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1.  The Effect of Therapeutic Anticoagulation on Overall Survival in Men Receiving First-Line Docetaxel Chemotherapy for Metastatic Castration-Resistant Prostate Cancer 
Clinical genitourinary cancer  2014;13(1):32-38.
We examined the effect of therapeutic anticoagulation on overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line docetaxel chemotherapy. Anticoagulant use (low-molecular-weight heparin [LMWH] or warfarin) was retrospectively ascertained from a large single-institution database; all patients who were prescribed anticoagulants had a clinical indication for anticoagulation (ie, deep vein thrombosis or pulmonary embolism, or both). Our study found that anticoagulant use was an independent predictor of improved survival in men with mCRPC receiving docetaxel.
Background
Anticoagulants have been postulated to possess antitumor activity, although clinical data supporting this claim are conflicting. No definitive data exist on the clinical impact of anticoagulation therapy in patients with prostate cancer. The aim of this study was to investigate the association between therapeutic anticoagulant use and survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel chemotherapy.
Patients and Methods
We retrospectively reviewed the records of 247 consecutive patients with mCRPC who received first-line docetaxel chemotherapy between 1998 and 2010 at a single institution. Among them, 29 patients (11.7 %) received therapeutic anticoagulation (low-molecular-weight heparin [LMWH] or warfarin) for the treatment of venous thromboembolism. Univariate and multivariable Cox proportional hazards regression models were used to investigate the effect of anticoagulant use on overall survival.
Results
In univariate analysis, anticoagulant use was associated with improved survival (hazard ratio [HR], 0.61; P = .024). Median survival was 20.9 months in the anticoagulation group versus 17.1 months in the control group (P = .024). In multivariable analysis, anticoagulant use remained a significant predictor of survival after adjusting for other baseline prognostic factors (HR, 0.49; P = .023). When each anticoagulant was considered separately in the multivariable model, LMWH remained significantly prognostic for survival (HR, 0.48; P = .035), whereas warfarin use did not.
Conclusions
Anticoagulant use (LMWH in particular) is an independent predictor of improved survival in men with mCRPC receiving docetaxel. These data provide the impetus to further explore the antitumor properties of anticoagulants in patients with prostate cancer and warrant validation in prospective studies.
doi:10.1016/j.clgc.2014.04.008
PMCID: PMC4332782  PMID: 24999166
Anticoagulation; Docetaxel; Metastatic castration-resistant prostate cancer; Overall survival
2.  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
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.  Enzalutamide in chemo-naïve castration-resistant prostate cancer: effective for most but not for all 
Asian Journal of Andrology  2014;16(6):807-808.
Continued research in the treatment of castration-resistant prostate cancer (CRPC) has allowed for a clearer understanding of this disease entity and further treatment advances. In a study recently published by Beer et al.1 in the New England Journal of Medicine, another advance to treatment was demonstrated for the androgen receptor (AR) signaling inhibitor, enzalutamide, in patients with chemotherapy-naïve metastatic CRPC. Although a large majority of patients responded favorably to enzalutamide in the prechemotherapy setting, a small but significant proportion of patients demonstrated no meaningful benefit to this agent. This highlights an important concept in the understanding of this disease: inherent and acquired resistance to AR-targeting therapies.
doi:10.4103/1008-682X.137680
PMCID: PMC4236319  PMID: 25155108
5.  Growth factor and signaling pathways and their relevance to prostate cancer therapeutics 
Cancer metastasis reviews  2014;33(0):581-594.
Treatments that target the androgen axis represent an effective strategy for patients with advanced prostate cancer, but the disease remains incurable and new therapeutic approaches are necessary. Significant advances have recently occurred in our understanding of the growth factor and signaling pathways that are active in prostate cancer. In conjunction with this, many new targeted therapies with sound pre-clinical rationale have entered clinical development and are being tested in men with castration-resistant prostate cancer. Some of the most relevant pathways currently being exploited for therapeutic gain are HGF/c-Met signaling, the PI3K/AKT/mTOR pathway, Hedgehog signaling, the endothelin axis, Src kinase signaling, the IGF pathway, and angiogenesis. Here, we summarize the biological basis for the use of selected targeted agents and the results from available clinical trials of these drugs in men with prostate cancer.
doi:10.1007/s10555-013-9475-z
PMCID: PMC4090293  PMID: 24402967
Prostate cancer; Angiogenesis; mTOR; c-Met; Hedgehog pathway; Insulin-like growth factor pathway
6.  Very high risk localized prostate cancer: definition and outcomes 
Purpose
Outcomes in men with NCCN high-risk prostate cancer (PCa) can vary substantially--some will have excellent cancer-specific survival, whereas others will experience early metastasis even after aggressive local treatments. Current nomograms, which yield continuous risk probabilities, do not separate high-risk PCa into distinct sub-strata. Here we derive a binary definition of very-high-risk (VHR) localized PCa to aid in risk stratification at diagnosis and selection of therapy.
