LHRH Antagonist Research Articles

Risk of Hormone Escape in a Human Prostate Cancer Model Depends on Therapy Modalities and Can Be Reduced by Tyrosine Kinase Inhibitors

Almost all prostate cancers respond to androgen deprivation treatment but many recur. We postulated that risk of hormone escape -frequency and delay- are influenced by hormone therapy modalities. More, hormone therapies induce crucial biological changes involving androgen receptors; some might be targets for escape prevention. We investigated the relationship between the androgen deprivation treatment and the risk of recurrence using nude mice bearing the high grade, hormone-dependent human prostate cancer xenograft PAC120. Tumor-bearing mice were treated by Luteinizing-Hormone Releasing Hormone (LHRH) antagonist alone, continuous or intermittent regimen, or combined with androgen receptor (AR) antagonists (bicalutamide or flutamide). Tumor growth was monitored. Biological changes were studied as for genomic alterations, AR mutations and protein expression in a large series of recurrent tumors according to hormone therapy modalities. Therapies targeting Her-2 or AKT were tested in combination with castration. All statistical tests were two-sided. Tumor growth was inhibited by continuous administration of the LH-RH antagonist degarelix (castration), but 40% of tumors recurred. Intermittent castration or complete blockade induced by degarelix and antiandrogens combination, inhibited tumor growth but increased the risk of recurrence (RR) as compared to continuous castration (RRintermittent: 14.5, RRcomplete blockade: 6.5 and 1.35). All recurrent tumors displayed new quantitative genetic alterations and AR mutations, whatever the treatment modalities. AR amplification was found after complete blockade. Increased expression of Her-2/neu with frequent ERK/AKT activation was detected in all variants. Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it. Anti-hormone treatments influence risk of recurrence although tumor growth inhibition was initially similar. Recurrent tumors displayed genetic instability, AR mutations, and alterations of phosphorylation pathways. We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.

New Agonist- and Antagonist-Based Treatment Approaches for Advanced Prostate Cancer

Increased understanding of prostate cancer biology has led to new treatment strategies and promising new agents for treating prostate cancer, in particular peptide-based agonists and antagonists. In this review article, new therapy modalities and potential approaches for the treatment of advanced prostate cancer are discussed, including agonists and antagonists of luteinizing hormone-releasing hormone, antagonists of bombesin/gastrin-releasing peptide, and growth hormone-releasing hormone and somatostatin analogues. Though the prognosis of patients with prostate cancer is much improved by some of these treatment approaches, including combination treatment methods, extensive side-effects are still reported. These include sexual dysfunction, functional lesions of the liver and renal system, osteoporosis, anaemia and diarrhoea. Future studies should focus on new treatment agents and treatment approaches that can eliminate side-effects and improve quality of life in patients with prostate cancer on the basis of potent treatment efficacy.

What determines testosterone levels?

This study is interesting as a negative study. It shows that the type of luteinizing hormone releasing-hormone (LHRH) agonists and primary therapy is not significant when it comes to testosterone levels.1 This commentary focuses on the actual testosterone levels, which are clinically relevant as many patients were experiencing breakthrough levels on LHRH agonists. Chemically castrate status in terms of testosterone has been argued to be 20 ng/dL or 50 ng/dL, which converts to 0.69 nmol/L or 1.7 nmol/L.2 Current consensus is 20 ng/dL, which bilateral surgical castration typically achieves.3 The median values reported in this study for LHRH alone, radiation and surgery were 40, 37 and 36 ng/dL, or 1.4, 1.3 and 1.25 nmol/L, respectively. The interquartile ranges also suggest that most patients (75%) did not have castrate levels of testosterone. Admittedly, this study does mention testosterone was only obtained once and circumstances surrounding it were uncertain. Anti-androgen status is also not mentioned. Bicalutamide and other anti-androgens are known to elevate testosterone levels as monotherapy and may have a confounding effect on the testosterone levels reported. Most likely testosterone was measured when prostate-specific antigen (PSA) was rising on LHRH agonist and one can surmise that the ordering physician was looking for and found “testosterone escape” (a single value above 50 ng/dL or 1.7 nmol/L) in many of the patients in this study.4 Although as stated previously, perhaps 20 ng/dL should be the current definition. The importance of testosterone escape is backed by several studies. It is known anti-androgens do not help orchiectomy patients in overall survival, but do for patients on LHRH agonists.5 Breakthrough testosterone levels on medication that did not occur for surgically castrate patients would be a likely explanation. Progression-free survival in non-metastatic patients in another study was longer, the lower the testosterone level.6 In this clinical scenario of testosterone escape, standard treatment was switching LHRH agonists, adding an anti-androgen and bilateral orchiectomy. Now, a new option with LHRH antagonists arises. It has been reported to have modest results with respect to decreasing PSA, but can possibly alleviate voiding symptoms more than LHRH agonist therapy.7 Regardless, the actual testosterone level is important for patients on LHRH agonists with rising PSA. Venkateswaran and colleagues make the case that it should be checked no matter what the primary therapy.1

