Delay Prostate Cancer Progression Research Articles

Enzalutamide Monotherapy vs Active Surveillance in Patients With Low-risk or Intermediate-risk Localized Prostate Cancer

There are few published studies prospectively assessing pharmacological interventions that may delay prostate cancer progression in patients undergoing active surveillance (AS). To compare the efficacy and safety of enzalutamide monotherapy plus AS vs AS alone in patients with low-risk or intermediate-risk prostate cancer. The ENACT study was a phase 2, open-label, randomized clinical trial conducted from June 2016 to August 2020 at 66 US and Canadian sites. Eligible patients were 18 years or older, had received a diagnosis of histologically proven low-risk or intermediate-risk localized prostate cancer within 6 months of screening, and were undergoing AS. Patients were monitored during 1 year of treatment and up to 2 years of follow-up. Data analysis was conducted in February 2021. Randomized 1:1 to enzalutamide, 160 mg, monotherapy for 1 year or continued AS, as stratified by cancer risk and follow-up biopsy type. The primary end point was time to pathological or therapeutic prostate cancer progression (pathological, ≥1 increase in primary or secondary Gleason pattern or ≥15% increased cancer-positive cores; therapeutic, earliest occurrence of primary therapy for prostate cancer). Secondary end points included incidence of a negative biopsy result, percentage of cancer-positive cores, and incidence of a secondary rise in serum prostate-specific antigen (PSA) levels at 1 and 2 years, as well as time to PSA progression. Adverse events were monitored to assess safety. A total of 114 patients were randomized to treatment with enzalutamide plus AS and 113 to AS alone; baseline characteristics were similar between treatment arms (mean [SD] age, 66.1 [7.8] years; 1 Asian individual [0.4%], 21 Black or African American individuals [9.3%], 1 Hispanic individual [0.4%], and 204 White individuals [89.9%]). Enzalutamide significantly reduced the risk of prostate cancer progression by 46% vs AS (hazard ratio, 0.54; 95% CI, 0.33-0.89; P = .02). Compared with AS, odds of a negative biopsy result were 3.5 times higher; there was a significant reduction in the percentage of cancer-positive cores and the odds of a secondary rise in serum PSA levels at 1 year with treatment with enzalutamide; no significant difference was observed at 2 years. Treatment with enzalutamide also significantly delayed PSA progression by 6 months vs AS (hazard ratio, 0.71; 95% CI, 0.53-0.97; P = .03). The most commonly reported adverse events during enzalutamide treatment were fatigue (62 [55.4%]) and gynecomastia (41 [36.6%]). Three patients in the enzalutamide arm died; none were receiving the study drug at the time of death. No deaths were considered treatment-related. The results of this randomized clinical trial suggest that enzalutamide monotherapy was well-tolerated and demonstrated a significant treatment response in patients with low-risk or intermediate-risk localized prostate cancer. Enzalutamide may provide an alternative treatment option for patients undergoing AS. ClinicalTrials.gov Identifier: NCT02799745.

ATF6α promotes prostate cancer progression by enhancing PLA2G4A-mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis.

BackgroundDespite the clinical success of androgen receptor (AR)‐targeted therapies, prostate cancer (PCa) inevitably progresses to castration‐resistant prostate cancer (CRPC). Transcription factor 6 α (ATF6α), an effector of the unfolded protein response (UPR) that modulates the cellular response to endoplasmic reticulum (ER) stress, has been linked to tumor development, metastasis, and relapse. However, the role of ATF6α in CRPC remains unclear.MethodsThe effect of ATF6α on the CRPC‐like phenotype in PCa cells was evaluated by 3‐(4,5‐dimethylthiazol‐2‐yl)−5‐(3‐carb‐Oxymethoxyphenyl)−2‐(4‐sulfophenyl)−2H‐tetrazolium inner salt (MTS), 5‐Bromo‐2‐deoxyUridine (BrdU) incorporation analysis, and cell death assay. Mechanistically, bioinformatic analysis was utilized to evaluate the potential of PLA2G4A as the target of ATF6α. Moreover, Western blot analysis, real‐time polymerase chain reaction, chromatin immunoprecipitation, arachidonic acid (AA), and prostaglandin E2 (PGE2) assays were performed to identify the regulatory effect of ATF6α on PLA2G4A.ResultsIn this study, we found that the increase of ATF6α expression in response to androgen deprivation generates PCa cells with a CRPC‐like phenotype. PCa cells with high levels of ATF6α expression are resistant to ferroptosis, and genetic and pharmacological inhibition of ATF6α could, therefore, promote the ferroptotic death of tumor cells and delay PCa progression. Molecular analyses linked ATF6α regulation of ferroptosis to the PLA2G4A‐mediated release of AA and the resulting increase in PGE2 production, the latter of which acts as an antiferroptotic factor.ConclusionsThis study defines ATF6α as a novel antiferroptotic regulator that exacerbates PCa progression. In addition, our data establish ATF6α‐PLA2G4A signaling as an important pathological pathway in PCa, and targeting this pathway may be a novel treatment strategy.

