Showing papers on "Castration Resistance published in 2010"

Molecular genetics of prostate cancer: new prospects for old challenges

Abstract: Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor that led to the advent of androgen deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Here, we present an overview of major themes in prostate cancer research, focusing on current knowledge of principal events in cancer initiation and progression. We discuss recent advances, including new insights into the mechanisms of castration resistance, identification of stem cells and tumor-initiating cells, and development of mouse models for preclinical evaluation of novel therapuetics. Overall, we highlight the tremendous research progress made in recent years, and underscore the challenges that lie ahead.

Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

Abstract: Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.

Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor

Abstract: Androgen receptor (AR) splice variants lacking the ligand binding domain (ARVs), originally isolated from prostate cancer cell lines derived from a single patient, are detected in normal and malignant human prostate tissue, with the highest levels observed in late stage, castration-resistant prostate cancer. The most studied variant (called AR-V7 or AR3) activates AR reporter genes in the absence of ligand and therefore, could play a role in castration resistance. To explore the range of potential ARVs, we screened additional human and murine prostate cancer models using conventional and next generation sequencing technologies and detected several structurally diverse AR isoforms. Some, like AR-V7/AR3, display gain of function, whereas others have dominant interfering activity. We also find that ARV expression increases acutely in response to androgen withdrawal, is suppressed by testosterone, and in some models, is coupled to full-length AR (AR-FL) mRNA production. As expected, constitutively active, ligand-independent ARVs such as AR-V7/AR3 are sufficient to confer anchorage-independent (in vitro) and castration-resistant (in vivo) growth. Surprisingly, this growth is blocked by ligand binding domain-targeted antiandrogens, such as MDV3100, or by selective siRNA silencing of AR-FL, indicating that the growth-promoting effects of ARVs are mediated through AR-FL. These data indicate that the increase in ARV expression in castrate-resistant prostate cancer is an acute response to castration rather than clonal expansion of castration or antiandrogen-resistant cells expressing gain of function ARVs, and furthermore, they provide a strategy to overcome ARV function in the clinic.

Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance

Abstract: The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology. Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC. Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis. Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro. In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression. N-cadherin-specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion. These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance. Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit.

Role of Cationic Channel TRPV2 in Promoting Prostate Cancer Migration and Progression to Androgen Resistance

Abstract: Castration resistance in prostate cancer (PCa) constitutes an advanced, aggressive disease with poor prognosis, associated with uncontrolled cell proliferation, resistance to apoptosis, and enhanced invasive potential. The molecular mechanisms involved in the transition of PCa to castration resistance are obscure. Here, we report that the nonselective cationic channel transient receptor potential vanilloid 2 (TRPV2) is a distinctive feature of castration-resistant PCa. TRPV2 transcript levels were higher in patients with metastatic cancer (stage M1) compared with primary solid tumors (stages T2a and T2b). Previous studies of the TRPV2 channel indicated that it is primarily involved in cancer cell migration and not in cell growth. Introducing TRPV2 into androgen-dependent LNCaP cells enhanced cell migration along with expression of invasion markers matrix metalloproteinase (MMP) 9 and cathepsin B. Consistent with the likelihood that TRPV2 may affect cancer cell aggressiveness by influencing basal intracellular calcium levels, small interfering RNA-mediated silencing of TRPV2 reduced the growth and invasive properties of PC3 prostate tumors established in nude mice xenografts, and diminished expression of invasive enzymes MMP2, MMP9, and cathepsin B. Our findings establish a role for TRPV2 in PCa progression to the aggressive castration-resistant stage, prompting evaluation of TRPV2 as a potential prognostic marker and therapeutic target in the setting of advanced PCa.

Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression.

Abstract: There are few successful therapies for castration-resistant prostate cancer (CRPC). Recently, CRPC has been thought to result from augmented androgen/androgen receptor (AR) signaling pathway, for most of which AR overexpression has been observed. In this study, Twist1, a member of basic helix-loop-helix transcription factors as well as AR was upregulated in response to hydrogen peroxide, and the response to which was abolished by an addition of N-acetyl-L-cysteine and Twist1 knockdown. In addition, castration-resistant LNCaP derivatives and hydrogen peroxide-resistant LNCaP derivatives exhibited a similar phenotype to each other. Then, both castration and AR knockdown increased intracellular reactive oxygen species level. Moreover, Twist1 was shown to regulate AR expression through binding to E-boxes in AR promoter region. Silencing of Twist1 suppressed cell growth of AR-expressing LNCaP cells as well as castration-resistant LNCaP derivatives by inducing cell-cycle arrest at G1 phase and cellular apoptosis. These findings indicated that castration-induced oxidative stress may promote AR overexpression through Twist1 overexpression, which could result in a gain of castration resistance. Modulation of castration-induced oxidative stress or Twist1/AR signaling might be a useful strategy for developing a novel therapeutics in prostate cancer, even in CRPC, which remains dependent on AR signaling by overexpressing AR.

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

Abstract: 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.

Identification of EP4 as a potential target for the treatment of castration-resistant prostate cancer using a novel xenograft model

Abstract: More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type androgen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues confirmed that EP4 expression was higher in CRPC compared with hormone-naive prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the absence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC.

