Therapy For Metastatic Prostate Cancer Research Articles

Retrospective Audit: Does Prior Assessment by Oral And Maxillofacial Surgeons Reduce the Risk of Osteonecrosis Of the Jaw in Patients Receiving Bone-Targeted Therapies For Metastatic Cancers To the Skeleton? – Part II

Men who receive bone-targeted therapy for metastatic prostate cancer are at increased risk of osteonecrosis of the jaw (ONJ). Development of ONJ has been associated with the administration of bone-targeted therapies in association with other risk factors. ONJ can be distressing for a patient because it can cause pain, risk of jaw fracture, body image disturbance, difficultly eating, and difficulty maintaining good oral hygiene. The aim of this article is to report results of an audit of prior assessment by oral and maxillofacial surgeons (OMFS) before initiation of bone-targeted therapies and whether it may reduce the risk of ONJ in patients receiving bone-targeted therapies for advanced cancers.

The Juxtaposition of Population Science and Individual Treatment Recommendations for Intermittent Androgen Deprivation Therapy.

Ever since it was discovered in the 1940s that androgens promoteprostatecancergrowth, testosteronesuppressionhasbeen the mainstay of therapy for metastatic prostate cancer.1 Initially, this was achieved by surgical removal of the testicles and later by medical therapy with blocking luteinizing hormonal–releasing hormonal therapy.Theadventofmedical therapyallowedtheability to suppress testosterone and then hold dosing to allow recoveryoftestosteronelevels,andpatientscouldthenberedosed whenthecancer recurredwithtestosteronerecovery.Therewas an initial thought that this “intermittent” dosing might prolong theefficacyof this therapy2 aswell as lead toabetterquality of life. Improved life quality is especially relevant given the myriad adverse effects of testosterone suppression, including hot flashes,weight gain,mooddisturbance, and fatigue over a longdurationof therapy formanymen—especiallyafter theadvent of the prostate-specific antigen (PSA) test and treatment of patients with only biochemical evidence of disease recurrence after prostatectomy or radiation therapy. Themeta-analysis conducted byMagnan et al3 is exhaustive, and the team is to be commended for the extensivework and appropriate use of the establishedmethodological guidelines assessing studies comparing intermittent androgen deprivation therapy (ADT)withcontinuousADTforprostate cancer.Oneclearoutput fromthismeta-analysis isdocumentation of the vast variability of both the quality of the trials and the patientpopulationsstudied.Theauthorshaveanalyzedthedata anddrawnconclusionsbasedonstatistical findingsusingpopulation science. In other words, they use statistical techniques to assess a population (rather than individuals) and arrive at a conclusion that they suggest is relevant to all patients. However, I propose that there is clinical uncertainty in the data. The fact that one of the largest andmost robust phase 3 studies, S9346, begins the “Conclusion” section of its abstract with“Our findingswere statistically inconclusive”4(p1314) could be construed as emblematic of this fact. It is with this uncertainty inmind that Ipropose the followingquestion:Canpopulation science guide well-informed individual treatment recommendations forwho should, andwho should not, undergo intermittentADT?Myanswer to this question is “No.”The following 2 case scenarios best illustrate this conundrum.

ID: 263: Loss of IL-6/Stat3 signalling drives metastatic prostate cancer in mice and men

Prostate cancer (PCa) is one of the most frequently diagnosed forms of cancer in men. The majority of newly diagnosed PCa are non-aggressive and it remains a clinical challenge to distinguish these from lethal cancers. Hyperactive IL-6/Stat3 signalling is thought to be an important driving force in PCa. However, targeting of the IL-6/Stat3 axis in PCa patients failed to elicit therapeutic benefit. Here, we tested the hypothesised oncogenic role of IL-6/Stat3 in PCa progression. Surprisingly, we find that genetic inactivation of IL-6 or Stat3 dramatically promotes PCa cancer progression leading to widespread metastasis formation. Mechanically, IL-6/Stat3 signaling activates p19ARF-triggered senescence and directly regulates ARF-MDM2-p53 axis. Intriguingly, in vivo blocking of IL-6/STAT3 signalling by the JAK1/2 inhibitor ruxolitinib in human LNCaP xenografts showed significantly enhanced tumour size and weight. The ruxolitinib-treated xenografts also had markedly increased numbers of Ki-67+ cancer cells accompanied by a decrease in STAT3 and p14ARF expression. In human biopsies and metastatic specimens, we find massive loss of Stat3 and p14ARF expression, the human homologue of murine p19ARF, significantly correlating our findings with a high risk of disease recurrence. These findings identify STAT3 and ARF as powerful markers (potential biomarkers) to stratify high from low-risk PCa patients. Our findings of IL-6/STAT3-regulated ARF tumour suppressive pathway point to risk of anti-IL-6 inhibition as therapy in metastatic prostate cancer.