Focus on Transitional Disease: A Critical Interval to Delay Progression of Prostate Cancer.

Focus on Transitional Disease: A Critical Interval to Delay Progression of Prostate Cancer.

Early intervention exercise training does not delay prostate cancer progression in Pten−/− mice

There is convincing evidence that men with advanced prostate cancer experience improved quality of life as a result of exercise therapy, although there is limited preclinical, and no clinical, data to directly support the notion that exercise training improves prostate cancer prognosis or outcome. The aim of this study was to investigate the effect of regular exercise training on the early stages of prostate cancer progression, as well as assessing whether alterations to prostate cancer metabolism are induced by exercise. Mice with prostate-specific deletion of Pten (Pten-/- ) remained sedentary or underwent 6 weeks of endurance exercise training or high-intensity exercise training involving treadmill running. At the conclusion of the training period, the prostate lobes were excised. A portion of fresh tissue was used to assess glucose, glutamine, and fatty acid metabolism by radiometric techniques and a second portion was fixed for histopathology. Despite the implementation of an effective exercise regime, as confirmed by improvements in running capacity, neither prostate mass, cell proliferation or the incidence of high-grade prostate intraepithelial hyperplasia or noninvasive carcinoma in situ were significantly different between groups. Similarly, neither glucose uptake, oxidation and de novo lipogenesis, glutamine oxidation, or fatty acid uptake, oxidation and storage into various lipids were significantly different in prostate tissue obtained from untrained and exercise trained mice. These results show that 6 weeks of moderate or high-intensity exercise training does not alter substrate metabolism in the prostate or slow the progression of Pten-null prostate cancer. These results question whether exercise is a useful therapy to prevent or delay prostate cancer progression.

Metformin Inhibits Prostate Cancer Progression by Targeting Tumor-Associated Inflammatory Infiltration.

Purpose: Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in prostate cancer.Experimental Design: By using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, in vitro macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer.Results: Treating TRAMP mice with metformin delays prostate cancer progression from low-grade prostatic intraepithelial neoplasia to high-grade PIN, undifferentiated to well-differentiated, and PIN to adenocarcinoma with concurrent inhibition of inflammatory infiltration evidenced by reduced recruitment of macrophages. Furthermore, metformin is capable of inhibiting the following processes: inflammatory infiltration after androgen deprivation therapy (ADT) induced by surgically castration in mice, bicalutamide treatment in patients, and hormone deprivation in LNCaP cells. Mechanistically, metformin represses inflammatory infiltration by downregulating both COX2 and PGE2 in tumor cells.Conclusions: Metformin is capable of repressing prostate cancer progression by inhibiting infiltration of tumor-associated macrophages, especially those induced by ADT, by inhibiting the COX2/PGE2 axis, suggesting that a combination of ADT with metformin could be a more efficient therapeutic strategy for prostate cancer treatment. Clin Cancer Res; 24(22); 5622-34. ©2018 AACR.

