Correlation between the presence of the nuclear AR-V7 androgen receptor and clinical evolution of prostate cancer: in vitro analysis of a combination of compounds targeting PI3K

Introduzione: PCa è una malattia multiforme e biologicamente molto eterogenea. Diversi meccanismi chiave nella progressione della malattia da androgeno-dipendente ad androgeno-indipendente (CRCP) possono essere attribuiti ad alterazione nella via di segnalazione di AR. Scopo: Il disegno del nostro progetto è di valutare in vitro gli effetti di diversi composti che hanno come target mutazioni diverse coinvolte nello sviluppo e nella progressione del tumore della prostata e confrontare questi risultati con l’esperienza clinica di risposta alla terapia di pazienti con PCa con diversa progressione ed espressione di AR-V7 nel nucleo. Materiali e Metodi: Docetaxel, appartiene al gruppo dei taxani. L’abiraterone, inibitore del CYP17A1, ha come bersaglio l’attività sia della 17α-idrossilasi che della 17,20-liasi. L’enzalutamide, inibitore non steroideo di seconda generazione che legandosi al AR con maggiore affinità, riduce l'efficienza della traslocazione nucleare di AR e compromette sia il legame del DNA agli elementi di risposta degli androgeni che il reclutamento di coattivatori. La linea cellulare LnCaP deriva da un linfonodo di un paziente con cancro della prostata metastatico, mantiene la sensibilità agli androgeni. Esprime PSA (prostate specific antigen) e PSMA (Prostate specific membrane antigen), mantiene p53 wt e presenta PTEN (phosphatase and tensin homolog) mutato che porta all’attivazione costitutiva della via di AKT. VCaP sono cellule che derivano da metastasi vertebrali isolate da una vertebra lombare di un paziente refrattario alla terapia ormonale. Queste cellule esprimono PSA e PAP (prostatic acid phosphatase). VCaP esprimono AR wt ma presentano un’amplificazione di AR risultando in livelli più elevati di AR-FL, inoltre presentano la variazione di splicing 7, AR-V7. Esprimono PTEN ed il gene di fusione TMPRSS2-ERGPTEN. Risultati: Su queste cellule stiamo valutando gli inibitori di PI3K/AKT/ mTOR, Wortmannin e RAD001 in combinazione con farmaci che interferiscono con la via di AR. Inoltre abbiamo valutato l’inibizione sulla survivina nelle cellule trattate con una combinazione di YM155 e Abiraterone, Enzalutamide, o Docetaxel. La Wortmannin, inibisce PI3K; RAD001, inibitore di mTOR; YM155, inibisce la survivina. Abbiamo scelto diverse concentrazioni e i trattamenti sono stati effettuati per 24, 48 e 72 ore. La sopravvivenza è stata valutata con MTT, e la morte delle cellule con la colorazione del tripan blue. Infine per valutare la capacità delle cellule trattate di rientrare nel ciclo cellulare abbiamo allestito un test di clonogenicità dopo trattamenti di 24 ore. Le cellule trattate a 24 ore sono state processate per l’estrazione dell’RNA, dobbiamo valutare in RT-PCR l’espressione di alcuni geni per vedere l’azione dei composti sul ciclo cellulare (ciclina D, p27) e l’apoptosi (Bcl-2, Bvl-xl e Bax e survivina). Abbiamo studiato i primer ( ciclina D1, p27, Bcl-2, Bvl-xl e Bax e survivina ) e messo a punto le condizioni di RT-PCR, usando il SYBR Green, più adeguate per vedere l’assetto di questi geni comparati al gene GADPH. Conclusioni: Dai primi risultati è emerso che il docetaxel ha una maggiore capacità di inibire la crescita cellulare di entrambe le linee cellulari: dopo trattamento con 5nM solo il 14% e il 30% rispettivamente LnCaP e delle VCap continuano a proliferare. Il trattamento con Abiraterone riduce del solo 40% la crescita delle LnCap e del 20% quella delle VCaP, mentre l’Enzalutamide riduce del 55% le LnCaP (sopravvivono 45%) e del 30% (sopravvivono 70%) le VCap. Il trattamento di queste cellule con inibitori di PI3K/AKT/mTor effettivamente riduce la sopravvivenza delle cellule esaminare. Da questi primi risultati sulle LnCap emerge inibendo PI3K/mTor aumenta anche l’efficacia del trattamento di sostanze che agiscono su momenti diversi della sensibilità agli androgeni. Sulle VCaP abbiamo un quadro meno completo, queste cellule crescono molto lentamente

Beyond the immune suppression: the immunotherapy in prostate cancer

Prostate cancer (PCa) is the second most common cancer in men.Aswell in many other human cancers, inflammation and immune suppression have an important role in their development.We briefly describe the host components that interact with the tumor to generate an immune suppressive environment involved in PCa promotion and progression.Different tools provide to overcome the mechanisms of immunosuppression including vaccines and immune checkpoint blockades. With regard to this, we report results of most recent clinical trials investigating immunotherapy in metastatic PCa (Sipuleucel-T, ipilimumab, tasquinimod, Prostvac-VF, and GVAX) and provide possible future perspectives combining the immunotherapy to the traditional therapie

Laparoscopic versus open radical prostatectomy in high prostate volume cases: impact on oncological and functional results

