The treatment of hormone-refractory prostate cancer: docetaxel and beyond

Two randomized clinical trials demonstrated a survival benefit of 20% to 24% with docetaxel-based therapy when compared with survival with mitoxantrone and prednisone after failure of androgen ablation therapy. These studies supported the approval of docetaxel-based therapy for the treatment of metastatic hormone-refractory prostate cancer by the US Food and Drug Administration in May 2005. Clinical trials in hormone-refractory prostate cancer are now focused on building on the survival improvement seen with docetaxel-based therapy. This article presents a summary of some of the more promising treatments and regimens for advanced prostate cancer.     

Prostate cancer: epidemiology, screening, and biomarkers

Carcinoma of the prostate continues to be a major health problem in the United States. Beginning in 1988, a marked increase in detection of prostate cancer occurred due to the development of a test for prostate-specific antigen (PSA). Controversy exists, however, about the value of PSA as a tumor marker. Although it has prognostic significance both before and after definitive therapy for prostate cancer, it is unclear whether routine PSA screening will translate into a survival advantage for patients. Because of its limitations, PSA may not ultimately be a good enough marker to be used as a screening tool. However, molecular biology has led to a rapid rise in the number of potential new prostate tumor markers, which may eventually overcome the weaknesses of PSA. Considerable progress has occurred in the diagnosis and management of prostate cancer: more is understood about the risk factors for the disease, possible ways to prevent it, and new ways to diagnose and monitor it. These developments have already translated into better patient care, while also identifying where further improvements are needed.     

Radiation therapy after radical prostatectomy: strike early, strike hard! The case for adjuvant radiation therapy

With a large local tumor, when surgical extirpation results in a positive surgical margin, adjuvant radiotherapy is the routine approach for a variety of solid tumors, such as head and neck cancers, rectal cancer, lung cancer, and breast cancer. With prostate cancer, however, surgery and radiotherapy are considered as alternative single-modality treatments, and their combination is far less enthusiastically embraced. Despite a trend toward earlier clinical diagnosis of prostate cancer since the introduction of prostate-specific antigen (PSA) screening, modern surgical series continue to show a 15%-25% incidence of positive surgical margins. Postoperative radiotherapy, whether delivered as "adjuvant therapy" shortly after surgery or as "salvage therapy" when serum PSA becomes detectable, effectively improves local control and prolongs disease-free survival.     

RNA interference-directed knockdown of urokinase plasminogen activator and urokinase plasminogen activator receptor inhibits prostate cancer cell invasion, survival, and tumorigenicity in vivo

The invasive ability of tumor cells plays a key role in prostate cancer metastasis and is a major cause of treatment failure. Urokinase plasminogen activator-(uPA) and its receptor (uPAR)-mediated signaling have been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study was undertaken to investigate the biological roles of uPA and uPAR in prostate cancer cell invasion and survival, and the potential of uPA and uPAR as targets for prostate cancer therapy. uPA and uPAR expression correlates with the metastatic potential of prostate cancer cells. Thus, therapies designed to inhibit uPA and uPAR expression would be beneficial. LNCaP, DU145, and PC3 are prostate cancer cell lines with low, moderate, and high metastatic potential, respectively, as demonstrated by their capacity to invade the extracellular matrix. In this study we utilized small hairpin RNAs (shRNAs), also referred to as small interfering RNAs, to target human uPA and uPAR. These small interfering RNA constructs significantly inhibited uPA and uPAR expression at both the mRNA and protein levels in the highly metastatic prostate cancer cell line PC3. Our data demonstrated that uPA-uPAR knockdown in PC3 cells resulted in a dramatic reduction of tumor cell invasion as indicated by a Matrigel invasion assay. Furthermore, simultaneous silencing of the genes for uPA and uPAR using a single plasmid construct expressing shRNAs for both uPA and uPAR significantly reduced cell viability and ultimately resulted in the induction of apoptotic cell death. RNA interference for uPA and uPAR also abrogated uPA-uPAR signaling to downstream target molecules such as ERK1/2 and Stat 3. In addition, our results demonstrated that intratumoral injection with the plasmid construct expressing shRNAs for uPA and uPAR almost completely inhibited established tumor growth and survival in an orthotopic mouse prostate cancer model. These findings uncovered evidence of a complex signaling network operating downstream of uPA-uPAR that actively advances tumor cell invasion, proliferation, and survival of prostate cancer cells. Thus, RNA interference-directed targeting of uPA and uPAR is a convenient and novel tool for studying the biological role of the uPA-uPAR system and raises the potential of its application for prostate cancer therapy.     

