Late toxicity and five year outcomes after high-dose-rate brachytherapy as a monotherapy for localized prostate cancer

BACKGROUND To determine the 5-year outcome after high-dose-rate brachytherapy (HDR-BT) as a monotherapy. METHODS Between 10/2003 and 06/2006, 36 patients with low (28) and intermediate (8) risk prostate cancer were treated by HDR-BT monotherapy. All patients received one implant and 4 fractions of 9.5 Gy within 48 hours for a total prescribed dose (PD) of 38 Gy. Five patients received concomitant androgen deprivation therapy (ADT). Toxicity was scored according to the common terminology criteria for adverse events from the National Cancer Institute (CTCAE) version 3.0. Biochemical recurrence was defined according to the Phoenix criteria and analyzed using the Kaplan Meier method. Predictors for late grade 3 GU toxicity were analyzed using univariate and multivariate Cox regression analyses. RESULTS The median follow-up was 6.9 years (range, 1.5-8.0 years). Late grade 2 and 3 genitourinary (GU) toxicity was observed in 10 (28%) and 7 (19%) patients, respectively. The actuarial proportion of patients with late grade 3 GU toxicity at 5 years was 17.7%. Late grade 2 and 3 gastrointestinal (GI) toxicities were not observed. The crude erectile function preservation rate in patients without ADT was 75%. The 5 year biochemical recurrence-free survival (bRFS) rate was 97%. Late grade 3 GU toxicity was associated with the urethral volume (p = 0.001) and the urethral V120 (urethral volume receiving ≥120% of the PD; p = 0.0005) after multivariate Cox regression. CONCLUSIONS After HDR-BT monotherapy late grade 3 GU was observed relatively frequently and was associated with the urethral V120. GI toxicity was negligible, the erectile function preservation rate and the bRFS rate was excellent.

Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019)

BACKGROUND Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa-the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)-includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.

Guidance of treatment decisions in risk-adapted primary radiotherapy for prostate cancer using multiparametric magnetic resonance imaging: a single center experience.

BACKGROUND Magnetic resonance imaging (MRI) of the prostate is considered to be the most precise noninvasive staging modality for localized prostate cancer. Multiparametric MRI (mpMRI) dynamic sequences have recently been shown to further increase the accuracy of staging relative to morphological imaging alone. Correct radiological staging, particularly the detection of extraprostatic disease extension, is of paramount importance for target volume definition and dose prescription in highly-conformal curative radiotherapy (RT); in addition, it may affect the risk-adapted duration of additional antihormonal therapy. The purpose of our study was to analyze the impact of mpMRI-based tumor staging in patients undergoing primary RT for prostate cancer. METHODS A total of 122 patients admitted for primary RT for prostate cancer were retrospectively analyzed regarding initial clinical and computed tomography-based staging in comparison with mpMRI staging. Both tumor stage shifts and overall risk group shifts, including prostate-specific antigen (PSA) level and the Gleason score, were assessed. Potential risk factors for upstaging were tested in a multivariate analysis. Finally, the impact of mpMRI-based staging shift on prostate RT and antihormonal therapy was evaluated. RESULTS Overall, tumor stage shift occurred in 55.7% of patients after mpMRI. Upstaging was most prominent in patients showing high-risk serum PSA levels (73%), but was also substantial in patients presenting with low-risk PSA levels (50%) and low-risk Gleason scores (45.2%). Risk group changes occurred in 28.7% of the patients with consequent treatment adaptations regarding target volume delineation and duration of androgen deprivation therapy. High PSA levels were found to be a significant risk factor for tumor upstaging and newly diagnosed seminal vesicle infiltration assessed using mpMRI. CONCLUSIONS Our findings suggest that mpMRI of the prostate leads to substantial tumor upstaging, and can considerably affect treatment decisions in all patient groups undergoing risk-adapted curative RT for prostate cancer.