Materials and Methods
We queried the Johns Hopkins radical prostatectomy database to identify 753 men with NCCN high-risk localized PCa (Gleason sum 8–10, PSA >20 ng/ml, or clinical stage ≥T3). 28 alternate permutations of adverse grade, stage, and cancer volume were compared by their hazard ratios for metastasis and cancer-specific mortality. VHR criteria with top-ranking hazard ratios were further evaluated by multivariable analyses and inclusion of a clinically meaningful proportion of the high-risk cohort.
Results
The VHR cohort was best defined by primary pattern 5 present on biopsy, or ≥5 cores with Gleason sum 8–10, or multiple NCCN high-risk features. These criteria encompassed 15.1% of the NCCN high-risk cohort. Compared to other high-risk men, VHR men were at significantly higher risk for metastasis (H.R. 2.75) and cancer-specific mortality (H.R. 3.44) (p <0.001 for both). Among high-risk men, VHR men also had significantly worse 10-year metastasis-free survival (37% vs 78%) and cancer-specific survival (62% vs 90%).
Conclusions
Men who meet VHR criteria form a subgroup within the current NCCN high-risk classification who have particularly poor oncologic outcomes. Use of these characteristics to distinguish VHR localized PCa may help in counseling and selection optimal candidates for multimodal treatments or clinical trials.
doi:10.1038/pcan.2013.46
PMCID: PMC3945953  PMID: 24189998
Prostate cancer; risk stratification; metastasis; survival; high-risk prostate cancer
7.  Survival in Men With Nonmetastatic Prostate Cancer Treated With Hormone Therapy: A Quantitative Systematic Review 
Purpose
We aimed to describe disease-free survival (DFS) and overall survival (OS) in men with localized or locally advanced prostate cancer receiving immediate hormone therapy as adjunct to radiation therapy, adjunct to radical prostatectomy, or stand-alone therapy.
Materials and Methods
A systematic literature search of MEDLINE, EMBASE, CancerLit, the Cochrane Library, and Current Contents (from 1986 to September 2006) yielded 35 high-quality clinical trials (n = 11,105 patients) which formed the evidence base. Selected studies were required to address early hormone therapy in nonmetastatic prostate cancer only. Data on DFS and OS were extracted from individual trials, summarized statistically, and displayed in graphic form.
Results
Survival probabilities were extracted from 16 trials (n = 5,987 patients) addressing hormone therapy as an adjunct to radiation therapy, 11 trials (n = 1,885 patients) investigating hormone therapy as an adjunct to prostatectomy, and 10 trials (n = 3,233 patients) evaluating hormone therapy alone. In men receiving hormones and radiation, estimated 5-year DFS and OS were 52% and 82%, whereas median DFS and OS were 5.4 years and more than 7 years, respectively. In men receiving hormones and surgery, 5-year DFS and OS were 64% and 90%, whereas median DFS and OS were more than 6 years and more than 7 years, respectively. In men receiving hormones alone, 5-year DFS and OS were 57% and 70%, whereas median DFS and OS were 6.0 years and more than 7 years, respectively.
Conclusion
This systematic review provides a new baseline for expected DFS and OS in patients treated with hormone therapy for nonmetastatic prostate cancer. Survival in these men may be longer than estimated previously.
doi:10.1200/JCO.2007.11.1559
PMCID: PMC4133788  PMID: 17971600
8.  Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases 
Cancer letters  2012;323(2):135-146.