Overcoming Persistent Dependency on Androgen Signaling after Progression to Castration-Resistant Prostate Cancer

Abstract: Prostate cancer is the most common form of cancer in males in the United States, and the second leading cause of cancer death. Initially, most cases of prostate cancer respond well to hormone therapy; however, resistance often develops rapidly, leading to castration-resistant prostate cancer (CRPC). Several mechanisms for castration resistance have been proposed, of which the most significant seems to be the "intracrine" production of androgens from adrenal androgen or intratumorally via the de novo route. This mechanism stimulates disease progression through reactivation of androgen receptor signaling in patients who have previously undergone castration therapy. 17,20-lyase is essential for androgen synthesis in both the adrenal glands and CRPC tissue, and some 17,20-lyase inhibitors and second-generation anti-androgens that were developed to treat CRPC are currently under clinical investigation, with encouraging preliminary data reported so far. However, resistance to some of these therapies has already been noted. The study of circulating tumor cells will likely be important not only to identify patients likely to receive benefit from this therapeutic approach, but also to further understand the molecular mechanisms of resistance.

Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer.

Abstract: Hormone therapies targeting androgen receptor signaling are the mainstay of treatment for patients with advanced prostate cancer. The length of clinical remission induced by hormone therapies varies substantially among treated patients. Why some patients progress rapidly after treatment while others benefit with prolonged remission is a question that remains unsolved. The androgen receptor signaling pathway is the key molecular determinant of castration resistance, and a key target for prostate cancer drug design. Recent advances in characterizing molecular processes leading to the development of castration-resistant prostate cancer, including the discovery of multiple androgen receptor splicing variants, offer opportunities for rational development of new clinical tools or approaches to predict, monitor or control/prevent prostate cancer progression in the castrate setting.

Intermittent androgen suppression for prostate cancer

Abstract: Although androgen deprivation therapy (ADT) has been a cornerstone of the management of prostate cancer for more than 50 years, controversy remains regarding its optimum application. Intermittent androgen suppression (IAS) has been researched since the mid-1980s as a way of reducing the adverse effects and cost of continuous androgen suppression. With preclinical evidence suggesting a potential benefit in terms of time to androgen independence, IAS has been the focus of a number of clinical phase II and III trials. Overall, these trials suggest that IAS is neither inferior nor superior to continuous androgen suppression, with respect to time to castration resistance and cancer-specific survival, but has significant advantages in terms of adverse effects, quality of life and cost. A number of unresolved questions remain, however, including how to select patients for therapy, the optimum duration of therapy, when to restart therapy after the off cycle, and how to define progression to castration-resistant disease. Landmark randomized clinical trials comparing IAS to continuous androgen suppression are in progress and will hopefully answer many of these questions. In future, the use of second-line drugs in the off-treatment phase holds potential for delaying disease progression in men on IAS. At present, men with advanced disease who are deemed candidates for ADT should be informed of IAS as a treatment option, considered experimental from an informed consent point of view, but promising based on current evidence.

Emerging Therapies in Castrate-Resistant Prostate Cancer

Abstract: Prostate cancer is the most common cancer in men in the United States, and despite screening and early treatment, more than 27,000 men are predicted to die of the disease this year, almost all of whom will die of castrate-resistant, metastatic cancers that have progressed despite androgen deprivation therapy, also known as hormonal therapy. In recent years, an increased understanding of molecular mechanisms of prostate cancer progression and castration resistance has led to improved treatment strategies. This review focuses on emerging therapies for the treatment of castrate-resistant prostate cancer, with an emphasis on the importance of the drug targets as well as the state of current clinical trials, including those utilizing hormonal therapies, biological agents, and immunotherapy that are underway or have recently been completed.

Inhibition of 5alpha-reductase enhances testosterone-induced expression of U19/Eaf2 tumor suppressor during the regrowth of LNCaP xenograft tumor in nude mice.

Abstract: BACKGROUND Intermittent androgen deprivation therapy (IADT) was developed to improve the quality of life and retard prostate cancer progression to castration resistance. IADT involves regrowth of the tumor during the off cycle upon testosterone recovery. Our previous studies showed that testosterone is more potent than dihydrotestosterone (DHT) in the induction of a subset of androgen-responsive genes during rat prostate regrowth. However, it is not clear if the same phenomenon would occur during androgen-induced regrowth of prostate tumors. Understanding the differences between testosterone and DHT in inducing androgen-responsive genes during prostate tumor regrowth may provide new insight for improving IADT. METHODS Nude mice bearing androgen-sensitive LNCaP xenograft were castrated and followed up for 7–10 days before being randomized into various androgen manipulations, consisting of continuous castration (C) or testosterone replacement (T) in the absence or presence of dutasteride (D), a 5α-reductase inhibitor that blocks the conversion of testosterone to DHT. Testes-intact animals in the absence or presence of D were used as controls. The expression of five androgen-responsive genes, including the tumor suppressor U19/Eaf2, was determined using real-time RT-PCR, 3 days after randomization. RESULTS In LNCaP tumors, the expression of U19/Eaf2 was higher in the T+D group as compared with T alone (2.87-fold, P < 0.05). In contrast, dutasteride treatment in testes-intact animals inhibited the expression of U19/Eaf2. CONCLUSIONS Inhibition of 5α-reductase during LNCaP tumor regrowth enhanced the expression of U19/Eaf2, an androgen-regulated tumor suppressor. This finding suggests that off cycle 5α-reductase inhibition may enhance the efficacy of IADT. Prostate 70: 1575–1585, 2010. © 2010 Wiley-Liss, Inc.