Abstract 677: Possible role of nimbolide in prevention and therapy of prostate cancer

Abstract Prostate cancer is one of the most commonly diagnosed cancers worldwide. Current therapies for metastatic prostate cancer are only marginally effective, and hence novel treatment modalities are urgently needed. Considerable evidence suggests that chronic inflammation plays a pivotal role in the development and progression of prostate cancer. Thus agents that can suppress these inflammatory mediators could form the basis of novel therapy for prostate cancer patients. In our study, we focused on analyzing the potential anticancer effects of nimbolide, a terpenoid lactone derived from Azadirachta indica (Neem tree) against prostate cancer. Data from the in vitro studies indicated that nimbolide could inhibit cell proliferation, induce apoptosis and suppress cellular invasion and migration. Interestingly, nimbolide also abrogated the activation of pro-inflammatory STAT3 transcription factor, and this effect was found to be mediated via an increased production of reactive oxygen species (ROS), whereas depletion of ROS attenuated p-STAT3 inhibitory effects of the drug. The in vivo efficacy of nimbolide was also analyzed in transgenic adenocarcinoma of mouse prostate (TRAMP) model, in which this triterpenoid significantly suppressed the tumor progression and growth without exhibiting any significant adverse effects. Overall our findings indicate that nimbolide exhibits significant anticancer effects in prostate cancer, and these effects may be mediated at least in part through the modulation of STAT3 signaling pathway. Citation Format: Jingwen Zhang, Muthu K. Shanmugam, Amudha Deivasigamani, Alan P. Kumar, Kam M. Hui, Gautam Sethi. Possible role of nimbolide in prevention and therapy of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 677. doi:10.1158/1538-7445.AM2015-677

Early side effects and first results of radioligand therapy with (177)Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre study.

BackgroundRadioligand therapy (RLT) with 177Lu-DKFZ-617 PSMA (Lu-PSMA) (prostate-specific membrane antigen) is a novel targeted therapy of metastatic prostate cancer. We analysed retrospectively the early side effects and the response rate in the first patients, who received a therapy with Lu-PSMA in our departments.MethodsRLT was performed in ten hormone- and/or chemo-refractory patients with distant metastases and progressive disease (mean age 73.5 years). 68Ga-PSMA HBED-CC PET/CT was performed in all patients prior to RLT. The median PSA level prior to the therapy was 298.5 ng/ml (range 5–853 ng/ml). All patients received CBC, renal and liver function tests the day before and 2 days after application (mean administered activity 5.6 GBq, range 4.1–6.1 GBq), followed by further tests every 2 weeks. All patients were contacted by telephone every week regarding side effects or any positive and negative changes.ResultsEight weeks after the therapy, seven patients (70 %) experienced a PSA decline, of whom six experienced more than 30 % and five more than 50 %. Three patients showed a progressive disease according to the PSA increase. No patient experienced any side effects immediately after injection of Lu-PSMA. Relevant hematotoxicity (grade 3 or 4) occurred 7 weeks after the administration in just one patient. The same patient showed a leucopenia grade 2. Two patients showed a disturbance of only 1 hematologic cell line, whereas one patient showed a reduction of grades 1 and 2 in leucocytes and thrombocytes, respectively. Six patients did not show any hematotoxicity during the 8 weeks after therapy. There was no relevant nephrotoxicity (grade 3 or 4).ConclusionsOur initial results indicate that RLT with Lu-PSMA is safe and seems to have low early side-effect profile. A relevant PSA decline was detected in 70 % of patients.

Clinical outcomes and nadir prostate-specific antigen (PSA) according to initial PSA levels in primary androgen deprivation therapy for metastatic prostate cancer.