Patients with castration-resistant prostate cancer (CRPC) frequently have metastases to the bone, which may cause pain and lead to a deterioration in quality-of-life. Bone-seeking radiopharmaceuticals are agents which, when administered systemically, localize to the site of bone metastases and deliver focal radiation there. In this review, we will summarize the current literature on bone-targeting radiopharmaceuticals for CRPC, focusing on strontium-89, samarium-153, rhenium-186 and radium-223. We will discuss their indications, clinical efficacy, and toxicities and highlight some of the challenges in optimizing treatment with these agents. Historically, clinical trials with these drugs have failed to demonstrate survival improvements, restricting their use for palliative purposes only. Radium-223 is the first agent in this class to show an overall survival advantage in CRPC patients with bone metastases. This landmark finding will likely have a considerable impact on the treatment paradigm of bone-metastatic CRPC, and will pave the way for further developments in the future.
doi:10.1016/j.canlet.2012.04.001
PMCID: PMC4124611  PMID: 22521546
Bone metastases; Castration-resistant prostate cancer; Radiopharmaceuticals; Radium-223; Samarium-153; Strontium-89
9.  Current status of immunological approaches for the treatment of prostate cancer 
Current opinion in urology  2010;20(3):241-246.
Purpose of review
The recent Food and Drug Administration approval of sipuleucel-T for metastatic castration-resistant prostate cancer and of the anticytotoxic T-lymphocyte antigen 4 antibody (Ipilimumab) for metastatic melanoma has led to a renewed interest in immunotherapy for prostate and other cancers. Ipilimumab has entered phase III testing for prostate cancer, as has a viral-based anti-prostate-specific antigen vaccine (ProstVac-VF). Complementing these phase III studies are a number of innovative phase II studies, aimed at bringing immunotherapy forward in the setting of less advanced disease, as well as a number of interesting trials combining immunotherapy with conventional therapy for prostate cancer.
Recent findings
Although a number of immunotherapy trials have been initiated, few mature results are available at the current time. These data are likely to mature in the setting of an increasingly complex treatment paradigm in which multiple hormonal and novel agents are available.
Summary
Immunotherapy for prostate cancer represents an attractive treatment approach, with the currently available agent sipuleucel-T providing a significant survival benefit without appreciable toxicity. Novel approaches to improve the efficacy of this and other immune-active agents are currently under evaluation.
doi:10.1097/MOU.0b013e3283381793
PMCID: PMC4124631  PMID: 20179598
immune checkpoints; immunotherapy; prostate cancer; T cell; vaccine
10.  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
11.  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
12.  Castration-resistant prostate cancer: latest evidence and therapeutic implications 
Medical oncologists who treat men with castration-resistant prostate cancer (CRPC) have seen an abundance of new agents approved by the United States Food and Drug Administration in the last decade for a disease that was previously difficult to treat after becoming resistant to androgen-deprivation therapy. Advances in understanding of the mechanisms of castration-resistance and prostate cancer progression have highlighted several pathways and targets that appear promising to better treat CRPC. As the majority of CRPC appears to continue to rely on the androgen receptor for growth and progression, several of these agents directly or indirectly target the androgen receptor. A novel microtubule-targeted agent, cabazitaxel, has demonstrated an overall survival benefit following progression on docetaxel. Other agents target tumor immunogenicity and immune checkpoint pathways to attempt to harness the host immune system. The recently approved radiopharmaceutical, radium-223 dichloride, has demonstrated impressive results in patients with extensive bony metastases with minimal toxicity. Lastly, further understanding of the pathways underlying CRPC progression has led to late-phase clinical trials with the novel agents: custirsen, tasquinimod and cabozantinib. This article reviews the approved therapies for CRPC, the agents currently in late-phase clinical trials, and notable early-phase trials of novel therapies and their combinations, with particular attention to trials incorporating novel biomarkers and intermediate endpoints to better identify those men who may or may not benefit from specific therapies.
doi:10.1177/1758834014529176
PMCID: PMC4107711  PMID: 25057303
cabozantinib; castration-resistant prostate cancer; custirsen; radium-223 dichloride; tasquinimod
13.  Does short-term ADT before and during radiation therapy improve outcomes in locally advanced prostate cancer? 
SUMMARY
This Practice Point discusses the 10-year data of the RTOG 8610 trial, published by Roach III and colleagues, which suggest that a short, 4-month course of neoadjuvant–concomitant androgen deprivation therapy (ADT) might be sufficient to improve clinically relevant long-term outcomes in men with bulky, locally advanced prostate cancer. The results show that patients randomized to receive short-term ADT before and during radiation therapy (RT), rather than RT alone, had improved long-term disease-specific mortality, freedom from distant metastases, disease-free survival, freedom from biochemical failure, and possibly even overall survival. Importantly, no increase in the risk of fatal cardiac events was seen. The study did not, however, address the issue of the optimum duration of ADT; recent data suggest that longer courses of ADT (≥2 years), when added to RT, might further improve disease-free and even overall survival, especially in patients with high-grade disease.
doi:10.1038/ncpuro1175
PMCID: PMC4036454  PMID: 18665153
androgen deprivation therapy; disease-free survival; locally advanced prostate cancer; overall survival; radiation therapy
14.  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
15.  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
17.  Update: Immunological Strategies for Prostate Cancer 
Current urology reports  2010;11(3):202-207.