Poly (ADP-Ribose) Polymerase (PARP), an Emerging Target for Controlling Metastatic Prostate Cancer under BRCAness

PARP1 is identified as an enzyme for addition of poly (ADP-ribose) to target protein(s) and is also important for DNA repair at the site of DNA single strand break (SSB). However, under PARP-inactivated states, unrepaired SSB is converted to double strand break (DSB) in S-phase, and then homologous recombination (HR) system participates in repair of DSB-injured DNA. In this process, BRCA1/2 and their binding effectors, such as RAD51 and PALB1, are recruited to the injured site for initiating HR-based DNA repair. If HR-associated molecules, such as BRCA1/2, are deficient via a dysfunctional mutation or down-regulated (so called, BRCAness), cancer cells undergo further DSBs and eventually result in apoptotic cell death. In response to HR-deficiency, PARP1 is activated to repress SSB, a source of DSB before DNA replication, hence suggesting a new target of PARP1 for inducing synthetic lethality under BRCAness. Indeed, PARP1 inhibitor (PARPi) is found to be useful for delaying the progression of BRCA1/2-mutated ovarian cancers in phase-II clinical trials. Metastatic prostate cancer (PCa) is now the second leading cause of cancer deaths among males in the Western countries. Radiation and androgen receptor inhibition (ARi) (i.e., pharmaceutical castration) are the standard therapy to delay PCa progression, but these conventional treatments result in a malignant selection of castration-resistant PCa clones. Previous studies described the potential use of PARPi for sensitizing radiotherapy or chemotherapy to castration-sensitive PCa in a rodent model. The recent highlighted finding is that ARi treatment down-regulates BRCA1, Rad51, Rad54 and RMI2, all are necessary for HR post-DNA DSB damage, thus indicating the acquisition of BRCAness-like phenotypes by ARi. In this review, we will describe the recent information on significance of PARPi in advanced PCa. Clinical effects are now being evaluated in patients with metastatic PCa, and some are promising. PARP1 inhibition may become a principle-based strategy for arresting metastatic PCa, if patient selection is carefully performed, on the basis of genomic (or phenotypic) detection of BRCAness.

Abstract 1821: Sympathetic nerves regulate a metabolic switch promoting angiogenesis through adrenergic signaling in prostate cancer

Abstract Nerves pattern the vasculature during development and regeneration. Recent studies have shown that the sympathetic nervous system (SNS) is coopted to promote carcinogenesis, and that depletion of SNS β-adrenergic receptors (βARs) in the prostate stromal compartment inhibits tumor growth. As the vasculature is in direct contact with the SNS, and regulates tumor glucose and oxygen delivery, we aimed to identify the stromal populations that mediate SNS signaling and the mechanisms by which loss of βAR signaling inhibits prostate cancer progression. In vivo xenograft tumor growth was measured in Adrb2-/-; Adrb3-/- mice using an orthotopic PC3-luciferase model. Prostate cancer progression in the transgenic autochthonous HI-myc model was assessed after conditional Adrb2 deletion in stromal populations by intercrossing Adrb2fl/fl line to stromal Cre lines. Metabolism was measured ex vivo by flow quantification of the lipophilic cationic dye TMRE whose accumulation reflects mitochondrial membrane potential, and by NADH autofluorescence under UV excitation. In vitro oxidative phosphorylation and glycolytic flux were measured in primary prostate endothelial cells (VeraVec) using the Seahorse bioanalyzer and targeted gas chromatography-mass spectrometry (GC/MS). Deletion of the SNS βAR neural receptors in the microenvironment synergized to arrest exponential tumor growth. Imaging the tumor vasculature revealed a defect in vessel branching, a phenotype also observed after chemical sympathectomy, suggesting altered angiogenesis in the absence of βAR stimulation. Histology revealed an increase in vascular innervation and density during the transition from low to high grade pre-neoplastic PIN. Conditional Adrb2 deletion (Adrb2cKO) in endothelial cells (ECs), but not myeloid cells or pericytes, not only inhibited angiogenesis, but also reduced disease progression throughout all histopathological cancer stages. Transcriptome analysis of flow isolated Adrb2cKO ECs suggested an increase in oxidative metabolism and upregulation of mitochondrial Coa6. Ex vivo analysis of ECs revealed a metabolic switch during the low to high grade PIN transition, and this switch was inhibited by Adrb2cKO. Further in vitro characterization by Adrb2 knockdown revealed a metabolic shift in ECs to oxidative phosphorylation, which was mediated by Coa6 upregulation. As Coa6 cooperates with Cox10 in respiratory complex IV assembly, conditional co-deletion of Adrb2 and Cox10 in the HI-myc mouse rescued aerobic glycolysis, angiogenesis, and cancer progression. Our data thus demonstrates that the SNS mediates a pro-angiogenic switch during the early stages of prostate carcinogenesis. Moreover, we identified ECs as SNS stromal targets, and that abrogation of βAR signaling inhibits the angio-metabolic switch and delays prostate cancer progression, suggesting a novel therapeutic target for prostate cancer treatment. Citation Format: Ali Zahalka, Anna Arnal-Estape, Maria Maryanovich, Fumio Nakahara, Cristian Cruz, Paul S. Frenette. Sympathetic nerves regulate a metabolic switch promoting angiogenesis through adrenergic signaling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1821. doi:10.1158/1538-7445.AM2017-1821