前列腺癌雄激素受体和PI3K/Akt 信号通路相互作用研究进展

前列腺癌的发生、进展依赖于雄激素,因此去势手术成为治疗晚期前列腺癌的标准疗法。但是去势后大多前列腺癌最终将转化为雄激素非依赖性前列腺癌,甚至进展为激素难治性前列腺癌,使得肿瘤的进展不受低水平雄激素的影响。即使如此,大多数激素非依赖性前列腺癌,依然阳性表达雄激素受体。因而雄激素受体在前列腺癌发生发展中起着重要作用。而PI3K/Akt信号通路能够通过维持细胞生存、抑制细胞凋亡、促进细胞代谢及血管生成等促进前列腺癌进展。本综述旨在总结前人研究,阐述雄激素受体和PI3K/Akt信号通路之间相互作用关系。研究表明Akt信号通路能够正性或者负性调控AR蛋白表达、蛋白的稳定性及其转录活性,从而维持细胞的生存、代谢。而AR即可以通过基因转录途径抑制Akt活化又能通过非转录基因途径激活Akt及其下游蛋白。因此,AR和Akt信号通路相互协同促进前列腺癌的发生及其向雄激素非依赖性前列腺癌进展。     

E-1899: An Eastern Cooperative Oncology Group Study Comparing Ketoconazole Plus Hydrocortisone with Docetaxel Plus Estramustine for Asymptomatic, Androgen-Independent, Nonmetastatic Prostate Cancer Patients with Rising PSA Levels

Many prostate cancer patients with rising prostate-specific antigen (PSA) levels following radical prostatectomy or radiotherapy receive "early" hormonal therapy, despite its uncertain benefit. When these patients ultimately progress to androgen independence, their management remains controversial, with many receiving second-line hormonal therapy. Chemotherapy for the treatment of advanced prostate cancer has a defined palliative benefit; studies to establish its potential impact on survival are ongoing. E-1899 is an intergroup phase III trial comparing second-line hormonal therapy with ketoconazole plus hydrocortisone with docetaxel plus estramustine in patients with androgen-independent prostate cancer with rising PSA levels who have no evidence of metastases.     

Endocrine treatment of prostate cancer

Although androgen deprivation as a treatment for patients with prostate cancer was described more than 60 years ago its optimal use remains controversial. The widespread use of prostate-specific (PSA) assay has lead to earlier diagnosis and earlier detection of recurrent disease. This means that the systemic side effects of androgen deprivation and quality of life have become more important. Debates continue regarding the proper use and timing of endocrine therapy with orchiectomy, oestrogen agonists, gonadotropin hormone-releasing hormone (GnRH) agonists, GnRH antagonists, and androgen antagonists. A critical review of the literature was performed. Data support that androgen deprivation is an effective treatment for patients with advanced prostate cancer. However, although it improves survival, it is not curative, and creates a spectrum of unwanted effects that influence quality of life. Castration remains the frontline treatment for metastatic prostate cancer, where orchiectomy, oestrogen agonists and GnRH agonists produce equivalent clinical responses. Maximum androgen blockade (MAB) is not significantly more effective than single agent GnRH agonist or orchiectomy. Nonsteroidal antiandrogen monotherapy is as effective as castration in treatment of locally advanced prostate cancer offering quality of life benefits. Adjuvant endocrine treatment is able to delay disease progression at any stage. There is, however, controversy of the possible survival benefit of such treatment, including patients having PSA relapse after definitive local treatment for prostate cancer. Neoadjuvant endocrine treatment has its place mainly in the external beam radiotherapy setting. Intermittent androgen blockade is still considered experimental. The decision regarding the type of androgen deprivation should be made individually after informing the patient of all available treatment options, including watchful waiting, and on the basis of potential benefits and adverse effects. Several large studies are under way to investigate the role of adjuvant endocrine treatment in the field of early prostate cancer, intermittent androgen deprivation and endocrine therapy alone compared with endocrine therapy with radiotherapy. The real challenge, however, is to develop better means to avert hormone-refractory prostate cancer and better treatments for patients with hormone-refractory disease when it occurs.     

