short-term improvements in quality of care cannot be unequivocally demonstrated. Prostate cancer centers serve an important role in counseling and medical education and may thus help disseminate evidence-based treatment strategies.     

A Nod Scid mouse model to study human prostate cancer

Prostate cancer is the second cause of cancer mortality in men in Western countries. To study new therapeutic approaches such as gene therapy, animal models of human prostate cancer with metastatic behavior are mandatory. We used the Nod Scid mouse strain to develop an orthotopic animal model. Two androgen-independent cell lines (PC-3 and DU 145) were used. Local tumor growth and metastases were analyzed. The tumor take rates were close to those reported in the literature. However, a high frequency of various metastatic sites has been observed (liver, lung, spleen, adrenal, kidney, lymph node, and diaphragm). It can be concluded that the Nod Scid mouse is a relevant preclinical animal model to study human prostate cancer. Metastatic sites seem more numerous in comparison to other orthotopic mice models described.     

从大样本临床研究看PSA筛查检出前列腺癌的意义

前列腺癌是全球性的公共健康挑战。前列腺特异性抗原(PSA)作为基础筛查显著提高了前列腺癌诊断率,但潜在的副作用不容忽视。前列腺癌筛查能否降低死亡率仍有争议,数个大样本临床研究的结论莫衷一是。欧洲前列腺癌筛查随机研究以及瑞典哥德堡研究显示筛查降低死亡率,而美国前列腺、肺、结直肠和卵巢癌筛查研究的结论相反。对前列腺癌筛查的担忧主要包括筛查本身的并发症以及对惰性前列腺癌的过度诊断和治疗。目前总体证据支持进行前列腺癌筛查,但需要采取措施积极改进筛查的策略。     

Prostate cancer: a serious disease suitable for prevention

Prostate cancer is among the most common causes of death from cancer in men, and accounts for 10% of all new male cancers worldwide. The diagnosis and treatment of prostate cancer place a substantial physical and emotional burden on patients and their families, and have considerable financial implications for healthcare providers and society. Given that the risk of prostate cancer continues to increase with age, the burden of the disease is likely to increase in line with population life‐expectancy. Reducing the risk of prostate cancer has gained increasing coverage in recent years, with proof of principle shown in the Prostate Cancer Prevention Trial with the type 2 5α‐reductase (5AR) inhibitor, finasteride. The long latency period, high disease prevalence, and significant associated morbidity and mortality make prostate cancer a suitable target for a risk‐reduction approach. Several agents are under investigation for reducing the risk of prostate cancer, including selenium/vitamin E and selective oestrogen receptors modulators (e.g. toremifene). In addition, the Reduction by Dutasteride of Prostate Cancer Events trial, involving >8000 men, is evaluating the effect of the dual 5AR inhibitor, dutasteride, on the risk of developing prostate cancer. A successful risk‐reduction strategy might decrease the incidence of the disease, as well as the anxiety, cost and morbidity associated with its diagnosis and treatment.