bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitization of neuroendocrine prostate cancer by RRx-001.
Authors: Peehl Donna , Zhao Honguan , Ning Shoucheng 
Published: February 2018

280 Background: RRx-001 is a first-in-class dinitroazetidine nontoxic anticancer agent. Its actions include upregulation of oxidative stress, depletion of GSH and NADPH, anti-angiogenesis, epigenetic modulation and induction of viral mimicry. In a phase II clinical study (NCT02489903), RRx-001 reversed resistance to reintroduced platinum doublets in small cell lung cancer (SCLC) and other tumor types. RRx001 demonstrated clinical activity with a complete metabolic response of metastatic castration-resistant neuroendocrine prostate cancer (NEPC) after treatment with RRx-001 and reintroduced platinum doublets. Here, we used a preclinical model to further investigate RRx-001 sensitization of NEPC to platinum therapy. Methods: NCI-H660 spheroids were pre-treated with 1 mM RRx-001 or vehicle prior to treatment with carboplatin or docetaxel and cell proliferation was assessed. Cells were also pre-treated with both 1 mM RRx-001 and 10 mM N-acetyl cysteine (NAC) or 1 mM Buthionine-S,R-sulfoximine (BSO) to investigate the role of reactive oxygen species (ROS) in RRx-001 activity. NCI-H660 xenografts were pre-treated with RRx-001 (mimicking clinical activity) or vehicle prior to treatment with carboplatin, and tumor volume and body weight were monitored. Results: RRx-001 pre-treatment significantly decreased the IC50 of carboplatin from ~86 mM to 36 mM in vitro, whereas no significant effect was observed on the IC50 of docetaxel. The ROS inhibitor NAC reversed > 70% of RRx-001 sensitization to carboplatin, while co-pre-treatment with the ROS generator BSO significantly enhanced RRx-001 activity. In vivo, pre-treatment with RRx-001 prior to carboplatin significantly decreased tumor volume compared to vehicle, with ~50% greater reduction in mean tumor volume at 30 days. Body weight was not affected by RRx-001. Conclusions: This preclinical study supports the concept that “priming” with RRx-001 may be an effective therapeutic strategy to resensitize NEPC to initially highly effective platinum doublets. A phase 3 trial is planned, and studies with additional preclinical NEPC models will identify the mechanism of action of RRx-001.
Effect of the leukocyte chemoattractant chemerin on PTEN via CMKLR1 in human prostate cancer.
Authors: Pachynski Russell Kent , Crowder Robert , Shin William , Rennier Keith 
Published: February 2018

282 Background: Recent data in preclinical models has shown that phosphatase and tensin homolog (PTEN) loss correlated with decreased tumor immune cell infiltration as well as decreased response to T cell-based immunotherapy. Chemerin ( RARRES2) is a recently identified endogenous leukocyte chemoattractant shown to recruit innate immune cells through its G-protein coupled receptor CMKLR1. RARRES2 is commonly downregulated in prostate and other cancers (eg sarcoma) compared to their normal tissue counterparts. Our previous preclinical studies showed that forced overexpression of chemerin in tumors was capable of recruiting immune effector cells into the tumor microenvironment and suppressing tumor growth. Methods: Here, we investigate the effects of chemerin on tumor cell intrinsic processes by exposing prostate and sarcoma tumor lines to exogenous recombinant chemerin in vitro. Evaluation of PTEN was performed at both the mRNA and protein levels, using both quantitative PCR as well as Western blotting. PTEN immunoprecipitation by and Malachite Green assays were used to determine PTEN activity. In vitro invasion assays were performed to investigate the functional impact of chemerin exposure on tumor intrinsic activity. Knockdown of CMKLR1 using siRNA was performed to determine its role in tumor response. Results: Using both prostate and sarcoma tumor lines, we found exogenous chemerin was able to significantly upregulate PTEN expression at both the mRNA and protein levels in a dose-dependent manner. PTEN phosphatase activity was also significantly increased by chemerin. Exposure to chemerin did not result in increased apoptosis or altered in vitro proliferation. Importantly, chemerin treatment significantly decreased in vitro tumor invasion. Knockdown of CMKLR1 resulted in loss of chemerin-induced PTEN and PTEN activity and restored tumor migration, suggesting a link between this GPCR and PTEN. Conclusions: For the first time to our knowledge, we have shown a link between chemerin and PTEN expression and activity in both prostate and sarcoma tumor lines. This work has potential clinical implications on both tumor cell intrinsic and extrinsic responses to chemerin-based immunotherapeutic strategies.
Evaluation of self-reported symptoms and interference issues in prostate cancer patients.
Authors: Taha Mahdi 
Published: February 2018