Forced LIGHT expression in prostate tumors overcomes Treg mediated immunosuppression and synergizes with a prostate tumor therapeutic vaccine by recruiting effector T lymphocytes.

LIGHT, a ligand for lymphotoxin-β receptor (LTβR) and herpes virus entry mediator, is predominantly expressed on activated immune cells and LTβR signaling leads to the recruitment of lymphocytes. The interaction between LIGHT and LTβR has been previously shown to activate immune cells and result in tumor regression in a virally-induced tumor model, but the role of LIGHT in tumor immunosuppression or in a prostate cancer setting, where self antigens exist, has not been explored. We hypothesized that forced expression of LIGHT in prostate tumors would shift the pattern of immune cell infiltration toward an anti-tumoral milieu, would inhibit T regulatory cells (Tregs) and would induce prostate cancer tumor associated antigen (TAA) specific T cells that would eradicate tumors. Real Time PCR was used to evaluate expression of forced LIGHT and other immunoregulatory genes in prostate tumors samples. For in vivo studies, adenovirus encoding murine LIGHT was injected intratumorally into TRAMP-C2 prostate cancer cell tumor bearing mice. Chemokine and cytokine concentrations were determined by multiplex ELISA. Flow cytometry was used to phenotype tumor infiltrating lymphocytes and expression of LIGHT on the tumor cell surface. Tumor-specific lymphocytes were quantified via ELISpot assay. Treg induction and Treg suppression assays determined Treg functionality after LIGHT treatment. LIGHT in combination with a therapeutic vaccine, PSCA TriVax, reduced tumor burden. LIGHT expression peaked within 48 hr of infection, recruited effector T cells that recognized mouse prostate stem cell antigen (PSCA) into the tumor microenvironment, and inhibited infiltration of Tregs. Tregs isolated from tumor draining lymph nodes had impaired suppressive capability after LIGHT treatment. Forced LIGHT treatment combined with PSCA TriVax therapeutic vaccination delays prostate cancer progression in mice by recruiting effector T lymphocytes to the tumor and inhibiting Treg mediated immunosuppression. Prostate 75:280-291, 2015. © 2014 Wiley Periodicals, Inc.

A Low Dietary Ratio of Omega-6 to Omega-3 Fatty Acids May Delay Progression of Prostate Cancer

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men. Studies show that consumption of polyunsaturated fatty acids (PUFA) modulates the development and progression of prostate cancer. High amounts of omega-6 fatty acids have been linked with increased prostate cancer risk, whereas omega-3 fatty acids have been shown to inhibit PCa growth. However, because omega-3 and omega-6 are both essential fatty acids and part of a complete diet, it is more relevant to determine the ideal ratio of the two that would allow patients to benefit from the therapeutic properties of omega-3 fatty acids. LNCaP prostate cancer cells were treated with dietary-based ratios of omega-6 to omega-3 fatty acids under hormone-deprivation conditions, and effects on various cellular processes were determined. A low omega-6 to omega-3 PUFA ratio can delay the progression of cells toward castration-resistance by suppressing pathways involved in prostate cancer progression, such as the Akt/mTOR/NFκB axis. It also suppresses the expression of cyclin D1, and activation of caspase-3 and annexin V staining shows induction of proapoptotic events. Taken together, our data demonstrates that maintaining a low omega-6 to omega-3 fatty acids ratio can enhance efficacy of hormone ablation therapy.