Prostate cancer is the second most common cause of cancer-related death in US men. Along with initial therapy using surgery, radiotherapy, or cryotherapy, hormonal therapy is the mainstay of treatment. For men with advanced (metastatic) disease, docetaxel-based chemotherapy is US Food and Drug Administration (FDA)-approved, and provides a significant survival advantage. This relative paucity of treatment options drives an ongoing quest for additional treatment modalities; among these is immunotherapy. The concept that prostate cancer is a malignancy that can be targeted by the immune system may seem counterintuitive; certainly kidney cancer and melanoma are more traditionally thought of as immune responsive cancers. However, prostate cancer arises in a relatively unique organ and may express a number of proteins (antigens) against which an immune response can be generated. More importantly, several of these agents have now demonstrated a significant survival benefit in randomized controlled clinical trials, and one agent in particular (Sipuleucel-T, Dendreon Corporation, Seattle, WA) could be FDA-approved in 2010. This update summarizes recent clinical developments in the field of prostate cancer immunotherapy, with a focus on dendritic cell vaccines, virus-based vaccines, DNA-based vaccines, and cell-based vaccines. In addition, the notion of agents that target immune checkpoints is introduced. Enthusiasm for prostate cancer immunotherapy is founded upon its potential to mediate targeted, specific, tumor cell destruction without significant systemic toxicity; however, this has yet to be fully realized in the clinical arena.
doi:10.1007/s11934-010-0106-8
PMCID: PMC4020436  PMID: 20425628
Immunotherapy; Immune checkpoints; Prostate cancer; T cell; Vaccine; CTLA-4; PD-1; GVAX; ProstVac VF; Sipuleucel-T
18.  Ruthenium-based chemotherapeutics: are they ready for prime time? 
Since the discovery of cis-platinum, many transition metal complexes have been synthesized and assayed for antineoplastic activity. In recent years, ruthenium-based molecules have emerged as promising antitumor and anti-metastatic agents with potential uses in platinum-resistant tumors or as alternatives to platinum. Ruthenium compounds theoretically possess unique biochemical features allowing them to accumulate preferentially in neoplastic tissues and to convert to their active state only after entering tumor cells. Intriguingly, some ruthenium agents show significant activity against cancer metastases but have minimal effects on primary tumors. Two ruthenium-based drugs, NAMI-A and KP1019, have reached human clinical testing. This review will highlight the chemical properties, mechanism of action, preclinical data, and early phase clinical results of these two lead ruthenium compounds. Other promising ruthenium agents will also be reviewed with emphasis on the novel ruthenium compound ONCO4417, and DW1/2 that has demonstrated Pim-1 kinase inhibition in preclinical systems. Further development of these and other ruthenium agents may rely on novel approaches including rational combination strategies as well as identification of potential pharmacodynamic biomarkers of drug activity aiding early phase clinical studies.
doi:10.1007/s00280-010-1293-1
PMCID: PMC4020437  PMID: 20213076
Ruthenium; Chemotherapy; NAMI-A; KP1019; ONCO4417
19.  Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies 
Science translational medicine  2014;6(224):224ra24.
The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
doi:10.1126/scitranslmed.3007094
PMCID: PMC4017867  PMID: 24553385
20.  Is abiraterone acetate well tolerated and effective in the treatment of castration-resistant prostate cancer? 
SUMMARY
This Practice Point commentary discusses the findings of the first phase I trial to evaluate abiraterone acetate (an inhibitor of the androgen-regulating enzyme CYP17) in the treatment of castration-resistant prostate cancer. This open-label, dose-escalation study by Attard et al. showed that abiraterone was well tolerated but often induced a syndrome of secondary mineralocorticoid excess that improved with eplerenone (a mineralocorticoid receptor antagonist). Abiraterone is a potent suppressor of adrenal androgen synthesis, and produced lasting prostate-specific antigen responses in approximately half of the patients. A few patients had partial regression of distant metastases. Although promising, these results should be interpreted with caution owing to the small sample size and because the study was not primarily designed to examine drug efficacy. Multi-institutional, prospective trials should provide additional information on the tolerability and activity of this compound and further define the population most likely to benefit from this endocrine approach.