Mechanisms of prostate atrophy after LHRH antagonist cetrorelix injection: An experimental study in a rat model of benign prostatic hyperplasia

In the present study, we investigated the roles of TGF-β signaling pathway in a rat benign prostatic hyperplasia (BPH) model treated with cetrorelix. TGF-β1 and c-Myc expression were measured by qRT-PCR and Western blotting in the proximal and distal region of ventral prostatic lobes, respectively. We observed that treatment with cetrorelix led to a significant reduction of ventral prostate weight in a dose-dependent manner. In the proximal region, after cetrorelix treatment, the expression of TGF-β1 was dramatically increased (P<0.05), while the expression of c-Myc was significantly decreased (P<0.05). In comparison with the control group, the cetrorelix groups had more TUNEL-positive cells. Our findings strongly suggest that the TGF-β signaling pathway may be one of the major causes responsible for prostate volume reduction in BPH rats after cetrorelix treatment.

Abstract 5368: A phase II study of ipilumimab plus androgen deprivation therapy in castration-sensitive prostate carcinoma

Abstract Anti-CTLA-4 therapy (Ipilimumab, Yervoy™) was recently FDA-approved for the treatment of metastatic melanoma based on improved median overall survival observed in Phase III clinical trials. Since anti-CTLA-4 targets a T cell specific molecule, as opposed to a tumor specific molecule, it is being investigated as treatment for multiple malignancies, including prostate cancer. Given that anti-CTLA-4 mediates anti-tumor responses by enhancing T cell responses, it has been postulated that standard agents that enable tumor cell death may allow for priming of a T cell immune response that can be augmented by combination with CTLA-4 blockade. Therefore, we hypothesized that adding ipilimumab to standard androgen ablation (AA) therapy in men with metastatic prostate cancer (mPC) would improve immune and clinical responses. We designed a clinical trial whereby men with castrate-sensitive mPC, ECOG performance status ≤ 2 and normal organ and marrow function are registered ≤1 month of initiation of an LHRH agonist or antagonist (LHRHa). Men with autoimmune diseases, known brain metastases, small cell carcinoma morphology, known HIV, Hepatitis B or C infection, untreated symptomatic spinal cord compressions or chronic immunosuppressive therapies are excluded. Starting on day 29, patients receive 4 monthly doses of 10mg/kg ipilimumab. The primary endpoint of the trial is to estimate the rate of PSA ≤ 0.2ng/mL at 7 months, shown to be a powerful predictor of survival (Hussain et al. J Clin Oncol. 2006; 24:3984). Secondary endpoints include: immune responses, time to testosterone recovery (&amp;gt;50ng/mL), time to disease progression off AA, overall survival and safety of the combination.Accrual is ongoing. Data from 8 patients accrued to date show a significant increase in the frequency of T cells expressing the inducible costimulator (ICOS), as we have previously shown with ipilimumab monotherapy (Liakou et al. Proc Natl Acad Sci U S A. 2008;105:14987; Carthon et al. Clin Cancer Res. 2010;16:2861), and significant increases in memory T cell markers. ICOS+ T cells play an important role in anti-tumor responses mediated by anti-CTLA-4 therapy (Fu et al. Cancer Res. 2011;71:5445). Significant changes in dendritic, natural killer and macrophage cell populations have not been observed. To date, one patient developed an asymptomatic grade 3 transaminitis after 2 doses of ipilimumab that resolved with high dose steroids. Assessment of immune responses induced by the combination of ipilimumab and AA, and evaluation of clinical endpoints are ongoing. Updated data will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5368. doi:1538-7445.AM2012-5368

Abiraterone in prostate cancer: a new angle to an old problem.

