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1.  A pilot phase II Study of digoxin in patients with recurrent prostate cancer as evident by a rising PSA 
Background
Digoxin was found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in a mouse model. We hypothesized that a therapeutic dose of digoxin could inhibit human PCa growth and disease progression.
Methods
An open label, single arm pilot study was performed. Patients (pts) with non-metastatic, biochemically relapsed PCa with prostate specific antigen doubling time (PSADT) of 3–24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone > 50 ng/dL at baseline. Digoxin was taken daily with dose titration to achieve a target therapeutic level (0.8 – 2 ng/ml); patients had routine follow-up including cardiac monitoring with 12-lead electrocardiograms (ECGs) and digoxin levels. The primary endpoint was the proportion of pts at 6 months post-treatment with a PSADT ≥ 200% from the baseline. HIF-1α downstream molecule vascular endothelial growth factor (VEGF) was measured in plasma.
Results
Sixteen pts were enrolled and 14 pts finished the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease >25% from baseline with a medium duration of 14 months. At 6 months, 5 of 13 (38%) pts had PSADT ≥ 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Two patients had durable PSA response for more than 1 year. Digoxin was well tolerated with possible relation of one grade 3 back pain. No patients had evidence of digoxin toxicity. The digoxin dose was lowered in 2 patients for significant ECGs changes (sinus bradycardia and QT prolongation), and there were probable digoxin-related ECG changes in 3 patients. Plasma VEGF was detected in 4 (25%) patients.
Conclusions
Digoxin was well tolerated and showed a prolongation of PSDAT in 38% of the patients. However, there was no significant difference comparing that of similar patients on placebo from historical data. Digoxin at the dose used in this study may have limited benefit for patients with biochemically relapsed prostate cancer.
PMCID: PMC4287984  PMID: 25580468
digoxin; prostate cancer; prostate specific antigen; PSA doubling time; HIF-1; VEGF
2.  Active Smoking May Negatively Affect Response Rate, Progression-Free Survival, and Overall Survival of Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib 
The Oncologist  2013;19(1):51-60.
An international multicenter retrospective study of sunitinib-treated metastatic renal cell carcinoma patients was performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. The results showed that active smoking may negatively affect the progression-free and overall survival of these patients.
Learning Objectives
Describe the association between risk factors for renal cell carcinoma and the outcome of sunitinib treatment for metastatic disease.Explain the impact of active smoking on the outcome of sunitinib-treated metastatic renal cell carcinoma.Discuss obesity, hypertension, and diabetes in relation to the outcome of sunitinib-treated metastatic renal cell carcinoma.
Background.
Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC).
Methods.
An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors.
Results.
Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002).
Conclusion.
Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.
doi:10.1634/theoncologist.2012-0335
PMCID: PMC3903056  PMID: 24309979
Active smoking; Metastatic renal cell carcinoma; Outcome; Sunitinib treatment
3.  Association of pretreatment neutrophil-to-lymphocyte ratio (NLR) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line docetaxel 
BJU international  2014;114(0):E11-E17.
Objective
To determine whether the pretreatment neutrophil-to-lymphocyte ratio (NLR), a measure of systemic inflammatory response, is associated with overall survival (OS) in men receiving chemotherapy with docetaxel for metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods
Records from 238 consecutive patients who were treated with first-line docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 (and who had adequate information to enable calculation of NLR) were reviewed.
Univariable and multivariable Cox regression models were used to predict OS after chemotherapy initiation.
Results
In univariable analyses, the NLR as a discrete variable (optimal threshold 3.0) was significantly associated with OS (P = 0.001).
In multivariable analyses, a lower NLR (≤3.0) was associated with lower risk of all-cause mortality (P = 0.002).
In Kaplan-Meier analysis, the median OS was higher (18.3 vs 14.4 months) in patients that did not have an elevated NLR than in those with an elevated NLR (log-rank; P < 0.001).
Conclusions
Men who were treated with first-line docetaxel for mCRPC who had a low pretreatment NLR (≤3.0) had significantly longer OS.
NLR may be a potentially useful clinical marker of systemic inflammatory response in predicting OS in men with mCRPC who receive docetaxel and may be helpful to stratify patients for clinical trials.
These findings derived from a retrospective analysis need to be validated in larger populations in prospective studies, and in the context of different therapies.
doi:10.1111/bju.12531
PMCID: PMC4004702  PMID: 24529213
neutrophil-to-lymphocyte ratio; prostate cancer; chemotherapy; metastatic castration-resistant prostate cancer; docetaxel; overall survival
4.  Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial 
The Lancet. Oncology  2013;14(9):893-900.