Radiation Therapy after Radical Prostatectomy for Prostate Cancer: Evaluation of Complications and Influence of Radiation Timing on Outcomes in a Large,Population-Based Cohort

PurposeTo evaluate the influence of timing of salvage and adjuvant radiation therapy on outcomes after prostatectomy for prostate cancer.MethodsUsing the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified prostate cancer patients diagnosed during 1995–2007 who had one or more adverse pathological features after prostatectomy. The final cohort of 6,137 eligible patients included men who received prostatectomy alone (n = 4,509) or with adjuvant (n = 894) or salvage (n = 734) radiation therapy. Primary outcomes were genitourinary, gastrointestinal, and erectile dysfunction events and survival after treatment(s).ResultsRadiation therapy after prostatectomy was associated with higher rates of gastrointestinal and genitourinary events, but not erectile dysfunction. In adjusted models, earlier treatment with adjuvant radiation therapy was not associated with increased rates of genitourinary or erectile dysfunction events compared to delayed salvage radiation therapy. Early adjuvant radiation therapy was associated with lower rates of gastrointestinal events that salvage radiation therapy, with hazard ratios of 0.80 (95% CI, 0.67–0.95) for procedure-defined and 0.70 (95% CI, 0.59, 0.83) for diagnosis-defined events. There was no significant difference between ART and non-ART groups (SRT or RP alone) for overall survival (HR = 1.13 95% CI = (0.96, 1.34) p = 0.148).ConclusionsRadiation therapy after prostatectomy is associated with increased rates of gastrointestinal and genitourinary events. However, earlier radiation therapy is not associated with higher rates of gastrointestinal, genitourinary or sexual events. These findings oppose the conventional belief that delaying radiation therapy reduces the risk of radiation-related complications.     

A stochastic model for survival of early prostate cancer with adjustments for leadtime, length bias, and over-detection

To compare the survival between screen-detected and clinically detected cancers, we applied a series of non-homogeneous stochastic processes to deal with leadtime, length bias, and over-detection by using full information on detection modes obtained from the Finnish randomized controlled trial for prostate cancer screening. The results show after 9-year follow-up the hazard ratio of prostate cancer death for screen-detected cases against clinically detected cases increased from 0.24 (95% CI: 0.16-0.35) without correction for these biases, to 0.76 after correction for leadtime and length biases, and finally to 1.03 (95% CI: 0.79-1.33) for a further adjustment for over-detection. Adjustment for leadtime and length bias but no over-detection led to a 24% reduction in prostate cancer death as a result of prostate-specific antigen test. The further calibration of over-detection indicates no gain in survival of screen-detected prostate cancers (excluding over-detected case as stayer considered in the mover-stayer model) as compared with the control group in the absence of screening that is considered as the mover. However, whether the model assumption on over-detection is robust should be validated with other data sets and longer follow-up.     

Clinical experience with gene therapy for the treatment of prostate cancer

Localized prostate cancer can be treated effectively with radical prostatectomy or radiation therapy. The treatment options for metastatic prostate cancer are limited to hormonal therapy; hormone-refractory cancer is treated with taxane-based chemotherapy, which provides only a modest survival benefit. New treatments are needed. The gene for the initiation of prostate cancer has not been identified; however, gene therapy can involve tumor injection of a gene to kill cells, systemic gene delivery to target and kill metastases, or local gene expression intended to generate a systemic response. This review will provide an overview of the various strategies of cancer gene therapy, focusing on those that have gone to clinical trial, detailing clinical experience in prostate cancer patients.     