283 Background: Prostate cancer is a leading cause of global morbidity and mortality and in the next few years is expected to be the leading cause of death among men in the United States. Both the disease and its treatments produce a variety of symptoms that impact prostate cancer outcomes, of which the more common symptoms are in relation to sexual dysfunction. A large body of literature has established that systematic patient reporting of symptoms during routine oncology care leads to clinical benefits. At our comprehensive community cancer center we evaluate patients’ reported symptoms using the Symptom Inventory Tool (SIT), an assessment tool that captures the patients' perceived symptom burden for real-time clinical intervention taken at the point of no intervention and every ≥ 21 days thereafter. Methods: The 27-question SIT is comprised of the M.D. Anderson Symptom Inventory Tool (MDASI), a validated assessment instrument, with 8 supplementary questions and a free-text box added by Cancer Treatment Centers of America. Symptoms are rated “at the worst” on a numeric scale ranging from 0 to 10, as experienced by pts in the past 24 hours. The SIT became an integral part of patient care at CTCA beginning in 2012. Results: Over a 45 month period (9/1/2012 to 05/31/2016), prostate cancer pts at CTCA completed the SIT at intake and again ≥ 21 days after. A total of 2,937 assessments were analyzed. The assessments consisted of 1,065 completed at baseline, 1,065 completed at the 2nd follow up (FU), and 807 completed at 3rd FU or greater. Further analysis of baseline SIT identified the pts who rated the above symptoms as “very burdensome” with a score of ≥ 5. 2nd SIT results from these PC patients revealed that those with a heavier symptoms burden at baseline would be more likely to experience a significant decrease in their symptoms burden than the average PC patient population. Conclusions: The SIT was successful in identifying symptoms burden and interference with life issues in prostate cancer patients. Sexual dysfunction and disturbed sleep were the most common reported symptoms. Early identification of patients with heavy symptom-burden allowed immediate intervention and improvement in approximately a one-fourth to two-thirds of patients.
Integrative transcriptional analysis of enzalutamide-resistant castration resistant prostate cancer cells using RNA sequencing.
Authors: Kim Tae Heon , Kang Minyong , Oh Ji Youn , Kang Yumi 
Published: February 2018

284 Background: Enzalutamide (ENZ)-resistance is a clinically challaengeable issue for management of castration-resistant prostate cancer (CRPC) patients. Here, we aimed to investigate the distinct features of transcriptional expression in ENZ-resistant CRPC cells using RNA sequencing, focusing on the histone modification enzymes as AR co-regulators. Methods: We chronically treated various concentration of ENZ (1 to 40 µM) for 6 to 9 months to establish ENZ-resistant CRPC cells by using C4-2B cells. To explore the phenotypic features of ENZ-resistant CRPC cells (ENZ-R), we analyzed the gene expression patterns, particularly AR target genes, following ENZ treatment. We performed cell viability assay, clonogenic assay, apotosis assay and tumor sphere formation assay. To examine the distinct features of transcriptional expression in ENZ-resistant CRPC cells, we conducted RNA sequencing and classified the key differential expression genes (DEG) according to Gene Ontology Database. Results: ENZ-R cells showed a higher cell viability and clonogenic proliferation compared to control cells following ENZ treatment. Also, ENZ-R cells showed higher gene expression of AR target gens (KLK2, KLK3, TTMPRSS) than those in control cells after dihydrotestosterone treatment. Of note, ENZ-R cells significantly expressed full length AR as well as AR splicing variant 7. Moreover, RNA sequencing revealed that 367 up-regulated genes and 223 down-regulated genes were identified as DEG compared to control cells. We further analyzed these DEG of histone modification enzyme as AR co-regulators, and therefore; we finally determined the candidate 28 target genes of histone modification enzyme (23 up-regulated and 5 down-regulated genes). We validated the differential expression of these key histone modification enzyme genes in ENZ-R cells by using real-time PCR. Conclusions: In sum, we established the ENZ-R cells and identified the 28 candidate DEG of histone modification enzyme in ENZ-R cells by performing RNA sequencing analysis. Our study can offer the valuable information for exploring the ENZ-resistant mechanisms, particularly focusing on the imbalance of AR co-regulators.
New HSP90 selective inhibitors as therapeutic agents for prostate and bladder cancer.
Authors: Liu Weiya , Jensen Derek , Lee Eugene , Gills Jessie , Holzbeierlein Jeffrey M. 
Published: February 2018