Adrenal Androgen Synthesis Inhibitor Therapies in Castration-Resistant Prostate Cancer

Abstract: It is well recognized that the vast majority of prostate cancers rely on testosterone for growth. Even after medical or surgical castration, a significant number of men will unfortunately experience disease progression manifested as an increasing prostate-specific antigen (PSA) or objective tumor growth. Left untreated, castration-resistant prostate cancer (CRPC) is uniformly fatal. It causes close to 30,000 deaths annually in the United States, with most men living only 2–4 years from the time castration resistance develops. In recent years, research has shown that despite castration resistance these tumors still retain sensitivity to low levels of circulating testosterone and other androgens. By inhibiting androgen synthesis, targeted adrenal androgen synthesis inhibitors slow the growth of castration-resistant tumors. The major agents in use today include corticosteroids, ketoconazole, aminoglutethimide, estrogens and progestins, as well as the novel CYP17 inhibitors abiraterone acetate, TAK-700 and TOK-001. The following article reviews the clinical data supporting the use of each of these adrenal androgen synthesis inhibitors in advanced prostate cancer, including the dosing, schedules, and common side effects.

Prostate cancer: New insight into mechanisms of castration resistance

Abstract: Constitutively active androgen receptor splice variants (arvs) have been implicated in the progression of prostate cancer to a castration-resistant state. two new papers add to our understanding of how this might occur, highlighting the involvement of full-length androgen receptor (ar). in the first study, sun et al. report isolation of a novel splice variant arv567es, so-called because it lacks exons 5, 6 and 7, which encode the ligand-binding domain. as expected, arv567es was found to be constitutively active and the researchers turned their attention to its role in castration-resistant prostate cancer (CrPC). they detected arv567es expression in over 50% of prostate cancer specimens taken from men who had received androgen deprivation therapy and subsequently died from their disease, with particular abundance in tumors exhibiting the lowest levels of androgen. a role in disease progression was confirmed in xenograft experiments, where human cells expressing arv567es were capable of forming castration-resistant tumors in immunocompromised mice. until now, it was believed that constitutively active arvs signal independently of the full-length receptor, but here investigators report a previously unknown physical interaction between the two. Binding of arv567es to full-length receptor was found to trigger ligandindependent nuclear translocation and enhanced transcriptional activity of the ar, resulting in cell proliferation despite low androgen concentrations. these data suggest that splice variants can signal in two ways—with or without full-length ar. watson and colleagues have gone a step further in their research, suggesting that the full-length receptor is an absolute requirement for arv-driven castration resistance. their work is based on another constitutively active splice variant, ar-v7, which is associated with poor prognosis if detected early in a patient’s disease course. mDv3100 is a promising antiandrogen—currently in a phase iii trial for CrPC—which exerts its effects by blocking the ar ligandbinding domain. watson and his team hypothesized that because ar-v7 lacks the ligand-binding domain, its activity would be unaffected by mDv3100, and as a result patients whose tumors express Original articles Sun, S. et al. Castration resistance

Reinduction of hormone sensitivity to goserelin following chemotherapy with vinorelbine in castration-resistant prostate cancer.

Abstract: Primary androgen ablation leads to symptomatic improvement and a reduction in prostate-specific antigen (PSA) serum levels in patients with advanced prostate cancer, but all patients eventually become refractory to hormone therapy with progression of the disease and a life expectancy of about a year. We describe a patient who developed castration resistance, was treated with vinorelbine, and continues to be progression free on therapy with luteinizing hormone releasing hormone agonists alone, more than 2.5 years following cessation of treatment with vinorelbine.

NF-KappaB2/p52 Activation and Androgen Receptor Signaling in Prostate Cancer

Abstract: : The goal of this project is to characterize the role of NF-kappaB2/p52 in the aberrant activation of AR signaling in castrationresistant prostate cancer. Our preliminary data demonstrate that NF-kappaB2/p52 is expressed at high levels in prostate canceand that overexpression of NF- B2/p52 facilitates castration resistant prostate cancer progression by activation of AR signalingand rescue of cancer cells from apoptotic death induced by androgen deprivation. Our hypothesis is that NF-kappaB2/p52activates the AR and protects prostate cancer cells from apoptotic cell death induced by androgen deprivation therapy, leadingto the development of castration resistance prostate cancer. The specific aims are: 1. To determine the role of p52 activation inandrogen responsiveness and progression of castration resistant prostate cancer. 2. To determine the effect of expression op52 on the development and progression of prostate cancer in a transgenic mouse model. 3. To determine the mechanisms oAR activation by p52.