Abiraterone acetate is an orally administered potent inhibitor of cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17), which is essential for synthesis of testosterone from cholesterol. Although decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer, residual androgens may still be detected in patients treated with luteinizing hormone-releasing hormone agonists or antagonists. Treatment with abiraterone results in rapid, and complete, inhibition of androgen synthesis in the adrenal glands and potentially within the tumor itself. An overall survival benefit of maximal androgen suppression was recently shown in a randomized placebo-controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate-resistant prostate cancer previously treated with docetaxel chemotherapy. Abiraterone's efficacy shows the importance of androgen signaling in patients with castrate-resistant metastatic disease, with additional confirmation from recent studies of other novel agents such as MDV3100, an androgen receptor signaling inhibitor. These promising results now pose a new angle to an old problem about hormonal therapy and raise new questions about how resistance develops, how to best sequence therapy, and how to optimize combinations with other emerging novel agents.

Combining Growth Hormone-Releasing Hormone Antagonist With Luteinizing Hormone-Releasing Hormone Antagonist Greatly Augments Benign Prostatic Hyperplasia Shrinkage

Benign prostatic hyperplasia often affects aging men. Antagonists of the neuropeptide growth hormone-releasing hormone reduced prostate weight in an androgen induced benign prostatic hyperplasia model in rats. Luteinizing hormone-releasing hormone antagonists also produce marked, protracted improvement in lower urinary tract symptoms, reduced prostate volume and an increased urinary peak flow rate in men with benign prostatic hyperplasia. We investigated the influence of a combination of antagonists of growth hormone-releasing hormone and luteinizing hormone-releasing hormone on animal models of benign prostatic hyperplasia. We evaluated the effects of the growth hormone-releasing hormone antagonist JMR-132, given at a dose of 40 μg daily, the luteinizing hormone-releasing hormone antagonist cetrorelix, given at a dose of 0.625 mg/kg, and their combination on testosterone induced benign prostatic hyperplasia in adult male Wistar rats in vivo. Prostate tissue was examined biochemically and histologically. Serum levels of growth hormone, luteinizing hormone, insulin-like growth factor-1, dihydrotestosterone and prostate specific antigen were determined. Marked shrinkage of the rat prostate (30.3%) occurred in response to the combination of growth hormone-releasing hormone and luteinizing hormone-releasing hormone antagonists (p<0.01). The combination strongly decreased prostatic prostate specific antigen, 6-transmembrane epithelial antigen of the prostate, interleukin-1β, nuclear factor-κβ and cyclooxygenase-2, and decreased serum prostate specific antigen. A combination of growth hormone-releasing hormone antagonist with luteinizing hormone-releasing hormone antagonist potentiated a reduction in prostate weight in an experimental benign prostatic hyperplasia model. Results suggest that this shrinkage in prostate volume was induced by the direct inhibitory effects of growth hormone-releasing hormone and luteinizing hormone-releasing hormone antagonists exerted through their respective prostatic receptors. These findings suggest that growth hormone-releasing hormone antagonists and/or their combination with luteinizing hormone-releasing hormone antagonists should be considered for further development as therapy for benign prostatic hyperplasia.

Testosterone suppression: Impact of testosterone level on disease progression in advanced prostate cancer.

46 Background: In patients with advanced prostate cancer, medical castration remains a mainstay of treatment. A testosterone level below 50 ng/dL has been previously accepted as an adequate level of androgen suppression and remains the benchmark level for clinical trials. However, there is mounting evidence that lower testosterone levels may be associated with improved clinical outcomes. We evaluated our cohort of patients with advanced prostate cancer to assess the impact of testosterone suppression on progression to castrate resistant prostate cancer (CRPC). Methods: Patient data was obtained from a prospective database of patients undergoing androgen deprivation therapy (ADT) at a tertiary centre from 2006-2011. A total of 39 patients were eligible for inclusion with at least 12 months follow-up. Patients were administered LHRH agonists or antagonist with testosterone and PSA assessments every 3 months. Patients were considered to have progressed to CRPC when there were at least 2 consecutive rises in PSA above nadir, clinical progression, or death from disease. Patients were stratified into two risk groups based on 6-month absolute and 1-year mean testosterone levels following initiation of ADT. Baseline characteristics between risk groups were compared using the Student’s t-test and chi-squared test. Probability of disease progression was assessed using the Kaplan-Meier method and compared using the log-rank test. Results: Median patient follow up was 2.3 years with 38% free of disease at last follow up. Patients with 6-month absolute testosterone less than 32 ng/dL had an increased time to CRPC (log rank p=0.06). Patients with 1-year mean testosterone less than 32 ng/dl had a significantly increased time to CRPC (log rank p=0.005). Patients did not differ significantly in their baseline characteristics. Conclusions: Adequate testosterone suppression during ADT may play a clinically significant role in delaying CRPC. While PSA levels are often used to assess for response to ADT, the current study suggests testosterone level in the first year following initiation of ADT may serve as an early predictor of disease progression.