Regulation of antioxidant responses in prostate cancer: Nrf2‐ dependent and independent effects of lycopene

Control of intracellular reactive oxygen species (ROS) concentrations is critical for cancer cell survival. Evidence from epidemiological, experimental studies and clinical trials suggests that lycopene may modify the risk or delay progression of prostate cancer. However, the molecular mechanisms involved are still unclear. The aim of this study is to determine the effects of lycopene on endogenous ROS and antioxidant responses in normal prostatic epithelial cells and in prostate cancer (PC) cells. Here, we show that levels of ROS generation were much higher in PC cells than in normal prostate cells (PrEC). Lycopene reduces ROS levels in a dose‐dependent manner in androgen‐dependent LNCaP but not in androgen‐independent DU145 and PC3. Intracellular levels of reduced GSH were highest in DU145 and associated with abundant levels of nuclear (NF‐E2)‐related factor 2 (Nrf2). Lycopene treatment did not significantly affect cell GSH or nuclear Nrf2 in either normal or PC cells. Using a cell‐based ARE‐reporter assay, we found that lycopene treatment increased ARE transcriptional activity in LNCaP but decreased ARE activity in DU145 cells. These findings indicate that lycopene may impair the PC cell survival machinery through regulating intracellular ROS and antioxidant response. Certain effects appear to be independent of Nrf2 signaling. (Supported by NIH, Muma family Endowment, USF)

Should Men Drink More Coffee to Delay Progression of Prostate Cancer?

"Should Men Drink More Coffee to Delay Progression of Prostate Cancer?." Nutrition and Cancer, 63(8), pp. 1161–1162

Carbidopa abrogates L‐dopa decarboxylase coactivation of the androgen receptor and delays prostate tumor progression

The androgen receptor (AR) plays a central role in prostate cancer progression to the castration-resistant (CR) lethal state. L-Dopa decarboxylase (DDC) is an AR coactivator that increases in expression with disease progression and is coexpressed with the receptor in prostate adenocarcinoma cells, where it may enhance AR activity. Here, we hypothesize that the DDC enzymatic inhibitor, carbidopa, can suppress DDC-coactivation of AR and retard prostate tumor growth. Treating LNCaP prostate cancer cells with carbidopa in transcriptional assays suppressed the enhanced AR transactivation seen with DDC overexpression and decreased prostate-specific antigen (PSA) mRNA levels. Carbidopa dose-dependently inhibited cell growth and decreased survival in LNCaP cell proliferation and apoptosis assays. The inhibitory effect of carbidopa on DDC-coactivation of AR and cell growth/survival was also observed in PC3 prostate cancer cells (stably expressing AR). In vivo studies demonstrated that serum PSA velocity and tumor growth rates elevated ∼2-fold in LNCaP xenografts, inducibly overexpressing DDC, were reverted to control levels with carbidopa administration. In castrated mice, treating LNCaP tumors, expressing endogenous DDC, with carbidopa delayed progression to the CR state from 6 to 10 weeks, while serum PSA and tumor growth decreased 4.3-fold and 5.4-fold, respectively. Our study is a first time demonstration that carbidopa can abrogate DDC-coactivation of AR in prostate cancer cells and tumors, decrease serum PSA, reduce tumor growth and delay CR progression. Since carbidopa is clinically approved, it may be readily used as a novel therapeutic strategy to suppress aberrant AR activity and delay prostate cancer progression.

Gene Expression and Biological Pathways in Tissue of Men with Prostate Cancer in a Randomized Clinical Trial of Lycopene and Fish Oil Supplementation