Progress of molecular targeted therapies for prostate cancers

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.     

Progress of molecular targeted therapies for prostate cancers

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.     

Prostate cancer: Re-focusing on androgen receptor signaling

Prostate cancer is the most common, non-dermatologic cancer in men. Since prostate cancer is highly associated with increased age, the incidence of this disease is expected to increase as the population ages. In its initial stages prostate cancer depends upon the actions of androgen, and androgen deprivation therapy induces tumor regression. Currently, androgen deprivation is achieved by either surgical or chemical androgen blockade. Unfortunately, nearly all prostate cancer patients develop tumors that grow despite androgen blockade and ultimately relapse. Many alterations in prostate cancer cells contribute to this state. Although chemotherapy induces short remissions in some patients, there are no curative therapies for metastatic disease. This review summarizes our current understanding in androgen signaling and the mechanisms that allow tumor cells to bypass androgen manipulation therapy. The identification of novel survival pathways and effector molecules that drive androgen independent growth is necessary to develop effective therapies for advanced prostate cancers.     

Adenoviral gene therapy, radiation, and prostate cancer

Viral gene therapy has exceptional potential as a specifically tailored cancer treatment. However, enthusiasm for cancer gene therapy has varied over the years, partly owing to safety concerns after the death of a young volunteer in a clinical trial for a genetic disease. Since this singular tragedy, results from numerous clinical trials over the past 10 years have restored the excellent safety profile of adenoviral vectors. These vectors have been extensively studied in phase I and II trials as intraprostatically administered agents for patients with locally recurrent and high-risk local prostate cancer. Promising therapeutic responses have been reported in several studies with both oncolytic and suicide gene therapy strategies. The additional benefit of combining gene therapy with radiation therapy has also been realized; replicating adenoviruses inhibit DNA repair pathways, resulting in a synergistic sensitization to radiation. Other, nonreplicating suicide gene therapy strategies are also significantly enhanced with radiation. Combined radiation/gene therapy is currently being studied in phase I and II clinical trials and will likely be the first adenoviral gene therapy mechanism to become available to urologists in the clinic. Systemic gene therapy for metastatic disease is also a major goal of the field, and clinical trials are currently under way for hormone-resistant metastatic prostate cancer. Second- and third-generation "re-targeted" viral vectors, currently being developed in the laboratory, are likely to further improve these systemic trials.     

Protein kinase A type II-α regulatory subunit regulates the response of prostate cancer cells to taxane treatment

In the last decade taxane-based therapy has emerged as a standard of care for hormone-refractory prostate cancer. Nevertheless, a significant fraction of tumors show no appreciable response to the treatment, while the others develop resistance and recur. Despite years of intense research, the mechanisms of taxane resistance in prostate cancer and other malignancies are poorly understood and remain a topic of intense investigation. We have used improved mutagenesis via random insertion of a strong promoter to search for events, which enable survival of prostate cancer cells after Taxol exposure. High-throughput mapping of the integration sites pointed to the PRKAR2A gene, which codes for a type II-α regulatory subunit of protein kinase A, as a candidate modulator of drug response. Both full-length and N-terminally truncated forms of the PRKAR2A gene product markedly increased survival of prostate cancer cells lines treated with Taxol and Taxotere. Suppression of protein kinase A enzymatic activity is the likely mechanism of action of the overexpressed proteins. Accordingly, protein kinase A inhibitor PKI (6–22) amide reduced toxicity of Taxol to prostate cancer cells. Our findings support the role of protein kinase A and its constituent proteins in cell response to chemotherapy.     