Metabolic stability of long-acting luteinizing hormone-releasing hormone antagonists

Long-acting luteinizing hormone-releasing hormone (LHRH) antagonists designed to be protease resistant consisted of a series of novel decapeptides structurally similar to LHRH. The aim of this study was to evaluate the in vitro metabolic stability of the LHRH decapeptides using pancreatin and homogenates models and identify the metabolites in rat liver homogenate for the purpose of illustrating the metabolic features of the decapeptides. The major metabolites in rat liver homogenate were identified by LC-ESI-MS(n). The half-lives of the 11 LHRH decapeptides were from 44 to 330 min in the pancreatin model. The half-lives of the five decapeptides in rat liver, kidney and lung homogenates were between 8 and 462 min. The most stable decapeptides were the LY616 and LY608 peptides with half-lives of 36 min in liver homogenate. Two major cleavage sites were found by analysing the metabolites of the LY618 peptide in rat liver homogenate, between the Pal(3)-Ser(4) and the Leu(7)-Ilys(8) peptide bonds. The major metabolites were produced via cleavages of peptide bonds at these sites, and further metabolic reactions such as hydroxylation, oxidative dechlorination, alcohol dehydration and isopropyl dealkylation were also observed.

Making the switch from LHRH antagonist to LHRH agonist

One very important issue faced by clinicians managing patients with prostate cancer is whether after initiating a man on a pure luteinizing-hormone-releasing hormone (LHRH) antagonist, he should then be switched to a longer-acting depot LHRH agonist. New evidence suggests that this therapeutic approach is both safe and effective.

Search for novel therapies for triple negative breast cancers (TNBC): analogs of luteinizing hormone-releasing hormone (LHRH) and growth hormone-releasing hormone (GHRH).

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that is clinically negative for the expression of estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2). Patients with TNBC have a worse clinical outcome, as measured by time to metastasis and median overall survival. Chemotherapy has been the mainstay of treatment of TNBC but responses are disappointing. A substantial proportion of TNBC expresses luteinizing hormone-releasing hormone (LHRH), receptors for LHRH, in addition to receptors for growth hormone-releasing hormone (GHRH). These receptors represent potential therapeutic targets. Potent antagonists of GHRH and LHRH receptors have been developed in recent years and these antagonists inhibit the growth, tumorigenicity and metastatic potential of various human experimental malignancies. These antagonists could be utilized for the treatment of TNBC. The targeted cytotoxic analog of LHRH, AN-152 (AEZS-108) containing doxorubicin, must also be strongly considered for therapy of TNBC. Experimental studies suggest the merit of clinical trials with LHRH antagonists and AEZS-108 in TNBC patients.

Abstract CN08-01: Targeting the androgen receptor in castration-resistant prostate cancer.

Abstract CN08-01: Targeting the androgen receptor in castration-resistant prostate cancer.

EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer

ObjectivesOur aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC). MethodsThe working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews. ResultsLuteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values >0.2ng/ml following radical prostatectomy (RP) and >2ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels <0.5ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (CT) are of limited importance if the PSA is <2.5ng/ml; bone scans and CT can be omitted unless PSA is >20ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75mg/m2 every 3wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications. ConclusionThe knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org.