To investigate the clinical outcomes of metastatic prostate cancer patients and the relationship between nadir prostate-specific antigen (PSA) levels and different types of primary androgen deprivation therapy (PADT). This study utilized data from the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database. A total of 2982 patients treated with PADT were enrolled. Kaplan-Meier analysis was used to compare progression-free survival (PFS) and overall survival (OS) in patients treated using combined androgen blockade (CAB) and non-CAB therapies. The relationships between nadir PSA levels and PADT type according to initial serum PSA levels were also investigated. Among the 2982 enrolled patients, 2101 (70.5 %) were treated with CAB. Although CAB-treated patients had worse clinical characteristics, their probability of PFS and OS was higher compared with those treated with a non-CAB therapy. These results were due to a survival benefit with CAB in patients with an initial PSA level of 500-1000 ng/mL. Nadir PSA levels were significantly lower in CAB patients than in non-CAB patients with comparable initial serum PSA levels. A small survival benefit for CAB in metastatic prostate cancer was demonstrated in a Japanese large-scale prospective cohort study. The clinical significance of nadir PSA levels following PADT was evident, but the predictive impact of PSA nadir on OS was different between CAB and non-CAB therapy.

Randomised phase 3 trial of enzalutamide in first line androgen deprivation therapy for metastatic prostate cancer: the ANZUP ENZAMET Trial (ANZUP 1304).

Randomised phase 3 trial of enzalutamide in first line androgen deprivation therapy for metastatic prostate cancer: the ANZUP ENZAMET Trial (ANZUP 1304).

Radical Prostatectomy or External Beam Radiation Therapy vs No Local Therapy for Survival Benefit in Metastatic Prostate Cancer: A SEER-Medicare Analysis

We assessed survival after radical prostatectomy, intensity modulated radiation therapy or conformal radiation therapy vs no local therapy for metastatic prostate cancer adjusting for patient comorbidity, androgen deprivation therapy and other factors. We identified men 66 years old or older with metastatic prostate cancer treated with radical prostatectomy, intensity modulated radiation therapy, conformal radiation therapy or no local therapy in the SEER-Medicare linked database from 2004 to 2009. Multivariable Cox proportional hazards models before and after inverse propensity score weighting were used to assess all cause and prostate cancer specific mortality. Competing risk regression analysis was done to assess prostate cancer specific mortality. Of 4,069 men with metastatic prostate cancer radical prostatectomy in 47, intensity modulated radiation therapy in 88 and conformal radiation therapy in 107 were selected as local therapy vs no local therapy in 3,827. Radical prostatectomy was associated with a 52% decrease (HR 0.48, 95% CI 0.27-0.85) in the risk of prostate cancer specific mortality after adjusting for sociodemographics, primary tumor characteristics, comorbidity, androgen deprivation therapy and bone radiation within 6 months of diagnosis. Intensity modulated radiation therapy was associated with a 62% decrease (HR 0.38, 95% CI 0.24-0.61) in the risk of prostate specific cancer specific mortality. Conformal radiation therapy was not associated with improved survival compared to no local therapy. Propensity score weighting yielded comparable results. Competing risk analysis revealed a 42% and 57% decrease (SHR 0.58, 95% CI 0.35-0.95 and SHR 0.43, 95% CI 0.27-0.68, respectively) in the risk of prostate cancer specific mortality for radical prostatectomy and intensity modulated radiation therapy. Local therapy with radical prostatectomy and intensity modulated radiation therapy but not with conformal radiation therapy was associated with a survival benefit in men with metastatic prostate cancer. This finding warrants prospective evaluation in clinical trials.

Changes in Skeletal Tumor Activity on (18)F-choline PET/CT in Patients Receiving (223)Radium Radionuclide Therapy for Metastatic Prostate Cancer.

Radium-223 dichloride is an alpha-emitting radiopharmaceutical shown to prolong survival in patients with castrate-resistant prostate cancer (CRPC) and symptomatic skeletal metastases. This report describes in two patientsthe acute changes in bone metastatic activity detected by F-18 choline PET/CT imaging midway during treatment with radium-223 dichloride. In addition to visual and standardized uptake value analysis, changes in the whole-body tumor burden were quantified by measuring the difference in net metabolically active tumor volume (MATV) and total lesion activity (TLA) between pre- and mid-treatment PET scans. After the third dose of radium-223 dichloride, near-total disappearance of abnormal skeletal activity was observed in one case (net MATV change from 260.7 to 0.8cc; net TLA change from 510.7 to 2.1), while a heterogeneous tumor response was observed in the other (net MATV change from 272.2 to 241.3cc; net TLA change from 987.1 to 779.4). Corresponding normalization and persistent elevation in serum alkaline phosphatase levels were observed in these cases, respectively. Further research is needed to determine the predictive value of serial F-18 choline PET/CT imaging in patients receiving radium-223 dichloride for CRPC.