Background
Bone metastasis is a hallmark of advanced prostate cancer. The endothelin pathway has a mechanistic role in bone metastases. Atrasentan, an endothelin receptor antagonist, has reported activity in prostate cancer. We assessed the survival impact of atrasentan in castration resistant prostate cancer (CRPC) patients with bone metastases being treated with standard-of-care docetaxel.
Methods
Men with metastatic CRPC were stratified for progression type (PSA or radiologic), baseline pain, extra skeletal metastases and bisphosphonate use and randomised using double-blinded methodology on a 1:1 ratio to docetaxel with atrasentan or placebo for up to 12 cycles of 3 weeks and treated until progression or unacceptable toxicity. Non-progressing patients were permitted to continue atrasentan or placebo for up to 52 weeks. Co-primary endpoints were progression-free (PFS) and overall survival (OS) where 930 patients are needed to detect a 25% increase in median overall survival of 18 months with the addition of atrasentan (1-sided log-rank α=0.025, power 87%, 4 years accrual, 2.5 additional years of follow-up).
Results
1038 patents were accrued. Treatment was halted in April 2011, after an independent data safety monitoring committee pre-planned futility interim analysis. There was no significant difference in OS (HR=1.04 (95% CI 0.90,1.19) p=0.64) or PFS (HR=1.02 (95% CI 0.89,1.16) p=0.81). There was no significant difference between arms for RECIST or PSA response, treatment related deaths or grade 3 or more toxicity. Although 370 patients continued on blinded study drug after cessation of docetaxel, atrasentan did not significantly prolong post-chemotherapy OS in this subset.
Interpretation
Atrasentan, when added to docetaxel, does not improve overall or progression-free survival in men with castration-resistant prostate cancer and bone metastases.
doi:10.1016/S1470-2045(13)70294-8
PMCID: PMC4277263  PMID: 23871417
5.  Using the EORTC QLQ-C30 in Clinical Practice for Patient Management: Identifying Scores Requiring a Clinician’s Attention 
Purpose
Patient-reported outcomes (PROs) are used increasingly for individual patient management. Identifying which PRO scores require a clinician’s attention is an ongoing challenge. Previous research used a needs assessment to identify EORTC-QLQ-C30 cut-off scores representing unmet needs. This analysis attempted to replicate the previous findings in a new and larger sample.
Methods
This analysis used data from 408 Japanese ambulatory breast cancer patients who completed the QLQ-C30 and Supportive Care Needs Survey-Short Form-34 (SCNS-SF34). Applying the methods used previously, SCNS-SF34 item/domain scores were dichotomized as no vs. some unmet need. We calculated area under the receiver operating characteristic curve (AUC) to evaluate QLQ-C30 scores’ ability to discriminate between patients with no vs. some unmet need based on SCNS-SF34 items/domains. For QLQ-C30 domains with AUC≥0.70, we calculated the sensitivity, specificity, and predictive value of various cut-offs for identifying unmet needs. We hypothesized that compared to our original analysis (1) the same six QLQ-C30 domains would have AUC≥0.70, (2) the same SCNS-SF34 items would be best discriminated by QLQ-C30 scores, and (3) the sensitivity and specificity of our original cut-off scores would be supported.
Results
The findings from our original analysis were supported. The same six domains with AUC≥0.70 in the original analysis had AUC≥0.70 in this new sample, and the same SCNS-SF34 item was the best discriminated by QLQ-C30 scores. Cut-off scores were identified with sensitivity≥0.84 and specificity≥0.54.
Conclusion
Given these findings’ concordance with our previous analysis, these QLQ-C30 cut-offs could be implemented in clinical practice and their usefulness evaluated.
doi:10.1007/s11136-013-0387-8
PMCID: PMC3843980  PMID: 23532341
EORTC QLQ-C30; patient-reported outcomes; clinical practice; cancer
6.  Recent Time Trends in the Epidemiology of Stage IV Prostate Cancer in the United States: Analysis of Data From the Surveillance, Epidemiology, and End Results Program* 
Urology  2009;75(6):1396-1404.
OBJECTIVES
To describe recent epidemiologic trends in stage IV prostate cancer. Although advances in screening and diagnostic techniques have led to earlier detection of prostate cancer, a portion of patients still present with late-stage disease.
METHODS
Population-based cancer registry data from the Surveillance, Epidemiology, and End Results Program (cases from 1988 to 2003, follow-up through 2005) were used to calculate annual age-adjusted incidence rates of stage IV prostate cancer (overall and for the subset presenting with distant metastases) and to assess time trends in patient, tumor, and treatment characteristics and survival.