BackgroundStudies suggest that micronutrients may modify the risk or delay progression of prostate cancer; however, the molecular mechanisms involved are poorly understood. We examined the effects of lycopene and fish oil on prostate gene expression in a double-blind placebo-controlled randomized clinical trial.MethodsEighty-four men with low risk prostate cancer were stratified based on self-reported dietary consumption of fish and tomatoes and then randomly assigned to a 3-month intervention of lycopene (n = 29) or fish oil (n = 27) supplementation or placebo (n = 28). Gene expression in morphologically normal prostate tissue was studied at baseline and at 3 months via cDNA microarray analysis. Differential gene expression and pathway analyses were performed to identify genes and pathways modulated by these micronutrients.ResultsGlobal gene expression analysis revealed no significant individual genes that were associated with high intake of fish or tomato at baseline or after 3 months of supplementation with lycopene or fish oil. However, exploratory pathway analyses of rank-ordered genes (based on p-values not corrected for multiple comparisons) revealed the modulation of androgen and estrogen metabolism in men who routinely consumed more fish (p = 0.029) and tomato (p = 0.008) compared to men who ate less. In addition, modulation of arachidonic acid metabolism (p = 0.01) was observed after 3 months of fish oil supplementation compared with the placebo group; and modulation of nuclear factor (erythroid derived-2) factor 2 or Nrf2-mediated oxidative stress response for either supplement versus placebo (fish oil: p = 0.01, lycopene: p = 0.001).ConclusionsWe did not detect significant individual genes associated with dietary intake and supplementation of lycopene and fish oil. However, exploratory analyses revealed candidate in vivo pathways that may be modulated by these micronutrients.Trial RegistrationClinicalTrials.gov NCT00402285

Physical Activity after Diagnosis and Risk of Prostate Cancer Progression: Data from the Cancer of the Prostate Strategic Urologic Research Endeavor

Vigorous activity after diagnosis was recently reported to be inversely associated with prostate cancer-specific mortality. However, men with metastatic disease may decrease their activity due to their disease; thus, a causal interpretation is uncertain. We therefore prospectively examined vigorous activity and brisk walking after diagnosis in relation to risk of prostate cancer progression, an outcome less susceptible to reverse causation, among 1,455 men diagnosed with clinically localized prostate cancer. Cox proportional hazards regression was used to examine vigorous activity, nonvigorous activity, walking duration, and walking pace after diagnosis and risk of prostate cancer progression. We observed 117 events (45 biochemical recurrences, 66 secondary treatments, 3 bone metastases, 3 prostate cancer deaths) during 2,750 person-years. Walking accounted for nearly half of all activity. Men who walked briskly for 3 h/wk or more had a 57% lower rate of progression than men who walked at an easy pace for less than 3 h/wk (HR = 0.43; 95% CI: 0.21-0.91; P = 0.03). Walking pace was associated with decreased risk of progression independent of duration (HR brisk vs. easy pace = 0.52; 95% CI: 0.29-0.91; P(trend) = 0.01). Few men engaged in vigorous activity, but there was a suggestive inverse association (HR ≥3 h/wk vs. none = 0.63; 95% CI: 0.32-1.23; P(trend) = 0.17). Walking duration and total nonvigorous activity were not associated with risk of progression independent of pace or vigorous activity, respectively. Brisk walking after diagnosis may inhibit or delay prostate cancer progression among men diagnosed with clinically localized prostate cancer.

Abstract 4491: AZD5363, a novel Akt inhibitor, delays prostate cancer progression by inhibiting androgen-receptor activity