Consensus and differences in primary radiotherapy for localized and locally advanced prostate cancer in Switzerland: A survey on patterns of practice

INTRODUCTION External beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT), is an established treatment option for nonmetastatic prostate cancer. Despite high-level evidence from several randomized trials, risk group stratification and treatment recommendations vary due to contradictory or inconclusive data, particularly with regard to EBRT dose prescription and ADT duration. Our aim was to investigate current patterns of practice in primary EBRT for prostate cancer in Switzerland. MATERIALS AND METHODS Treatment recommendations on EBRT and ADT for localized and locally advanced prostate cancer were collected from 23 Swiss radiation oncology centers. Written recommendations were converted into center-specific decision trees, and analyzed for consensus and differences using a dedicated software tool. Additionally, specific radiotherapy planning and delivery techniques from the participating centers were assessed. RESULTS The most commonly prescribed radiation dose was 78 Gy (range 70-80 Gy) across all risk groups. ADT was recommended for intermediate-risk patients for 6 months in over 80 % of the centers, and for high-risk patients for 2 or 3 years in over 90 % of centers. For recommendations on combined EBRT and ADT treatment, consensus levels did not exceed 39 % in any clinical scenario. Arc-based intensity-modulated radiotherapy (IMRT) is implemented for routine prostate cancer radiotherapy by 96 % of the centers. CONCLUSION Among Swiss radiation oncology centers, considerable ranges of radiotherapy dose and ADT duration are routinely offered for localized and locally advanced prostate cancer. In the vast majority of cases, doses and durations are within the range of those described in current evidence-based guidelines.

Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database

AbstractBackground It is not easy to overview pending phase 3 trials on prostate cancer (PCa), and awareness of these trials would benefit clinicians. Objective To identify all phase 3 trials on {PCa} registered in the ClinicalTrials.gov database with pending results. Design and setting On September 29, 2014, a database was established from the records for 175 538 clinical trials registered on ClinicalTrials.gov. A search of this database for the substring “prostat” identified 2951 prostate trials. Phase 3 trials accounted for 441 studies, of which 333 concerned only PCa. We selected only ongoing or completed trials with pending results, that is, for which the primary endpoint had not been published in a peer-reviewed medical journal. Results and limitations We identified 123 phase 3 trials with pending results. Trials were conducted predominantly in North America (n = 63; 51) and Europe (n = 47; 38). The majority were on nonmetastatic disease (n = 82; 67), with 37 (30) on metastatic disease and four trials (3) including both. In terms of intervention, systemic treatment was most commonly tested (n = 71; 58), followed by local treatment 34 (28), and both systemic and local treatment (n = 11; 9), with seven (6) trials not classifiable. The 71 trials on systemic treatment included androgen deprivation therapy (n = 34; 48), chemotherapy (n = 15; 21), immunotherapy (n = 9; 13), other systemic drugs (n = 9; 13), radiopharmaceuticals (n = 2; 3), and combinations (n = 2; 3). Local treatments tested included radiation therapy (n = 27; 79), surgery (n = 5; 15), and both (n = 2; 2). A limitation is that not every clinical trial is registered on ClinicalTrials.gov. Conclusion There are many {PCa} phase 3 trials with pending results, most of which address questions regarding systemic treatments for both nonmetastatic and metastatic disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively. Patient summary This report describes all phase 3 trials on prostate cancer registered in the ClinicalTrials.gov database with pending results. Most of these trials address questions regarding systemic treatments for both nonmetastatic and metastatic disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively.

Non-metastatic castrate-resistant prostate cancer: a call for improved guidance on clinical management.