RESULTS
From 1988 to 2003, the age-adjusted incidence of stage IV prostate cancer significantly declined by 6.4% each year. The proportion of men diagnosed at younger ages, with poorly differentiated tumors, or who underwent a radical prostatectomy significantly increased over time. Five-year relative survival improved across the study period (from 41.6% to 62.3%), particularly in those diagnosed at younger ages or with moderately to well-differentiated tumors. Later years of diagnosis were independently associated with a decreased risk of death (from all causes and from prostate cancer specifically) after controlling for important patient, tumor, and treatment characteristics. Tumor grade and receipt of radical prostatectomy appeared to be the strongest independent prognostic indicators. Temporal trends were similar in the subset presenting with distant metastases, except that no significant improvement in survival was observed.
CONCLUSIONS
As younger men may expect to live longer with advanced prostate cancer, there remains a need to widen the range of therapeutic and supportive care options.
doi:10.1016/j.urology.2009.07.1360
PMCID: PMC4249683  PMID: 19969335
7.  The Effect of Prior Androgen Synthesis Inhibition on Outcomes of Subsequent Therapy with Docetaxel in Patients with Metastatic Castrate Resistant Prostate Cancer: Results from a Retrospective Analysis of a Randomized Phase 3 Clinical Trial (CALGB 90401) (Alliance) 
Cancer  2013;119(20):3636-3643.
Background
Preliminary data suggests a potential decreased benefit of docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients previously treated with abiraterone acetate, a novel androgen synthesis inhibitor (ASI). CALGB 90401 (Alliance), a phase 3 trial of mCRPC patients treated with docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes following docetaxel.
Methods
CALGB 90401 randomized 1050 men with chemotherapy-naïve, mCRPC to treatment with docetaxel and prednisone with either bevacizumab or placebo. 1005 men (96%) had data available regarding prior ketoconazole therapy. The effect of prior ketoconazole on overall survival (OS), progression-free survival (PFS), PSA decline, and objective response rate (ORR) observed was assessed using proportional hazards and Poisson regression method adjusted for validated prognostic factors and treatment arm.
Results
Baseline characteristics between patients with (N=277) and without (N=728) prior ketoconazole therapy were similar. There were no statistically significant differences between patients with and without prior ketoconazole therapy with respect to OS (median OS 21.1 vs. 22.3 months, stratified log-rank p-value=0.635); PFS (median PFS 8.1 vs. 8.6 months, stratified log-rank p-value=0.342); ≥50% PSA decline (61% vs. 66%, relative risk=1.09, adjusted p-value=0.129); or ORR (39% vs. 43%, relative risk=1.11, adjusted p-value=0.366).
Conclusions
As measured by OS, PFS, PSA and ORR, there is no evidence that prior treatment with ketoconazole impacts clinical outcomes in mCRPC patients treated with subsequent docetaxel-based therapy. Prospective studies are needed to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC.
doi:10.1002/cncr.28285
PMCID: PMC3795898  PMID: 23913744
8.  A Double Blind, Randomized, Neoadjuvant Study of the Tissue effects of POMx Pills in Men with Prostate Cancer Prior to Radical Prostatectomy 
Pomegranates slow prostate cancer xenograft growth and prolong PSA doubling times in single-arm human studies. Pomegranates’ effects on human prostate tissue are understudied. We hypothesized orally administered pomegranate extract (POMx; PomWonderful, Los Angeles, CA) would lower tissue 8-hydroxy-2-deoxyguanosine (8-OHdG), an oxidative stress biomarker. 70 men were randomized to 2 tablets POMx or placebo daily up to 4 weeks prior to radical prostatectomy. Tissue was analyzed for intra-prostatic Urolithin A, a pomegranate metabolite, benign and malignant 8-OHdG, and cancer pS6 kinase, NFκB, and Ki67. Primary end-point was differences in 8-OHdG powered to detect 30% reduction. POMx was associated with 16% lower benign tissue 8-OHdG (p=0.095), which was not statistically significant. POMx was well-tolerated with no treatment-related withdrawals. There were no differences in baseline clinicopathological features between arms. Urolithin A was detected in 21/33 patient in the POMx group vs. 12/35 in the placebo group (p=0.031). Cancer pS6 kinase, NFκB, Ki67, and serum PSA changes were similar between arms. POMx prior to surgery results in pomegranate metabolite accumulation in prostate tissues. Our primary end-point in this modest-sized short-term trial was negative. Future larger longer studies are needed to more definitely test whether POMx reduces prostate oxidative stress as well as further animal testing to better understand the multiple mechanisms through which POMx may alter prostate cancer biology.
doi:10.1158/1940-6207.CAPR-12-0423
PMCID: PMC3806642  PMID: 23985577
9.  Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer 
Cancer Medicine  2014;3(5):1322-1335.