Abstract Introduction and Objective: Despite initial response to androgen deprivation therapy, prostate cancer (PCa) inevitably progresses after 3 to 4 years to its castration-resistant state (CRPC). Consequently, there is an urgent need for novel therapeutic agents that can prevent or at least prolong the time to CRPC progression. The phosphoinositide 3-kinase (PI3K)/Akt pathway plays a key role in tumor progression and therefore is an attractive pharmacological target. In this study, we assessed the anti-cancer effects of the novel and selective Akt inhibitor, AZD5363, in vitro and in vivo in PCa. Methods: LNCaP and C4-2 cells were treated with AZD5363 and submitted to western blot, qRT-PCR and immunofluorescence analysis. AZD5363 was tested for its ability to modulate PSA transactivation by luciferase assay. Cell viability was assessed by crystal violet and cell cycle population by flow cytometry. For in vivo xenograft studies, LNCaP cells were inoculated s.c. in the flank region of athymic nude mice. Mice were castrated and randomly treated with AZD5363 or control by oral gavage. Tumor volume and serum prostate-specific antigen (PSA) were evaluated twice per week. Results: Here we report that AZD5363 inhibits cell growth in a dose-dependent manner (IC50 ± 200nM) in both LNCaP and C4-2, induces cell apoptosis as measured with PARP cleavage expression, Caspase 3 activity, and increases sub-G1 population (20.2% and 22.2% at 500nM for LNCaP and C4-2 cells, respectively). Interestingly, AZD5363 significantly abrogates androgen-induced PSA transactivation at concentrations > ∼100nM and down-regulates AR expression at concentrations > ∼1μM. These biologic events were accompanied by inhibition of downstream PI3K/Akt signaling. Most important, targeting the Akt-pathway in vivo significantly reduces tumor volume and serum PSA-levels and thereby delays progression to CRPC. Conclusions: This study reports as a preclinical proof-of-principle that targeting PI3K/Akt pathway with AZD5363 inhibits androgen-dependent PCa progression in vitro and in vivo, using the AR-axis as a pharmacodynamic tool. This work was supported by AstraZeneca, the Deutsche Forschungsgemeinschaft (German Research Foundation; Grant number: TH 1482/2-1), the Canadian Institutes of Health Research and l'Association pour la Recherche sur le Cancer (France). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4491. doi:10.1158/1538-7445.AM2011-4491

Oxidative Stress Measured by Urine F2-Isoprostane Level is Associated With Prostate Cancer

Oxidative stress is implicated in prostate cancer by several lines of evidence. We studied the relationship between the level of F2-isoprostanes, a validated biomarker of oxidative stress, and prostate cancer and high grade prostatic intraepithelial neoplasia. This case-control analysis within the Nashville Men's Health Study included men recruited at prostate biopsy. Body morphometrics, health history and urine were collected from more than 2,000 men before biopsy. F2-isoprostanes were measured by gas chromatography/mass spectrometry within an age matched sample of Nashville Men's Health Study participants that included 140 patients with high grade prostatic intraepithelial neoplasia, 160 biopsy negative controls and 200 prostate cancer cases. Multivariable linear and logistic regression was used to determine the associations between F2-isoprostane level, and high grade prostatic intraepithelial neoplasia and prostate cancer. Mean patient age was 66.9 years (SD 7.2) and 10.1% were nonwhite. Adjusted geometric mean F2-isoprostane levels were higher in patients with prostate cancer (1.82, 95% CI 1.66-2.00) or high grade prostatic intraepithelial neoplasia (1.82, 95% CI 1.68-1.96) than in controls (1.63, 95% CI 1.49-1.78, p <0.001), but were similar across Gleason scores (p = 0.511). The adjusted odds of high grade prostatic intraepithelial neoplasia and prostate cancer increased with increasing F2-isoprostane quartile (p-trend = 0.015 and 0.047, respectively) and the highest F2-isoprostane quartile was associated with significantly increased odds of prostate cancer (OR 2.44, 95% CI 1.17-5.09, p = 0.017). Pre-diagnosis urine F2-isoprostane level is increased in men with high grade prostatic intraepithelial neoplasia or prostate cancer, suggesting urinary F2-isoprostane provides a biomarker for the role for oxidative stress in prostate carcinogenesis. F2-isoprostanes may also serve to estimate the efficacy of interventions targeting oxidative stress mechanisms in prostate cancer prevention or treatment.

Statin use is associated with improved prostate cancer survival: is it time for a clinical trial?

Evaluation of: Gutt R, Tonlaar N, Kunnavakkam R, Karrison T, Weichselbaum RR, Liauw SL. Statin use and risk of prostate cancer recurrence in men treated with radiation therapy. J. Clin. Oncol. 28, 2653–2659 (2010).Recent studies have reported an inverse association between statin use and risk of advanced prostate cancer. Thus, it is possible that statin exposure delays progression of prostate tumors to an advanced stage. The study by Gutt and colleagues gives two important contributions to this field of research. With a cohort of 691 men undergoing curative-intent radiation therapy for prostate cancer between 1996 and 2008, and with a median follow-up of 50 months, they demonstrate that statin use is associated with improved relapse-free survival. The result supports the idea that statins could delay prostate cancer progression. In addition, they demonstrate that low low-density lipoprotein levels are associated with improved relapse-free survival, supporting the idea that the prostate cancer progression-preventing effects of statins could be, at least in part, mediated by their systemic low-density lipoprotein-lowering effect. The study adds to the growing body of evidence on statins’ benefits against prostate cancer. The results have important implications when designing possible future clinical studies on this topic.