doi:10.1038/ncponc1262
PMCID: PMC4014058  PMID: 18957947
abiraterone acetate; castration-resistant prostate cancer; CyP17 enzyme; efficacy; tolerability
21.  Abiraterone acetate: a hat trick of clinical benefits 
The lancet oncology  2012;13(12):1173-1174.
doi:10.1016/S1470-2045(12)70460-6
PMCID: PMC4014059  PMID: 23142060
22.  Prostate angiosarcoma: a case report and literature review 
Angiosarcomas are a relatively rare histological subtype of sarcomas and represent <1% of all sarcomas. Prostate angiosarcoma is extremely rare and displays remarkable clinical and pathological heterogeneity. Despite the rarity, it usually presents with dysuria, hematuria, or pelvic pain and represents a treatment challenge. Only nine cases have been reported in the literature, and we report the 10th case of prostate angiosarcoma and the first case of prostate angiosarcoma with recurrent adenocarcinoma.
doi:10.1007/s12032-012-0188-x
PMCID: PMC4009976  PMID: 22351253
Prostate angiosarcoma; Urinary frequency; Hematuria; Radiation therapy
23.  CLINICAL PROBLEM-SOLVING 
The New England journal of medicine  2008;359(6):628-634.
A 64-year-old Filipino man presented to a Baltimore hospital with a 4-month history of worsening midback pain, progressive leg weakness, and intermittent bladder and bowel incontinence. He had no fever or pulmonary symptoms. Magnetic resonance imaging (MRI) of the thoracic spine revealed hypointense T1-weighted and hyperintense T2-weighted bone marrow signal involving vertebral bodies T2, T3, and T4 (findings that were consistent with osteomyelitis); vertebral compression fractures; an epidural fluid collection; and spinal cord compression (Fig. 1). Multiple blood cultures were negative. Because the spine was considered unstable, he underwent T2, T3, and T4 vertebrectomy with fusion from C3 to T8. Pathological studies of the operative specimen revealed granulation and chronic inflammation. No organisms were identified with the use of routine or special stains, including an auramine– phenol stain for acid-fast bacilli. Vertebral bone and material from the fluid collection were sent for fungal, mycobacterial, and routine bacterial cultures before the initiation of treatment with antimicrobial agents.
doi:10.1056/NEJMcps0708803
PMCID: PMC4007002  PMID: 18687644
24.  Chemotherapy and its evolving role in the management of advanced prostate cancer 
Asian Journal of Andrology  2014;16(3):334-340.
Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer (CRPC). Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ‘level-1 evidence’ that docetaxel-based chemotherapy led to prolongation in overall survival (OS). This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents (e.g. abiraterone and enzalutamide) have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include: how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.
doi:10.4103/1008-682X.122593
PMCID: PMC4023356  PMID: 24435058
cabazitaxel; chemotherapy; cyclophosphamide; docetaxel; mitoxantrone; prostate cancer; taxanes
25.  Targeting angiogenesis for the treatment of prostate cancer 
Introduction
While multiple therapies exist that prolong the lives of men with advanced prostate cancer, none are curative. This had led to a search to uncover novel targets for prostate cancer therapy, distinct from those of traditional hormonal approaches, chemotherapies, immunotherapies and bone-targeting approaches. The process of tumor angiogenesis is one target that is being exploited for therapeutic gain.
Areas covered
The most promising anti-angiogenic approaches for treatment of prostate cancer, focusing on clinical development of selected agents. These include VEGF-directed therapies, tyrosine kinase inhibitors, tumor-vascular disrupting agents, immunomodulatory drugs and miscellaneous anti-angiogenic agents. While none of these drugs have yet entered the market for the treatment of prostate cancer, several are now being tested in Phase III registrational trials.
Expert opinion
The development of anti-angiogenic agents for prostate cancer has met with several challenges. This includes discordance between traditional prostate-specific antigen responses and clinical responses, which have clouded clinical trial design and interpretation, potential inadequate exposure to anti-angiogenic therapies with premature discontinuation of study drugs and the development of resistance to anti-angiogenic monotherapies. These barriers will hopefully be overcome with the advent of more potent agents, the use of dual angiogenesis inhibition and the design of more informative clinical trials.
doi:10.1517/14728222.2012.668887
PMCID: PMC4005337  PMID: 22413953
angiogenesis; bevacizumab; cabozantinib; clinical trials; drug development; itraconazole; lenalidomide; prostate cancer; sunitinib; tasquinimod; vadimezan

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