前列腺癌雄激素受体和PI3K/Akt信号通路相互作用研究进展

前列腺癌的发生、进展依赖于雄激素,因此去势手术成为治疗晚期前列腺癌的标准疗法。但是去势后大多前列腺癌最终将转化为雄激素非依赖性前列腺癌,甚至进展为激素难治性前列腺癌,使得肿瘤的进展不受低水平雄激素的影响。即使如此,大多数激素非依赖性前列腺癌,依然阳性表达雄激素受体。因而雄激素受体在前列腺癌发生发展中起着重要作用。而PI3K/Akt信号通路能够通过维持细胞生存、抑制细胞凋亡、促进细胞代谢及血管生成等促进前列腺癌进展。本综述旨在总结前人研究,阐述雄激素受体和PI3K/Akt信号通路之间相互作用关系。研究表明Akt信号通路能够正性或者负性调控AR蛋白表达、蛋白的稳定性及其转录活性,从而维持细胞的生存、代谢。而AR即可以通过基因转录途径抑制Akt活化又能通过非转录基因途径激活Akt及其下游蛋白。因此,AR和Akt信号通路相互协同促进前列腺癌的发生及其向雄激素非依赖性前列腺癌进展。     

The impact of cell adhesion changes on proliferation and survival during prostate cancer development and progression

In the normal prostate epithelium, androgen receptor (AR) negative basal epithelial cells adhere to the substratum, while AR expressing secretory cells lose substratum adhesion. In contrast, prostate cancer cells both express AR and adhere to a tumor basement membrane. In this review, we describe the differential expression of integrins, growth factor receptors (GFRs), and AR in normal and cancerous epithelium. In addition, we discuss how signals from integrins, GFRs, and AR are integrated to regulate the proliferation and survival of normal and malignant prostate epithelial cells. While cell adhesion is likely of great importance when considering therapeutic approaches for treatment of metastatic prostate cancer, no data on integrin expression are available from tissues of prostate cancer metastasis. However, several drug targets that are upregulated after androgen ablative therapy regulate cell adhesion and thus novel targeted therapies indirectly interfere with cell adhesion mechanisms in prostate cancer cells.     

Usefulness of prostate-specific antigen nadir as predictor of androgen-independent progression of metastatic prostate cancer

The objective of this study was to analyze the value of the nadir level of prostate-specific antigen (PSA) to predict androgen-independent progression (AIP) in metastatic prostate cancer patients after androgen deprivation therapy. In a group of 185 metastatic prostate cancer patients who received androgen deprivation therapy serum PSA was determined every three months until AIP occurred. Multiple regression analysis was performed to define independent clinical and PSA-related predictors of AIP. AIP was assumed to be present after two consecutive increases in serum PSA after the PSA nadir. Independent predictors of the duration of AIP-free survival (less than 12 months versus more than 12 months) were the extent of bone involvement (six or fewer hot spots versus more than six) with an odds ratio (O.R.) of 3.95, Gleason score (7 or less versus more than 7) with an O.R. of 3.47, and PSA nadir (2 microg/L or less versus more than 2 microg/L) with an O.R. of 14.63. AIP was independently predicted by the extent of bone involvement with an O.R. of 1.72, Gleason score with an O.R. of 1.74, PSA nadir with an O.R. of 3.22, and time to reach the PSA nadir (9 months or less versus more than 9 months) with an O.R. of 2.84. When patients were stratified according to these predictors, those with three good prognostic factors had a median AIP-free survival of 58 months while those with two, one or no good prognostic factors had a median AIP-free survival of 19 months, 12 months and 7 months, respectively. We conclude that the PSA nadir seems to be a good predictor of AIP in patients with metastatic prostate cancer after androgen deprivation therapy. Time to PSA nadir, extent of bone involvement and Gleason score are also independent predictors. The combination of these prognostic factors allows to stratify metastatic prostate cancer patients for the prediction of AIP.     

Hormonal therapy for stage D cancer of the prostate.

Adenocarcinoma of the prostate is the most common malignant neoplasm occurring in men. About half of patients present with metastatic disease. The mainstay of the treatment of stage D cancer of the prostate is hormonal therapy. Bilateral simple orchiectomy remains the gold standard with which other therapies must be compared. Luteinizing hormone-releasing hormone analogues and antiandrogens are now most commonly used but are costly. Initiating hormonal therapy immediately on diagnosing metastatic disease appears to have some advantage over delaying therapy until a patient is symptomatic. Total androgen blockade also appears to be beneficial in terms of survival but at high cost.