Histone deacetylase inhibitors (HDACIs) are being tested in clinical trials for the treatment of solid tumors. While most studies have focused on the reexpression of silenced tumor suppressor genes, a number of genes/pathways are downregulated by HDACIs. This provides opportunities for combination therapy: agents that further disable these pathways through inhibition of residual gene function are speculated to enhance cell death in combination with HDACIs. A previous study from our group indicated that mitotic checkpoint kinases such as PLK1 and Aurora A are downregulated by HDACIs. We used in vitro and in vivo xenograft models of prostate cancer (PCA) to test whether combination of HDACIs with the pan-aurora kinase inhibitor AMG 900 can synergistically or additively kill PCA cells. AMG 900 and HDACIs synergistically decreased cell proliferation activity and clonogenic survival in DU-145, LNCaP, and PC3 PCA cell lines compared to single-agent treatment. Cellular senescence, polyploidy, and apoptosis was significantly increased in all cell lines after combination treatment. In vivo xenograft studies indicated decreased tumor growth and decreased aurora B kinase activity in mice treated with low-dose AMG 900 and vorinostat compared to either agent alone. Pharmacodynamics was assessed by scoring for phosphorylated histone H3 through immunofluorescence. Our results indicate that combination treatment with low doses of AMG 900 and HDACIs could be a promising therapy for future clinical trials against PCA.
doi:10.1002/cam4.289
PMCID: PMC4302682  PMID: 24989836
AMG 900; aurora kinase inhibitor; histone deacetylase inhibitors; prostate cancer; synergy; valproic acid; vorinostat
10.  Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors 
Epigenetics  2013;8(9):907-920.
Histone deacetylases (HDACs) have emerged as important targets for cancer treatment. HDAC-inhibitors (HDACis) are well tolerated in patients and have been approved for the treatment of patients with cutaneous T-cell lymphoma (CTCL). To improve the clinical benefit of HDACis in solid tumors, combination strategies with HDACis could be employed. In this study, we applied Analysis of Functional Annotation (AFA) to provide a comprehensive list of genes and pathways affected upon HDACi-treatment in prostate cancer cells. This approach provides an unbiased and objective approach to high throughput data mining. By performing AFA on gene expression data from prostate cancer cell lines DU-145 (an HDACi-sensitive cell line) and PC3 (a relatively HDACi-resistant cell line) treated with HDACis valproic acid or vorinostat, we identified biological processes that are affected by HDACis and are therefore potential treatment targets for combination therapy. Our analysis revealed that HDAC-inhibition resulted among others in upregulation of major histocompatibility complex (MHC) genes and deregulation of the mitotic spindle checkpoint by downregulation of genes involved in mitosis. These findings were confirmed by AFA on publicly available data sets from HDACi-treated prostate cancer cells. In total, we analyzed 375 microarrays with HDACi treated and non-treated (control) prostate cancer cells. All results from this extensive analysis are provided as an online research source (available at the journal’s website and at http://luigimarchionni.org/HDACIs.html). By publishing this data, we aim to enhance our understanding of the cellular changes after HDAC-inhibition, and to identify novel potential combination strategies with HDACis for the treatment of prostate cancer patients.
doi:10.4161/epi.25574
PMCID: PMC3883768  PMID: 23880963
analysis of functional annotation; HDACis; prostate cancer; mitotic spindle checkpoint; major histocompatibility complex; valproic acid; vorinostat; gene expression analysis
11.  Prevalence of Pain and Analgesic Use in Men With Metastatic Prostate Cancer Using a Patient-Reported Outcome Measure 
Journal of Oncology Practice  2013;9(5):223-229.
The authors' results provide a method for estimating accruals along the disease continuum, and for enabling design of trials appropriately powered to assess pain.
Purpose:
Contemporary tumor-directed therapies for metastatic castration-resistant prostate cancer (mCRPC) are approved to prolong life, but their effects on symptoms such as pain are less well understood as a result of the lack of analytically valid assessments of pain prevalence and severity, clinically meaningful definitions of therapeutic benefit, and methodologic standards of trial conduct. This study establishes pain characteristics in the mCRPC population using a PRO measure.
Materials and Methods:
Patients with prostate cancer participated in an anonymous survey at five US comprehensive cancer centers in the Prostate Cancer Clinical Trials Consortium that incorporated the Brief Pain Inventory (BPI), analgesic use, and interference with daily activities. Prevalence and severity of cancer-related pain and analgesic use were tabulated according to castration-resistant status and exposure to docetaxel chemotherapy.