BACKGROUND Guidelines on the clinical management of non-metastatic castrate-resistant prostate cancer (nmCRPC) generally focus on the need to continue androgen deprivation therapy and enrol patients into clinical trials of investigational agents. This guidance reflects the lack of clinical trial data with established agents in the nmCRPC patient population and the need for trials of new agents. AIM To review the evidence base and consider ways of improving the management of nmCRPC. CONCLUSION Upon the development of castrate resistance, it is essential to rule out the presence of metastases or micrometastases by optimising the use of bone scans and possibly newer procedures and techniques. When nmCRPC is established, management decisions should be individualised according to risk, but risk stratification in this diverse population is poorly defined. Currently, prostate-specific antigen (PSA) levels and PSA doubling time remain the best method of assessing the risk of progression and response to treatment in nmCRPC. However, optimising imaging protocols can also help assess the changing metastatic burden in patients with CRPC. Clinical trials of novel agents in nmCRPC are limited and have problems with enrolment, and therefore, improved risk stratification and imaging may be crucial to the improved management. The statements presented in this paper, reflecting the views of the authors, provide a discussion of the most recent evidence in nmCRPC and provide some advice on how to ensure these patients receive the best management available. However, there is an urgent need for more data on the management of nmCRPC.

Impact of hormonal therapy on survival and racial disparities in a large community-based cohort of older men with local/regional prostate cancer

Prostate cancer (CaP) is the most diagnosed non-cutaneous malignancy and the second leading cause of cancer mortality among United States males. Major racial disparities in incidence, survival, as well as treatment persist. The mortality is three times higher among African Americans (AAs) compared with Caucasians. Androgen carcinogenesis has been persistently implicated but results are inconsistent; and hormone manipulation has been the main stay of treatment for metastatic disease, supportive of the androgen carcinogenesis. The survival disadvantage of AAs has been attributed to the differences in socioeconomic factors (SES), tumor stage, and treatment. We hypostasized that HT prolongs survival in CaP and that the racial disparities in survival is influenced by variation in HT and primary therapies as well as SES. To address these overall hypothesis, we first utilized a random-effect meta-analytic design to examine evidence from randomized trials on the efficacy of androgen deprivation therapy in localized and metastatic disease, and assessed, using Cox proportional hazards models, the effectiveness of HT in prolonging survival in a large community-based cohort of older males diagnosed with local/regional CaP. Further we examined the role of HT and primary therapies on the racial disparities in CaP survival. The results indicated that adjuvant HT compared with standard care alone is efficacious in improving overall survival, whereas HT has no significant benefit in the real world experience in increasing the overall survival of older males in the community treated for local/regional disease. Further, racial differences in survival persist and were explained to some extent by the differences in the primary therapies (radical prostatectomy, radiation and watchful waiting) and largely by SES. Therefore, given the increased used of hormonal therapy and the cost-effectiveness today, more RCTs are needed to assess whether or not survival prolongation translates to improved quality of life, and to answer the research question on whether or not the decreased use of radical prostatectomy by AAs is driven by the Clinicians bias or AAs's preference of conservative therapy and to encourage AAs to seek curative therapies, thus narrowing to some degree the persistent mortality disparities between AAs and Caucasians. ^

Tumor suppression and apoptosis of human prostate carcinoma mediated by a genetic locus within human chromosome 10pter-q11.

Prostate cancer is the second leading cause of male cancer deaths in the United States. Yet, despite a large international effort, little is known about the molecular mechanisms that underlie this devastating disease. Prostate secretory epithelial cells and androgen-dependent prostate carcinomas undergo apoptosis in response to androgen deprivation and, furthermore, most prostate carcinomas become androgen independent and refractory to further therapeutic manipulations during disease progression. Definition of the genetic events that trigger apoptosis in the prostate could provide important insights into critical pathways in normal development as well as elucidate the perturbations of those key pathways in neoplastic transformation. We report the functional definition of a novel genetic locus within human chromosome 10pter-q11 that mediates both in vivo tumor suppression and in vitro apoptosis of prostatic adenocarcinoma cells. A defined fragment of human chromosome 10 was transferred via microcell fusion into a prostate adenocarcinoma cell line. Microcell hybrids containing only the region 10pter-q11 were suppressed for tumorigenicity following injection of microcell hybrids into nude mice. Furthermore, the complemented hybrids undergo programmed cell death in vitro via a mechanism that does not require nuclear localization of p53. These data functionally define a novel genetic locus, designated PAC1, for prostate adenocarcinoma 1, involved in tumor suppression of human prostate carcinoma and furthermore strongly suggest that the cell death pathway can be functionally restored in prostatic adenocarcinoma.