Inhibitory effects of antagonists of growth hormone releasing hormone on experimental prostate cancers are associated with upregulation of wild‐type p53 and decrease in p21 and mutant p53 proteins

The tumor suppressor gene p53 is implicated in cell cycle control and apoptosis. Antagonists of growth hormone-releasing hormone (GHRH) have been shown to inhibit human experimental prostate cancers. We investigated the involvement of p53 apoptotic pathways in this effect. Nude mice bearing xenografted PC-3, DU-145, and MDA-PCa-2b human prostate cancer lines were treated with a new potent GHRH antagonist MZ-J-7-138. To determine whether tumor inhibition by MZ-J-7-138 involves apoptotic mechanisms such as p53 and p21, we evaluated by Western Blot the expression of mutant mt-p53 in PC-3 and DU-145 and of wild type (wt-p53) in MDA-PCa-2b prostate cancers as well as p21. MZ-J-7-138 significantly inhibited the growth of PC-3, DU-145, and MDA-PCa-2b xenografts in nude mice. Androgen deprivation with the LHRH antagonist Cetrorelix enhanced the anti-proliferative effect of GHRH antagonist MZ-J-7-138 on MDA-PCa-2b tumors. The expression of mutant (mt-p53) and p21 protein in PC-3 and DU-145 tumors was significantly decreased by treatment with MZ-J-7-138, whereas wild type wt-p53 expression in MDA-PCA-2b tumors was up regulated by treatment with Cetrorelix. All three models investigated expressed specific, high affinity GHRH receptors. Our findings indicate that the anti-proliferative effects of GHRH antagonist MZ-J-7-138 and LHRH antagonist Cetrorelix on prostate cancers involve p53 and p21 signaling.

Combination therapy of recurrent prostate cancer with the proteasome inhibitor bortezomib plus hormone blockade

A single arm phase II trial of single-agent bortezomib (BZM) alone or combined with hormone blockade was conducted in patients with early PSA recurrence after definitive local therapy. The primary endpoint of this study was to determine the time to PSA relapse after BZM therapy alone or when BZM was combined with hormone blockade. The secondary endpoint was to determine the safety of combination therapy. Part A of the treatment schedule consisted of three cycles of BZM 1.3 mg/m2 IV given on days 1,4,8,11. If patients progressed on Part A, they were entered on Part B which consisted of a single dose of LH-RH antagonist, daily oral antiandrogen, and weekly BZM 1.3 mg/m2 for three out of four weeks for a total of three months. BZM treatment significantly decreased the slope of the log PSA (p=0.024) demonstrating that this agent alone was capable of slowing the rise of the PSA. Of eight patients treated with BZM alone five had stable disease, two progressed and 1 went off study secondary to toxicity. The major toxicity was neurotoxicity requiring discontinuation of therapy in three patients and treatment interruption in nine patients. Of those receiving Parts A and B or B only, there were 11 of 15 CRs with the average time to progression of 5.5 months. BZM treatment can change the slope of PSA rise and can be combined with hormone deprivation therapy without significant additional side effects; these agents are associated with a median time to CR of 42 days.

Guía de la EAU sobre el cáncer de próstata. Parte II: tratamiento del cáncer de próstata avanzado, recidivante y resistente a la castración

Objectives Our aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC). Methods The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews. Results Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values > 0.2 ng/ml following radical prostatectomy (RP) and > 2 ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels < 0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (CT) are of limited importance if the PSA is < 2.5 ng/ml; bone scans and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75 mg/m 2 every 3 wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications. Conclusion The knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org.

Innovations dans le traitement hormonal du cancer de la prostate localement avancé et/ou métastatique

Discovered over 40 years ago, hormonal therapy remains the cornerstone therapy of advanced prostate cancer and continues to evolve. Suppression of serum testosterone remains the mainstay of systemic treatment of prostate cancer. Antagonists of LH-RH are now available and can prevent the castration delay of agonists. They seem to have a clinical benefit in terms of PSA control. During the phase of resistance to extracellular castration, the androgen receptor is the dominant element. Intracellular steroidogenesis can be blocked by Abiraterone. Amplification and mutation of the androgen receptor may be controlled by antiandrogens of second generation. Thus, these new molecules, already or soon available, will renew the strategy of prostate cancer treatment.