Results:
Four hundred sixty-one patients with prostate cancer participated, of whom 147 had mCRPC involving bone (61% [89 of 147] docetaxel exposed, 39% [58 of 147] docetaxel naive). Pain of any level was more common among docetaxel-exposed versus docetaxel-naive patients with mCRPC (70% [62 of 89] v 38% [22 of 58], respectively; P < .001). BPI score ≥ 4 was reported by 38% (34 of 89) of docetaxel-pretreated and 24% (14 of 58) of docetaxel-naive patients with mCRPC; 40% of these patients with pain intensity ≥ 4 reported no current narcotic analgesic.
Conclusion:
Pain prevalence and severity were higher in patients with prior docetaxel exposure. Analgesics were underutilized. These results provide a method for estimating accruals along the disease continuum, and for enabling design of trials appropriately powered to assess pain.
doi:10.1200/JOP.2013.000876
PMCID: PMC3994234  PMID: 23943897
12.  Bone-targeting agents in prostate cancer 
Cancer metastasis reviews  2014;33(0):619-628.
Bone metastases are present in the vast majority of men with advanced prostate cancer, representing the main cause for morbidity and mortality. Recurrent or metastatic disease is managed initially with androgen deprivation but the majority of the patients eventually will progress to castration-resistant prostate cancer, with patients developing bone metastases in most of the cases. Survival and growth of the metastatic prostate cancer cells is dependent on a complex microenvironment (onco-niche) that includes the osteoblasts, the osteoclasts, the endothelium, and the stroma. This review summarizes agents that target the pathways involved in this complex interaction between prostate cancer and bone micro-environment and aim to transform lethal metastatic prostate cancer into a chronic disease.
doi:10.1007/s10555-013-9480-2
PMCID: PMC4087085  PMID: 24398856
Bone-targeting agents; Prostate cancer; Bone metastases
13.  An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer 
Investigational New Drugs  2014;32(6):1258-1268.
Summary
Background This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors. Methods Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m2). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated. Results CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m2. The MTD of CEP-11981 was determined to be 97.4 mg/m2, with DLTs observed at the 126.6 mg/m2 dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m2 and 1 patient at 126.6 mg/m2), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44 % patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m2. Conclusions In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.
doi:10.1007/s10637-014-0147-9
PMCID: PMC4226840  PMID: 25152243
Dose-finding study; Multitargeted inhibition; Safety profile; Tie-2; Tyrosine kinase inhibitor; Vascular endothelial growth factor
14.  Combining low-dose cyclophosphamide with GM-CSF–secreting prostate cancer immunotherapy enhances antitumor immune effects 
Prostate GVAX® is an allogeneic cell-based prostate cancer vaccine engineered to secrete GM-CSF. The release of GM-CSF by this immunotherapy serves to recruit dendritic cells, which then present tumor antigens to T cells, thus initiating antitumor immune responses. However, preclinical data show that, when used alone, cell-based immunotherapy is generally unable to break specific T-cell tolerance in tumor-bearing hosts. The study by Wada and colleagues employed an autochthonous prostate cancer mouse model to demonstrate that low-dose cyclophosphamide given prior to a cell-based GM-CSF–secreting vaccine (T-GVAX) abrogated immune tolerance, augmented prostatic CD8+ T-cell infiltration, mediated depletion of regulatory T cells (Tregs), and increased expression of dendritic cell maturation markers. In addition, this combination decreased the wet weight of mouse prostate glands, lowered histological tumor scores, and increased the density of apoptotic bodies. These findings add to existing data from other preclinical models showing enhancement of antitumor immunity when cyclophosphamide is administered in sequence with GM-CSF–secreting immunotherapy for the treatment of breast and pancreatic cancers. These studies provide a rationale for designing clinical trials that combine low-dose cyclophosphamide with GM-CSF–secreting cell-based immunotherapy in patients with prostate and other cancers.
doi:10.1517/13543780903530678
PMCID: PMC4124637  PMID: 20047504
antitumor immunity; cyclophosphamide; GVAX®; immunotherapy; prostate cancer
15.  Preclinical and Clinical Studies with the Multi-Kinase Inhibitor CEP-701 as Treatment for Prostate Cancer Demonstrate the Inadequacy of PSA Response as a Primary Endpoint 
Cancer biology & therapy  2007;6(9):1360-1367.
Purpose
CEP-701 is a potent inhibitor of trk receptors that causes cell death in prostate cancer (PC) models. CEP-701 binds to serum proteins and a preprostatectomy study was performed to assess prostate tissue penetration and clinical response to CEP-701.