Biomarqueurs pronostiques dans le cancer de la prostate : mieux prédire pour mieux traiter

Le cancer de la prostate (CP) est le cancer le plus fréquemment diagnostiqué en Amérique du Nord et est au troisième rang en termes de létalité chez les hommes. Suite aux traitements de première ligne, 20 à 30% des patients diagnostiqués avec un cancer localisé auront une récidive biochimique de la maladie. La déplétion androgénique mène fréquemment au développement du stade de résistance à la castration (RC). Ce dernier est associé avec une augmentation de la morbidité (métastases osseuses) et de la mortalité avec une survie moyenne inférieure à deux ans. L’évolution du CP est très hétérogène dans la population et il n’existe actuellement aucun biomarqueur pronostique permettant d’identifier les patients à risque de récurrence biochimique, de métastases osseuses et de développement d’une résistance à la castration. De nombreuses études ont démontré que les cytokines inflammatoires IL-6 et IL-8 jouent un rôle dans la pathogénèse du CP, notamment dans le développement de la résistance à la castration. Par ailleurs, les niveaux sériques élevés de ces cytokines ont été associés à un mauvais pronostic. Précédemment, notre laboratoire a démontré in vitro que la protéine IKKε entraîne une augmentation de la sécrétion de ces cytokines dans les cellules du CP et qu’elle est exprimée davantage dans les tissus de cancers plus avancés. Le premier objectif du présent mémoire fut d’évaluer dans des tissus humains la corrélation d’IKKε, IL-6 et IL-8 avec des paramètres cliniques. Nos résultats soulignent le potentiel d’IKKε comme biomarqueur tissulaire pronostique de récurrence biochimique et de métastases osseuses. Nous n’avons trouvé aucune association entre IL-6/IL-8 et les paramètres cliniques inclus dans l’étude. Le second objectif de ce projet fut d’évaluer la coexpression de ces trois molécules dans l’épithélium du CP. Nos résultats confirment les observations in vitro en mettant en évidence une forte association entre l’expression d’IKKε, IL-6 et IL-8. Le troisième objectif fut d’évaluer la relation entre les niveaux sériques et tissulaires d’IL-6 et d’IL-8. Aucune relation significative n’a été établie, suggérant que les cytokines sériques ne sont pas uniquement d’origine prostatique. En conclusion, mon projet de maîtrise aura permis de préciser le potentiel d’IKKε comme biomarqueur tissulaire pronostique et de valider pour la première fois dans des tissus humains sa co-expression avec les cytokines IL-6 et IL-8, dont le rôle dans la pathogénèse de la maladie est bien établi. Une étude plus exhaustive des voies de signalisation d’IKKε reste d’intérêt pour élucider notamment les mécanismes par lesquels IKKε stimule la production de cytokines et par quels moyens cette protéine pourrait être impliquée dans le développement d’un état résistant à la castration.

Resistance training and reduction of treatment side effects in prostate cancer patients