A randomized, multicenter, international phase II study of tasquinimod in chemotherapy naïve patients with metastatic castrate-resistant prostate cancer (CRPC).

4510 Background: Tasquinimod (TASQ) is a quinoline-3-carboxamide derivative that binds to S100A9 and displays anti-angiogenic properties and anti-tumor activity in prostate cancer (PC) models. Phase I studies in PC indicated that TASQ is well tolerated and may delay PC progression. Methods: 206 patients (pts) with metastatic CRPC were assigned (2:1) to either receive oral TASQ once-daily at an initial dose level of 0.25 mg/day escalating to 1.0 mg/day over 4 weeks, or placebo (P). The primary endpoint was proportion of pts without disease progression (DP) at 6 months, defined by PCWG2 or pain criteria, but excluding PSA. Secondary endpoints comprised safety, progression free survival (PFS), and changes in biological markers, including PSA. Results: 200 (133 TASQ, 67 P) pts with a median age of 72.5 years were evaluable for efficacy and safety. Median baseline characteristics were (TASQ/P): Karnofsky (95/95), Gleason (7/7), LDH (201/206 U/L), Alk Phos (98/87 U/L), Hgb (12.9/13.2 g/dL), PSA (29/19 μ g/L) and PSADT (4.2/5.0 mo). 6-mo progression free proportion for TASQ and P groups was 57% and 33% respectively (p=0.0001) and median PFS was 24.7 vs. 12.9 weeks. In clinical subgroups defined by PCWG2, the PFSs were (weeks/N): nodal 24.3/9 vs. 12.6/12; bone 30.6/90 vs. 13.4/42; visceral 23.9/32 vs. 12.1/10 for pts on TASQ and P. Pts treated with TASQ had significantly decreased serum LDH levels and stabilized bone alkaline phosphatase (BAP) levels, with less pronounced effects on PSA response and progression. Serious vascular events were more common in the TASQ arm (myocardial infarction, heart failure or stroke (3 % vs 0 %), deep vein thrombosis (4 % vs 0 %)). Common (>10%) adverse events (AEs) occurring more frequently in pts receiving TASQ included gastrointestinal disorders, fatigue, and musculoskeletal pains. and asymptomatic elevation of pancreatic enzymes and proinflammatory markers. G3-4 AEs (including labs) were reported in 38% pts on TASQ vs. 10 % on P. Conclusions: TASQ significantly slowed the rate of DP and improved PFS in pts with metastatic CRPC and a phase III study is planned. Side effects were manageable. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Active Biotech Active Biotech Active Biotech Active Biotech

A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model

High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression.

PC-1/PrLZ Contributes to Malignant Progression in Prostate Cancer

PC-1/PrLZ gene overexpression has been identified to be associated with prostate cancer progression. Previous studies have revealed that PC-1 possesses transforming activity and confers malignant phenotypes to mouse NIH3T3 cells. However, the functional relevance of PC-1 expression changes during prostate cancer development and progression remains to be evaluated. In this study, gain-of-function and loss-of-function analyses in LNCaP and C4-2 cells, respectively, were implemented. Experimental data showed that PC-1 expression was in positive correlation with prostate cancer cell growth and anchor-independent colony formation in vitro, as well as tumorigenicity in athymic BALB/c mice. Moreover, PC-1 expression was also found to promote androgen-independent progression and androgen antagonist Casodex resistance in prostate cancer cells. These results indicate that PC-1 contributes to androgen-independent progression and malignant phenotypes in prostate cancer cells. Furthermore, molecular evidence revealed that PC-1 expression stimulated Akt/protein kinase B signaling pathway, which has been implicated to play important roles in promoting androgen refractory progression in prostate cancer. Increased PC-1 levels in C4-2 cells may represent an adaptive response in prostate cancer, mediating androgen-independent growth and malignant progression. Inhibiting PC-1 expression may represent a novel therapeutic strategy to delay prostate cancer progression.