Methods
Growth assays and Western blot analyses were performed to evaluate CEP-701 kinase inhibition. In a preprostatectomy study, patients received CEP-701 for five days prior to prostatectomy and prostate tissue analyzed for CEP-701 levels. A phase II dose escalation study was performed in patients with hormone refractory PC with rising PSA and no metastases. Endpoints included PSA response and safety.
Results
CEP-701 binds to serum proteins limiting tissue penetration. An oral dose of 40 mg bid of CEP-701 for five days produced levels of 219 ± 38 nM in prostate at time of prostatectomy. No patients in the Phase II study met the primary response criteria of >50% PSA decline. Seven/9 patients had increase in PSA slope on CEP-701 compared to PSA slope prestudy. Five/9 patients had a decrease in PSA levels after stopping CEP-701. Laboratory studies showed increased PSA production by CEP-701 growth arrested human PC cells in vitro and in vivo.
Conclusions
Evaluation of PSA response is an inadequate indicator of response in CEP-701 treated PC patients. Therefore, the effectiveness of CEP-701 as treatment for prostate cancer has not been adequately tested. Based on a strong preclinical rationale, further clinical studies with CEP-701 using alternative endpoints are indicated.
PMCID: PMC4124640  PMID: 17786033
prostate cancer; PSA; kinase; peceptor; CEP-701
16.  Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer 
Oncotarget  2014;5(15):6102-6112.
Mislocalization of proteins is a common feature of cancer cells. Since localization of proteins is tightly linked to its function, cancer cells can inactivate function of a tumor suppressor protein through mislocalization. The nuclear exportin CRM1/XPO 1 is upregulated in many cancers. Targeting XPO 1 can lead to nuclear retention of cargo proteins such as p53, Foxo, and BRCA1 leading to cell cycle arrest and apoptosis. We demonstrate that selective inhibitors of nuclear export (SINE) can functionally inactivate XPO 1 in prostate cancer cells. Unlike the potent, but toxic, XPO 1 inhibitor leptomycin B, SINE inhibitors (KPT-185, KPT-330, and KPT-251) cause a decrease in XPO 1 protein level through the proteasomal pathway. Treatment of prostate cancer cells with SINE inhibitors lead to XPO 1 inhibition, as evaluated by RevGFP export assay, leading to nuclear retention of p53 and Foxo proteins, consequently, triggering apoptosis. Our data reveal that treatment with SINE inhibitors at nanomolar concentrations results in decrease in proliferation and colonogenic capacity of prostate cancer cells by triggering apoptosis without causing any cell cycle arrest. We further demonstrate that SINE inhibitors can be combined with other chemotherapeutics like doxorubicin to achieve enhanced growth inhibition of prostate cancer cells. Since SINE inhibitors offer increased bioavailability, reduced toxicity to normal cells, and are orally available they can serve as effective therapeutics against prostate cancer. In conclusion, our data reveals that nucleocytoplasmic transport in prostate cancer can be effectively targeted by SINE inhibitors.
PMCID: PMC4171616  PMID: 25026284
Nucleocytoplasmic transport; CRM1; XPO 1; SINE inhibitors; prostate cancer
17.  Screening assay for blood vessel maturation inhibitors 
In cancer patients, the development of resistance to anti-angiogenic agents targeting the VEGF pathway is common. Increased pericyte coverage of the tumor vasculature undergoing VEGF targeted therapy has been suggested to play an important role in resistance. Therefore, reducing the pericytes coverage of the tumor vasculature has been suggested to be a therapeutic approach in breaking the resistance to and increasing the efficacy of anti-angiogenic therapies. To screen compound libraries, a simple in vitro assay of blood vessel maturation demonstrating endothelial cells and pericytes association while forming lumenized vascular structures is needed. Unfortunately, previously described 3-dimensional, matrix based assays are laborious and challenging from an image and data acquisition perspective. For these reasons they generally lack the scalability needed to perform in a high-throughput environment. With this work, we have developed a novel in vitro blood vessel maturation assay, in which lumenized, vascular structures form in one optical plane and mesenchymal progenitor cells (10T1/2) differentiate into pericyte-like cells, which associate with the endothelial vessels (HUVECs). The differentiation of the 10T1/2 cells into pericyte-like cells is visualized using a GFP reporter controlled by the alpha smooth muscle actin promoter (SMP-8). The organization of these vascular structures and their recruited mural cells in one optical plane allows for automated data capture and subsequent image analysis. The ability of this assay to screen for inhibitors of pericytes recruitment was validated. In summary, this novel assay of in vitro blood vessel maturation provides a valuable tool to screen for new agents with therapeutic potential.
doi:10.1016/j.bbrc.2013.07.077
PMCID: PMC4086510  PMID: 23892038
Angiogenesis model; Pericyte; Imatinib; Sunitinib; Endoglin; Drug screening; Blood vessel maturation
18.  Bioactivity of Autologous Irradiated Renal Cell Carcinoma Vaccines Generated by ex Vivo Granulocyte-Macrophage Colony-stimulating Factor Gene Transfer1 
Cancer research  1997;57(8):1537-1546.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.