Purpose: To examine the effect of progressive resistance training on muscle function, functional performance, balance, body composition, and muscle thickness in men receiving androgen deprivation for prostate cancer. Methods: Ten men aged 59-82 yr on androgen deprivation for localized prostate cancer undertook progressive resistance training for 20 wk at 6- to 12-repetition maximum (RM) for 12 upper- and lower-body exercises in a university exercise rehabilitation clinic. Outcome measures included muscle strength and muscle endurance for the upper and lower body, functional performance (repeated chair rise, usual and fast 6-m walk, 6-m backwards walk, stair climb, and 400-m walk time), and balance by sensory organization test. Body composition was measured by dual-energy x-ray absorptiometry and muscle thickness at four anatomical sites by B-mode ultrasound. Blood samples were assessed for prostate specific antigen (PSA), testosterone, growth hormone (GH), cortisol, and hemoglobin. Results: Muscle strength (chest press, 40.5%; seated row, 41.9%; leg press, 96.3%; P < 0.001) and muscle endurance (chest press, 114.9%; leg press, 167.1%; P < 0.001) increased significantly after training. Significant improvement (P < 0.05) occurred in the 6-m usual walk (14.1%), 6-m backwards walk (22.3%), chair rise (26.8%), stair climbing (10.4%), 400-m walk (7.4%), and balance (7.8%). Muscle thickness increased (P < 0.05) by 15.7% at the quadriceps site. Whole-body lean mass was preserved with no change in fat mass. There were no significant changes in PSA, testosterone, GH, cortisol, or hemoglobin. Conclusions: Progressive resistance exercise has beneficial effects on muscle strength, functional performance and balance in older men receiving androgen deprivation for prostate cancer and should be considered to preserve body composition and reduce treatment side effects.

Calcitonin gene-related peptide, adrenomedullin and flushing

Administration of calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) can cause facial flushing, suggesting that the peptides may be important in hot flushes experienced particularly by post-menopausal women. Five studies have measured plasma CGRP concentrations in post-menopausal women who suffer from flushes; all demonstrated elevations of between 170% and 320% over control. Three of the studies showed a temporal relationship between flushes and CGRP elevation. A further study has shown that CGRP is elevated in the urine of women who suffer from flushes. Only a single study has investigated flushes in pre-menopausal women; no elevation of CGRP was observed. Flushes are also experienced by men undergoing androgen deprivation therapy. Whilst one study failed to find any increase in CGRP in the urine of these individuals, a small study has identified an increase in plasma CGRP. No studies have investigated plasma AM or the related peptide, intermedin/AM2. Overall, there is good evidence to show that flushes in post-menopausal women are accompanied by an increase in CGRP. CGRP could act centrally on the thermoregulatory centre of the hypothalamus as well as peripherally to cause vasodilation and sweating. However, it remains to be demonstrated that the elevated CGRP causes flushes. Recently developed CGRP antagonists provide an opportunity to test this hypothesis. If they are successful, they may represent a useful alternative to oestrogen replacement therapy.

TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer.

Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients.

Le blocage androgénique intermittent versus continu dans le traitement du cancer de la prostate

L’administration du blocage androgénique de façon intermittente pourrait offrir plusieurs avantages dans le traitement du cancer de la prostate. Toutefois, ce mode d’administration demeure controversé. Nous avons donc effectué une revue systématique et méta-analyse d’essais cliniques randomisés afin de comparer l’efficacité et la tolérabilité du blocage androgénique intermittent versus continu. Une analyse de non-infériorité a été effectuée pour la survie avec un seuil préétabli de 1,15 pour la borne supérieure de l’intervalle de confiance (IC). Au total, 15 études étaient éligibles. Le blocage androgénique intermittent était non inférieur au blocage androgénique continu avec un hazard ratio de 1,02 (IC à 95%: 0,93-1,11). Il y avait peu de différence entre les deux groupes pour la qualité de vie globale. Toutefois, plusieurs études ont rapporté une meilleure fonction physique et sexuelle avec le traitement intermittent. Le blocage androgénique intermittent est une alternative thérapeutique acceptable dans le cancer de la prostate.

Effect of investigation intensity and treatment differences on prostate cancer survivor's physical symptoms, psychological well-being and health-related quality of life: a two country cross-sectional study.