Effects of statin use on the response duration to androgen deprivation therapy in metastatic prostate cancer.

PurposeTo determine whether statin use delays the development of castration-resistant prostate cancer (CRPC) in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT).Materials and MethodsA total of 171 patients with metastatic prostate cancer at the time of diagnosis who were treated with ADT between January 1997 and December 2013 were retrospectively analyzed. The patients were classified into two groups: the nonstatin use group (A group) and the statin use group (B group). Multivariate analysis was performed on statin use and other factors considered likely to have an effect on the time to progression to CRPC.ResultsThe mean patient age was 67.1±9.1 years, and the mean follow-up period was 52 months. The mean initial prostate-specific antigen (PSA) level was 537 ng/mL. Of the 171 patients, 125 (73%) were in group A and 46 (27%) were in group B. The time to progression to CRPC was 22.7 months in group A and 30.5 months in group B, and this difference was significant (p=0.032). Blood cholesterol and initial PSA levels did not differ significantly according to the time to progression to CRPC (p=0.288, p=0.198). Multivariate analysis using the Cox regression method showed that not having diabetes (p=0.037) and using a statin (p=0.045) significantly increased the odds ratio of a longer progression to CRPC.ConclusionsStatin use in metastatic prostate cancer patients appears to delay the progression to CRPC. Large-scale, long-term follow-up studies are needed to validate this finding.

Current and Emerging Therapies in Metastatic Prostate Cancer

The face of metastatic prostate cancer (PC) has been remarkably reshaped with the current advances in its management. Kudos to the cuttingedge research that has pinpointed new targets and agents. The main stumbling block in this disease is progression on androgen deprivation therapy (ADT) and the development of castrate resistance. Despite this phenomenon, the majority of patients with PC continue to rely on androgen receptors (ARs) for disease growth and progression. Several of these newer agents directly or indirectly target ARs. Many drugs have earned US Food and Drug Administration (FDA) approval in the past decade by showing survival benefit, which is the gold standard endpoint in all the pivotal PC trials. An array of new targets and agents are being explored currently. The future of metastatic castration-resistant prostate cancer (mCRPC) appears exciting with the expanding armamentarium; however, the challenges of affordability and sequencing of the agents remain.

Abstract 3790: Artesunate inhibits multiple proinflammatory transcription factors leading to the suppression of growth and induction of apoptosis in prostate cancer cells

Abstract Prostate cancer (PCa) is common and a frequent cause of cancer death among men worldwide. Moreover, PCa rates have risen quite significantly in the last decade in Singapore men and although some of the increase can be attributed to enhanced detection, much of the increased incidence is associated with genetic alterations and life-style related factors. Current therapies for metastatic prostate cancer are only marginally effective, and hence new treatment modalities are urgently needed. Considerable evidence suggests that chronic inflammation plays a pivotal role in the development and progression of PCa. Thus, the agents that can suppress inflammatory mediators have a potential in treatment of PCa. One way to expedite drug development is to find new uses for drugs already in clinical use. Hence we propose to investigate the role of artesunate, (a drug approved for the treatment of multidrug-resistant malaria) in PCa using diverse prostate cancer cell lines. In this study, we investigated the effect of artesunate (ART) primarily on signal transducer and activator of transcription 3(STAT3) signaling pathway in both androgen independent (DU145) and androgen dependent (LNCaP) PCa cell lines and also prospectively tested the hypothesis of NF-κB and STAT3 inhibition using a virtual predictive functional proteomics tumor pathway technology platform. We found that ART inhibited constitutive and IL-6-induced activation of STAT3 in DU145 and LNCaP cells in a dose and time dependent manner. We observed that STAT3 suppression by ART was mediated through the inhibition of activation of upstream kinases such as (c-Src, JAK1, and JAK2) and generation of reactive oxygen species (ROS) was also involved in this process. Our preliminary findings further indicate that ART also suppressed constitutive NF-κB activation in PCa cells. ART exhibited significant anti-proliferative effects and abrogated the migratory/invasive potential of PCa cells. Moreover, ART down-regulated the expression of various NF-κB and STAT3 regulated gene products involved in proliferation, survival and angiogenesis, also induced apoptosis in PCa cells lines as evident by DNA fragmentation and Annexin V staining. Overall our preliminary results from experimental and predictive studies indicate that ART mediates its anti-tumor effects through suppression of NF-κB and STAT3 pathways in PCa. Citation Format: Alamelu Nachiyappan, Muthu K Shanmugam, Feng Li, Alan Prem Kumar, Gautam Sethi. Artesunate inhibits multiple proinflammatory transcription factors leading to the suppression of growth and induction of apoptosis in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3790. doi:10.1158/1538-7445.AM2014-3790