Response to degarelix after resistance to luteinizing hormone–releasing hormone agonist therapy for metastatic prostate cancer

Androgen deprivation with a luteinizing hormone-releasing hormone (LH-RH) agonist is the standard treatment for patients with metastatic prostate cancer who prefer nonsurgical options. Therapy with these agents is usually successful in achieving and maintaining castrate levels (< 50 ng/dl) of serum testosterone, but failures have been reported in up to 10% of patients. Traditionally, these patients are offered surgical castration with bilateral orchiectomy. However, the novel LH-RH antagonists may offer a nonsurgical alternative. We describe two patients with advanced prostate cancer who failed to achieve castrate levels of testosterone while on an LH-RH agonist, but subsequently responded to the LH-RH antagonist, degarelix. The first patient is a 63-year-old man who was treated with leuprolide for metastatic prostate cancer. He initially responded with prostate-specific antigen (PSA) that fell to 0.6 ng/ml. However, after 15 months of therapy, his PSA rose to 18.3 ng/ml and his testosterone was noted to be 208 ng/dl. He was switched to degarelix, and 4 weeks later his testosterone was adequately suppressed at 16 ng/dl. The second patient is a 41-year-old man with metastatic prostate cancer who was started on leuprolide, but after 3 months of therapy, was found to have a rising PSA and a testosterone of 96 ng/dl. Four weeks after switching to degarelix, his testosterone was 18 ng/dl and his PSA decreased concordantly. With continued monthly injections of degarelix, his testosterone has consistently remained to be at less than 20 ng/dl over 7 months of follow-up.

Les nouveautés 2010 : Les points forts de l’ASCO-GU, EAU, ASCO, AUA…

The main news in kidney oncourology are PET CaIX as potential new diagnostic and monitoring tool, the lack of progress in terms of drug combination therapy, the sequential approach remains the standard, lack of progress also in selecting good candidates for immunotherapy, the possible benefit of nephrectomy, that only the CARMENA study will determine, and the emergence of determining the risk of recurrence after nephrectomy using genomic study. Concerning non muscle invasive bladder cancer, endoscopic diagnosis seems improved by the NBI and immunofluorescence. The staging of pT1 tumors may evolve. The poor prognosis of Cis was stressed. The indication of cystectomy for BCG failure has been clarified. For muscle invasive bladder cancer, the prognostic impact of lympho-vascular invasion was reported. The importance of an extended lymphadenectomy has been demonstrated. In cases of symptomatic bone metastases, zoledronic acid increased overall survival. An analysis of performance and drawbacks of radio-hormonotherapy was performed. The denosumab and zoledronic acid were compared in prevention of bone loss during androgen deprivation. The antagonists of LH-RH, the cabazitaxel and immunotherapies could be part of the therapies for advanced prostate cancer. For penile cancer treatment, in case of suspicious nodes, ultrasound guided cytopuncture is useful. For testis cancer, the recurrence rate for stage I seminoma has been estimated, at 15%. The PET-scan is also helpful to assess the nodal tumoral spread during the staging and the follow-up of patients treated by chemotherapy.

In-vitro/in-vivo studies of the biodegradable poly-(d,l-lactide-co-glycolide) microspheres of a novel luteinizing hormone-releasing hormone antagonist for prostate cancer treatment

The introduction of luteinizing hormone-releasing hormone (LHRH) analogs and their antagonists is revolutionizing the treatment of prostate cancer. In this study, poly(D,L-lactideco-glycolide) (PLGA) microspheres containing a highly potent LHRH antagonist (LXT-101) of interest in the indication of prostate cancer were evaluated on release mechanisms in vitro and biological performance in vivo. LXT-101 microspheres were prepared by the water/oil/water double emulsion method and the solid/oil/oil method. The results showed that the mechanism of LXT-101 releasing from PLGA 14,000 microspheres was the cooperation of drug diffusion and polymer degradation. This clarified the relationship between the microsphere characterization and hormone level in vivo. The larger microspheres (33 μm) could inhibit the testosterone level to castration for a longer time (35 days) than the smaller microspheres (15 μm, 14 days). The formulation containing the hydrophilic additive (polyethylene glycol 6000) could suppress the testosterone level to castration for a longer time (> 35 days) than the formulation without polyethylene glycol (14 days). The appearance of testis, vesicular seminalis, and prostates changed after treatment. The weights of sexual organs decreased significantly. The in-vivo release of the LXT-101 PLGA 14,000 microspheres curve showed that in-vivo release started immediately after day 1 (22.7%) and was rapid during the first 5 days (40.2% release). The LXT-101 microspheres could be a promising drug delivery system candidate to treat sex hormone-dependent tumors and other related disorders.