Aim: To investigate effects on men's health and well-being of higher prostate cancer (PCa) investigation and treatment levels in similar populations. Participants: PCa survivors in Ireland where the Republic of Ireland (RoI) has a 50% higher PCa incidence than Northern Ireland (NI). Method: A cross-sectional postal questionnaire was sent to PCa survivors 2–18 years post-treatment, seeking information about current physical effects of treatment, health-related quality of life (HRQoL; EORTC QLQ-C30; EQ-5D-5L) and psychological well-being (21 question version of the Depression, Anxiety and Stress Scale, DASS-21). Outcomes in RoI and NI survivors were compared, stratifying into ‘late disease’ (stage III/IV and any Gleason grade (GG) at diagnosis) and ‘early disease’ (stage I/II and GG 2–7). Responses were weighted by age, jurisdiction and time since diagnosis. Between-country differences were investigated using multivariate logistic and linear regression. Results: 3348 men responded (RoI n=2567; NI n=781; reflecting population sizes, response rate 54%). RoI responders were younger; less often had comorbidities (45% vs 38%); were more likely to present asymptomatically (66%; 41%) or with early disease (56%; 35%); and less often currently used androgen deprivation therapy (ADT; 2%; 28%). Current prevalence of incontinence (16%) and impotence (56% early disease, 67% late disease) did not differ between RoI and NI. In early disease, only current bowel problems (RoI 12%; NI 21%) differed significantly in multivariate analysis. In late disease, NI men reported significantly higher levels of gynaecomastia (23% vs 9%) and hot flashes(41% vs 19%), but when ADT users were analysed separately, differences disappeared. For HRQoL, in multivariate analysis, only pain (early disease: RoI 11.1, NI 19.4) and financial difficulties (late disease: RoI 10.4, NI 7.9) differed significantly between countries. There were no significant between-country differences in DASS-21 or index ED-5D-5L score. Conclusions: Treatment side effects were commonly reported and increased PCa detection in RoI has left more men with these side effects. We recommended that men be offered a PSA test only after informed discussion.

Identificazione di un nuovo meccanismo microRNA-dipendente di resistenza all'inibizione della via di segnale PI3K/AKT nel carcinoma della prostata

Benché le alterazioni della via PI3K/AKT siano molto sudiate a causa del loro ruolo nella tumorigenesi, e rappresentino pertanto un importante bersaglio terapeutico, i risultati di numerosi studi clinici con inibitori di PI3K o AKT sono finora deludenti, in parte a causa dell’insorgenza di resistenza provocata dall'interruzione dei circuiti di feedback negativo. In questo studio, abbiamo scoperto che l’inattivazione farmacologica di AKT in cellule di carcinoma prostatico PC3 porta alla down-regolazione di un microRNA con funzione di oncosoppressore, il miR-145-5p, e ad un drammatico aumento di espressione di uno dei suoi geni target, cioè N/KRas. E’ interessante sottolineare che questo microRNA è considerato un marker di progressione metastatica nel carcinoma prostatico, il cui livello di espressione aiuta a discriminare tra pazienti con iperplasia prostatica benigna e cancro alla prostata. Inoltre, la bassa espressione di miR-145 aumenta il rischio di progressione della malattia da localizzata a metastatica. La conferma che l’aumento di Ras, osservato sia in termini di mRNA che di proteina, è dipendente dalla caduta del miR-145-5p, è stata poi ottenuta tramite un modello di PC3 ingegnerizzate per ottenere il silenziamento inducibile del miR-145-5p. Tramite un array di fosfoproteine siamo poi stati in grado di verificare che l’aumento di Ras provoca la riattivazione della cascata di PI3K/AKT e di ERK. Dal punto di vista meccanicistico, quindi, lo studio ha portato all’identificazione di un nuovo meccanismo di resistenza adattativa, in cui l’inattivazione di AKT provoca una caduta del miR-145-5p che, a sua volta, aumenta l’espressione di Ras e riattiva il signaling di PI3K, rendendo inefficace il trattamento farmacologico. Questi risultati sono particolarmente rilevanti alla luce di recenti studi (NCT04493853; NCT03072238; NCT02525068) e di trial clinici in corso (NCT04737109; NCT03673787), basati sulla somministrazione combinata di inibitori della sintesi degli androgeni con gli inibitori di AKT capitasertib o ipatasertib.