PMCID: PMC4084516  PMID: 9108457
19.  A non-comparative randomized phase II study of two doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naïve prostate cancer 
Urologic oncology  2011;31(5):581-588.
Objective
ATN-224 (choline tetrathiomolybdate) is an oral Cu2+/Zn2+-superoxide dismutase 1 (SOD1) inhibitor with preclinical antitumor activity. We hypothesized that ATN-224 may induce antitumor effects as an antiangiogenic agent at low dose-levels while possessing direct antitumor activity at higher dose-levels. The objective of this study was to screen its clinical activity in patients with biochemically recurrent hormone-naïve prostate cancer.
Methods
Biochemically-recurrent prostate cancer patients with prostate specific antigen doubling times (PSADT) <12 months, no radiographic evidence of metastasis, and no hormonal therapy within 6 months (with serum testosterone levels >150 ng/dL) were eligible. ATN-224 was administered at two dose-levels, 300 mg (n=23) or 30 mg (n=24) daily, by way of randomization. PSA progression was defined as a ≥50% increase (and >5 ng/mL) in PSA from baseline or post-treatment nadir. Endpoints included the proportion of patients who were free of PSA progression at 24 weeks, changes in PSA slope/PSADT, and safety. The study was not powered to detect differences between the two treatment groups.
Results
At 24 weeks, 59% (95% CI 33–82%) of men in the low-dose arm and 45% (95% CI 17–77%) in the high-dose arm were PSA progression-free. Median PSA progression-free survival was 30 weeks (95% CI 21–40+) and 26 weeks (95% CI 24–39+) in the low-dose and high-dose groups, respectively. Pre- and on-treatment PSA kinetics analyses showed a significant mean PSA slope decrease (p=0.006) and a significant mean PSADT increase (p=0.032) in the low-dose arm only. Serum ceruloplasmin levels, a biomarker for ATN-224 activity, were lowered in the high-dose group, but did not correlate with PSA changes.
Conclusions
Low-dose ATN-224 (30 mg daily) may have biologic activity in men with biochemically-recurrent prostate cancer, as suggested by an improvement in PSA kinetics. However, the clinical significance of PSA kinetics changes in this patient population remains uncertain. The absence of a dose-response effect also reduces enthusiasm, and there are currently no plans to further develop this agent in prostate cancer.
doi:10.1016/j.urolonc.2011.04.009
PMCID: PMC3227793  PMID: 21816640
20.  Pharmacodynamic study of Disulfiram in Men with Non-metastatic Recurrent Prostate Cancer 
Prostate cancer and prostatic diseases  2013;16(4):10.1038/pcan.2013.28.
Background
Preclinical drug screens identified disulfiram as a potent in vitro inhibitor of prostate cancer cell growth. Although many mechanisms for its anticancer activity have been proposed, tumor suppressor gene re-expression through promoter demethylation emerged as one of the more plausible.
Methods
We conducted an open-label, dose escalation trial of disulfiram in men with non-metastatic recurrent prostate cancer after local therapy. Dose escalation occurred if a demethylating “response” [i.e. ≥10% decrease in peripheral blood mononuclear cell (PBMC) global 5meC content] was observed in <3 patients in cohort 1. Cohort 1 and 2 received disulfiram 250 mg and 500 mg daily respectively. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months, changes in PSA doubling time and safety/tolerability.
Results
Changes in global 5meC content were observed in 2 of 9 patients (22.2%) in cohort 1 and 3 of 10 (30.0%) in cohort 2. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. No changes in PSA kinetics were observed in either cohort. Disulfiram was poorly tolerated with 6 patients experiencing grade 3 AEs (3 per cohort). Three of the responders displayed pre-treatment instability in their 5meC content.
Conclusions
A minority of patients had transient global PBMC demethylation changes. Instability in 5meC may limit the reproducibility of these findings, limiting our ability to confirm our hypothesis. Given the toxicities and no clinical benefits, further development of disulfiram should not be pursued in this population.
doi:10.1038/pcan.2013.28
PMCID: PMC3830644  PMID: 23958896
Disulfiram; prostate cancer; epigenetics; demethylation; hypomethylation
21.  Novel targeted therapeutics for metastatic castration-resistant prostate cancer 
Cancer letters  2009;291(1):1-13.
Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5 years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor κB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents.
doi:10.1016/j.canlet.2009.08.012
PMCID: PMC4029098  PMID: 19717225
Metastatic castration-resistant prostate; cancer; Targeted therapies; Immune therapies; Molecular targets; Clinical trials; Drug development
22.  Immunoexpression status and prognostic value of mammalian target of rapamycin and hypoxia-induced pathway members in papillary cell renal cell carcinomas☆ 
Human pathology  2012;43(12):2129-2137.
Summary
Dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways has been consistently identified in clear cell renal cell carcinomas. However, experience with non–clear cell renal cell carcinoma subtypes is scant. In this study, we evaluated the immunohistochemical expression of upstream (PTEN and phosphorylated AKT) and downstream (phosphorylated S6 and 4EBP1) effectors of the mammalian target of rapamycin pathway, as well as related cell-cycle proteins (p27 and c-MYC), and a member of the hypoxia-induced pathway (HIF-1α) in 54 patients with papillary renal cell carcinoma treated by nephrectomy. PTEN was lower in tumor than in normal kidney, and loss of PTEN expression was found in 48% of the patients. In tumor tissues, phosphorylated S6, 4EBP1, and HIF-1α were higher than in normal kidney. Conversely, scores of p27 were lower in tumor than in normal kidney. Finally, scores of c-MYC and phosphorylated AKT were similar in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 24% and 11%, respectively. Tumor progression was observed in 17% of the patients. None of the tested biomarkers predicted cancer-specific mortality or tumor progression. As expected, patients with high T-stage tumors had higher hazard ratios for cancer-specific mortality (hazard ratio, 6.9) and tumor progression (hazard ratio, 6.7). Patients with higher Fuhrman grades also had higher risks for cancer-specific mortality (hazard ratio, 11.4) and tumor progression (hazard ratio, 4.5). In summary, our study provides evidence of dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways in papillary renal cell carcinoma. Immunohistochemistry for members of the mammalian target of rapamycin pathway and for HIF-1α lacked prognostic significance in our cohort.
doi:10.1016/j.humpath.2012.01.009
PMCID: PMC4029100  PMID: 22542128
Papillary renal cell carcinoma; mTOR; PTEN; AKT; S6; 4EBP1; HIF-1α
23.  Future Directions in Castrate-Resistant Prostate Cancer Therapy 
Clinical genitourinary cancer  2010;8(1):37-46.
Although several new therapies have recently become available for the treatment of castrate-resistant prostate cancer (CRPC), the disease remains universally incurable and demands novel therapeutic approaches. To this end, great strides have been made in our understanding of the biologic and molecular mechanisms driving prostate cancer growth and progression in the past few years, resulting in widespread clinical investigation of numerous new targeted therapies. This review will highlight some of the key therapeutic agents that (in the opinion of the authors) may have the largest effect on the future management of CRPC, with a focus on both molecular targets and clinical trial design. These agents include angiogenesis inhibitors, mTOR pathway inhibitors, apoptosis-inducing drugs, IGF pathway inhibitors, Src family inhibitors, Hedgehog pathway antagonists, epigenetic therapies, PARP inhibitors, and prodrug approaches. The future of CRPC therapy appears brighter than ever before.
doi:10.3816/CGC.2010.n.006
PMCID: PMC4029111  PMID: 21208854
Clinical trials; CRPC; Drug development; Targeted therapy
24.  Role of Immunotherapy for Renal Cell Cancer in 2011 
High-dose interleukin-2 (HD IL-2) and interferon were the most commonly administered therapies before the recent introduction of targeted agents, including vascular endothelial growth factor and mammalian target of rapamycin pathway inhibitors. Although the new agents result in a progression-free survival benefit, high-dose IL-2 remains the only agent with proven efficacy in producing durable complete and partial responses in patients with metastatic renal cell carcinoma (RCC). Furthermore, although the use of single-agent interferon has decreased significantly since the introduction of targeted therapy, it remains in the frontline setting in combination with bevacizumab as a result of 2 large phase III trials. Lastly, improved understanding of immune regulation has led to the advancement of targeted immunotherapy using immune checkpoint inhibitors that have shown promising activity and are moving forward in clinical development. This article focuses on the current status of immunotherapy in the management of metastatic RCC.
PMCID: PMC4020430  PMID: 21917625
Renal cell cancer; immunotherapy; interleukin; tumor immunity
25.  Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group 
Purpose
To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.
Methods
A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
Results
The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as “new lesions” or “no new lesions,” changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.
Conclusion
PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
doi:10.1200/JCO.2007.12.4487
PMCID: PMC4010133  PMID: 18309951

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