Abstract SY13-03: Signal pathways in prostate cancer stem cells

Abstract New therapeutic strategies are needed to treat prostate cancer as it progresses to the castration resistant stage following treatment with drugs to reduce androgen production or interfere with androgen receptor function. Genetic analyses of DNA alterations and RNA expression show that multiple pathways can be involved in this cancer progression. An understanding of the cellular components needed to initiate prostate cancer and sustain it during the process of metastasis may help to elucidate new pathways for therapy. We have developed techniques to transform mouse and human benign prostate epithelial basal stem cells and define them as one cell of origin which can respond to multiple stimuli to produce cancers which are capable of maturing to more differentiated cell types including luminal, squamous and neuroendocrine phenotypes. Different subtypes of cells with the properties of cancer stem cells capable of transplantation of the cancer phenotype have been defined. Current work is focusing on the activation of specific kinase driven pathways to provide new targets for therapy in metastatic prostate cancer. We previously demonstrated that castration resistant prostate cancer (CRPC) tissues exhibit increased tyrosine phosphorylation, suggesting that enhanced tyrosine kinase activity may contribute to advanced disease. To identify specific kinase activation patterns in metastatic CRPC, we utilized phospho-tyrosine peptide enrichment and quantitative mass spectrometry using tissue from CRPC patients obtained at rapid autopsy. Evaluation of these rare metastatic CRPC samples for tyrosine phosphorylation and kinases revealed activated SRC, EGFR, RET, ALK, and other targets. Importantly, these kinase activation patterns exhibited intrapatient similarity and interpatient heterogeneity implying clonal origins of these lesions. To evaluate the function of these kinases in metastatic CRPC, we are analyzing their role during specific steps of the metastatic cascade. We hope our approach will improve an understanding of the mechanistic role of kinase activation in prostate cancer and identify promising therapeutic strategies targeting non-mutated kinases for metastatic CRPC. Citation Format: Owen N. Witte. Signal pathways in prostate cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY13-03. doi:10.1158/1538-7445.AM2014-SY13-03

Prostate cancer: the best fit for enzalutamide in metastatic prostate cancer.

The PREVAIL trial compared enzalutamide and placebo in patients with metastatic castration-resistant prostate cancer who had not received prior chemotherapy, demonstrating an improvement in overall survival and other clinical, radiographic, and biochemical outcomes. Herein, the implications of these data in the rapidly changing landscape of metastatic prostate cancer therapy are discussed.

Pharmacologic Suppression of JAK1/2 by JAK1/2 Inhibitor AZD1480 Potently Inhibits IL-6–Induced Experimental Prostate Cancer Metastases Formation

Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a cytokine that has been linked with prostate cancer pathogenesis by multiple studies. However, the direct functional roles of IL-6 in prostate cancer growth and progression have been unclear. In the present study, we show that IL-6 is produced in distant metastases of clinical prostate cancers. IL-6-activated signaling pathways in prostate cancer cells induced a robust 7-fold increase in metastases formation in nude mice. We further show that IL-6 promoted migratory prostate cancer cell phenotype, including increased prostate cancer cell migration, microtubule reorganization, and heterotypic adhesion of prostate cancer cells to endothelial cells. IL-6-driven metastasis was predominantly mediated by Stat3 and to lesser extent by ERK1/2. Most importantly, pharmacologic inhibition of Jak1/2 by AZD1480 suppressed IL-6-induced signaling, migratory prostate cancer cell phenotypes, and metastatic dissemination of prostate cancer in vivo in nude mice. In conclusion, we demonstrate that the cytokine IL-6 directly promotes prostate cancer metastasis in vitro and in vivo via Jak-Stat3 signaling pathway, and that IL-6-driven metastasis can be effectively suppressed by pharmacologic targeting of Jak1/2 using Jak1/2 inhibitor AZD1480. Our results therefore provide a strong rationale for further development of Jak1/2 inhibitors as therapy for metastatic prostate cancer.

Androgen receptor antagonists for prostate cancer therapy

Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.