To prospectively compare the laparoscopic versus open approach to RP in cases with high prostate volume and to evaluate a possible diferente impact of prostate volume

Influence of statin use on clinicopathological characteristics of localized prostate cancer and outcomes obtained after radical prostatectomy: a single center study

To assess the impact of statin use on biochemical recurrence (BCR) of prostate cancer after radical prostatectomy (RP)

A meta-analysis and systematic review of randomized controlled trials with degarelix versus gonadotropin-releasing hormone agonists for advanced prostate cancer

Our aim was to systematically evaluate the benefits of degarelix as antagonist versus agonists of gonadotropin-releasing hormones (GnRH) for the treatment of advanced prostate cancer (PC). This comparison was performed either in terms of biochemical or oncological or safety profiles. To this end we, carried out a systematic review and meta-analysis of the literature.We selected only studies directly and prospectively analyzing the two treatments in the same population (randomized phase III studies). We followed the Preferred Reporting Items for Systematic Reviews and meta-analyses process for reporting studies.After we eliminated studies according to the exclusion criteria, 9 publications were considered relevant to this review. These articles described 5 clinical trials that were eligible for inclusion. The follow-up duration in all trials did not exceed 364 days. This meta-analysis and review comprised a total of 1719 men, 1061 randomized to degarelix versus 658 to GnRH agonists treatment for advanced PC. Oncological results were evaluated only in 1 trial (CS21:408 cases) and they were not the primary endpoints of the study. Treatment emerging adverse events were reported in 61.4% and 58.8% of patients in the degarelix and GnRH agonists group, respectively (odds ratio, OR = 1.17; 95% confidence interval, 95% CI: 0.78-1.77, P > 0.1). Treatment related severe cardiovascular side effects were reported (trial CS21-30-35) in 1.6% and 3.6% of patients in the degarelix and GnRH agonists group, respectively (OR = 0.55, 95% CI: 0.26-1.14, P > 0.1).Our analysis evidences relevant limitations in particular for the comparative evaluation of the efficacy and the oncological results related to degarelix

GNRH-agonist or antagonist in the treatment of prostate cancer: a comparision based on oncological results

On the basis of the trials available, are we ready to consider GnRH antagonists better than agonists? Is there a population of patients who may benefit from antagonists more than agonists?We specifically focused our analysis on the significance of oncological results obtained in phase III trials directly comparing Degarelix with GnRH agonists. Oncological results were evaluated only in 1 trial (CS21) with some subanalysis and they were not the primary endpoints of the study. The follow-up duration was 364 days, and therefore, the number of events (all causes deaths and prostate cancer (PC), Prostate Specific Antigen (PSA), Hazard ratio (HR)-related deaths) was very low in both groups and this aspect strongly reduces the significance of overall survival evaluation. In our opinion, the CS21A open-label extension does not consent to obtain useful clinical data and the design of the study loses the possibility to have a longer randomized comparison between degarelix and agonist. Moreover, the fact that the crossover from leuprolide to degarelix was pre-defined at 12 months and not at agonist failure does not allow to gather data also on the effect of sequential treatment.The answer to the question whether we are ready to consider antagonists better than agonists, based on oncological results, is probably no. We have data in terms of testosterone suppression and PSA control rather than overall survival or clinical progression free survival. A PSA progression-free survival is a secondary endpoint that in our opinion is not sufficient. Large prospective comparative trials with long-term follow-up are needed to clarify this critical clinical question

Comment on: Androgen receptor axis-targeted agents for non-metastatic castration-resistant prostate cancer impact on overall survival and safety profile: an updated systematic review and meta-analysis

Systemic therapy with androgen deprivation (ADT) has been for long time the main treatment for advanced prostate cancer (PC), and for those men with early-stage PC who experience biochemical progression after primary treatments. A hormone sensitive (HS) phase of PC is always followed by the development of castration resistant (CRPC) growth and this progression is in part dependent on the use of ADT in the first period. According to the European Association of Urology (EAU) guidelines, CRPC can be defined as castrate serum testosterone (<50 ng/dL or 1.7 nmol/L) plus either biochemical or radiological progression

Quantitative analysis of urinary incontinence after prostatectomy: lack of standardization in trials

Urinary incontinence (UI) is an extremely common disease in all the world, able to significantly impact on the Quality of Life of patients. It is also associated to a great distress influencing social life with high costs for both patients and society

Intermittent androgen deprivation in prostate cancer cases with biochemical progression after radical prostatectomy: Are we ready to treat?

PURPOSE: To evaluate clinical data from published trials on the use of intermittent androgen deprivation (IAD) therapy in patients with biochemical relapse after radical prostatectomy (RP). METHODS: We searched the Medline and Cochrane Library databases for literature published on IAD and biochemical progression after radical prostatectomy. RESULTS: To date, we have oncological and functional data from phase 3 studies focused on metastatic and locally advanced stages that confirmed IAD as a valid option treatment. For the aim of this review, only Tunn study, was specifically focused on patients who relapsed after surgery but clear and mature results are still missed. CONCLUSIONS: The use of IAD in cases who relapse after RP is common in the clinical practice. Although specific recommendation on the use of IAD in this setting of patients are not available, we concluded that the real benefit of IAD in terms of long survival and quality of life is mainly for patients treated with surgery