To Treat or Not to Treat, That Is the Question: The Role of Bone-Targeted Therapy in Metastatic Prostate Cancer

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 62-year-old construction site manager experienced 6 weeks of back pain that was not responsive to over-the-counter nonsteroidal anti-inflammatory medications. He visited his wife's primary care physician for evaluation. He denied neurologic symptoms or worsening of pain while lying down. He smoked (30 pack-years, quit 4 years ago), and drinks 3 beers each evening and more on weekends (up to a six-pack). He has had two lower extremity fractures from falls at construction sites. At the time of the physical examination, he was 5 feet 11 inches tall and weighed 194 pounds. He was alert, oriented, and in mild distress. He had no percussion tenderness of his spine, and a neurologic examination was negative. A digital rectal examination revealed an enlarged prostate with an area of induration of the left, normal rectal tone, and guaiac-negative stool. Laboratory studies included normal blood counts, electrolytes, and renal and liver function tests (including lactic acid dehydrogenase and total protein). The prostate-specific antigen (PSA) was 114 ng/mL; he had no prior PSA test. A bone scan showed diffuse bony involvement including the T7 vertebral body and left pedicle, ribs, pelvis, and calvarium. Magnetic resonance imaging of his spine confirmed bone metastases but showed no evidence of extension into the epidural space or spinal cord compromise. A prostate biopsy revealed Gleason 4+4 adenocarcinoma of the prostate. Androgen deprivation therapy with leuprolide acetate was initiated, and the addition of a bone-targeted agent was considered.

The role of local therapy for metastatic prostate cancer

A lack of evidence exists regarding the role of nonsystemic treatments for men with metastatic prostate cancer. According to a recently published series of patients with metastatic disease at diagnosis, primary tumour treatment could improve rates of patient survival.

Distribution and geographic accessibility of prostate cancer clinical trials in the United States.

59 Background: An extremely small proportion of patients with cancer in the United States (US) enroll in clinical trials. While several barriers to trial accrual have been described, the geographic distribution and accessibility of clinical trial sites has not been comprehensively explored. Methods: ClinicalTrials.gov was queried to identify all active US clinical trials exploring first-line therapies for metastatic prostate cancer (PCa) on 9/16/2012. We evaluated the geographic distribution of trial sites and determined the relationship between the number of sites and the number of patients with advanced PCa per county and evaluated heterogeneity using Lorenz curves. We also estimated the minimum driving distance required to access a clinical trial site from each ZIP code in the continguous US; a distance >30 miles was defined as high travel burden consistent with prior studies. Results: We identified 958 sites associated with 42 PCa clinical trials (Table). The geographic distribution of clinical trial sites was very inhomogeneous with several states having only 1-2 trial sites. Among 3185 US counties, 2,669 (83.8%) had no clinical trials available for first-line treatment of metastatic PCa. Counties with larger populations of patients with advanced PCa had significantly higher numbers of clinical trial sites. For every 100 additional patients with advanced PCa per county, the number of available trial sites increased by 21.0% (95% CI: 16.5-25.7%). However, Lorenz curves indicated a high degree of inequality in trial accessibility (Gini index 0.71). Approximately 31% of the US population resided >30 miles from a PCa trial site. Conclusions: Clinical trials sites are poorly accessible, geographically, to a large subset of US PCa patients, a finding that likely contributes to dismal accrual. Innovative solutions are required to address geographic barriers to access. [Table: see text]

GATA2 as a potential metastasis-driving gene in prostate cancer

Effective treatment for metastatic prostate cancer is critically needed. The present study was aimed at identifying metastasis-driving genes as potential targets for therapy (oncotargets). A differential gene expression profile of metastatic LTL-313H and non-metastatic LTL-313B prostate cancer tissue xenografts, derived from one patient's specimen, was subjected to integrative analysis using the Ingenuity Upstream Regulator Analysis tool. Six candidate master regulatory genes were identified, including GATA2, a gene encoding a pioneer factor, a special transcription factor facilitating the recruitment of additional transcription factors. Elevated GATA2 expression in metastatic prostate cancer tissues correlated with poor patient prognosis. Furthermore, GATA2 gene silencing in human prostate cancer LNCaP cells led to a marked reduction in cell migration, tissue invasion, focal adhesion disassembly and to a dramatic change in cell transcriptomes, indicating that GATA2 plays a critical role in prostate cancer metastasis. As such, GATA2 could represent a prostate cancer metastasis-driving gene and a potential target for therapy of metastatic prostate cancer.