285 Background: Hsp90 is a molecular chaperone responsible for folding many of the proteins directly associated with cancer progression and consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Hsp90 family consist of four isoforms; Hsp90α, Hsp90β, Grp94 and Trap-1. The development of Hsp90 isoform-selective inhibitors represent an alternative approach towards the treatment of cancer that may limit some of the detriments. We demonstrate novel Hsp90 inhibitors, on prostate and bladder cancer cells, which shows both potent antiproliferative effects and specific selectivity for Hsp90β. Methods: PC3MM2, LNCap-LN3, C4-2b, LAPC4 (prostate cancer) and T24, UC3 (bladder cancer) cancer cells were utilized. Cell Titer-Glo luminescent anti-proliferative assay was used to determine the IC50 numbers after 72h treatment. Trypan Blue Cytotoxicity assay was performed for 24h treatment with increasing concentrations of KUNB inhibitors. Effects of KUNB inhibitors on Hsp90’s client protein degradation were investigated by Western Blot. Results: KUNB31 manifested an IC50 of 3.00 µM against UC3 bladder cancer cells, UC3 cells were then evaluated via western blot analyses of known Hsp90α- and Hsp90β-dependent client proteins following treatment with KUNB31 for 24 hours. The data showed that, KUNB31 would not induce the heat shock response like 17AAG, and did cause Hsp90β related protein degradation (CXCR4). Moreover, Hsp27, PKM2, Her2, Hsf-1and Akt all showed degradation to different extent. KUNB105 exhibited potent anti-proliferative in both prostate and bladder cancer cells. IC50 number was determined as 1.24 µM for PC3MM2, 1.18 µM for LNCap-LN3, 1.03 µM for C4-2b, 2.56 µM for LAPC4, 0.20 µM for T24, and 0.30 µM for UC3 cancer cells. Conclusions: KUNB novel Hsp90β selective inhibitors, exhibit potent anti-proliferative and cytotoxic activity along with client protein degradation, without induction of HSR in prostate and bladder cancer cell lines. KUNB compound’s selective inhibition on Hsp90β isomers supports the development of Hsp90-selective inhibitors as a method to overcome the detriments associated with pan-inhibition in cancer treatment.
Abiraterone acetate in metastatic castration-resistant prostate cancer post-docetaxel: A “real-life” retrospective analysis of outcomes in a Brazilian public health institution.
Authors: Flores Thais Caroline Menegasso , Emerich Carolina da Silva Miranda , Zaffaroni Facundo , Debiasi Márcio , Dutra Carolina 
Published: February 2018

287 Background: Abiraterone acetate (AA) is a selective inhibitor of CYP17 and showed to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel in the COU-AA-301 trial. AA is not widely available for patients treated at the public health system (SUS) and real-life data regarding this treatment in Brazil are lacking. This study aims to describe the epidemiological profile and outcomes of patients diagnosed with mCRPC who progressed after docetaxel treated with AA in a Brazilian public health institution. Methods: We retrospectively reviewed clinical data of patients with mCRPC who progressed after docetaxel and were treated with AA (1000mg/d PO) plus prednisone (5mg/BID PO) from January 2015 to December 2016 in our instituition. Patient demographic and clinical characteristics were described using summary statistics. Kaplan-Meyer method was used to estimate OS and time to prostate-specific antigen (PSA) progression for AA treatment. Results: 37 patients were included for analysis. Median age was 71 yo. Median PSA at AA start was 57 ng/mL (range 0.10-6,676.00), Gleason score was > 7 in 59.5% and ≤7 in 32.4%. 75.7% of patients had symptomatic bone metastasis requiring opioids. At a median follow up of 68 months, the median duration of treatment was 5 months with a median OS of 13 months and a median time to PSA progression of 4 months. Gleason score did not correlate with outcomes (p = 0.56). Although patients who had a prior hormone therapy (PHT) > 12mo had better OS (15mo) when compared to those with PHT < 12 (10mo), this difference was not statistically significant (p = 0.26). AA was well tolerated and disease progression was the main reason for AA discontinuation (86.8%). Conclusions: This analysis shows that AA is an effective and safe treatment option for patients in public health system in a developing country, with comparable outcomes to COU 301 trial in OS, showing benefits regardless Gleason and PHT status. These patients did not receive later lines of treatment, and this could have impacted OS in this study. The incorporation of AA in the SUS should be considered.
Overcoming resistance to antiandrogens with a TGF-β RI inhibitor in preclinical mouse model of PCa.
Authors: Paller Channing Judith , Pu Hong , Begemann Diane , Nakazawa Mary , Kyprianou Natasha 
Published: February 2018

288 Background: Epithelial-mesenchymal transition (EMT) is a significant contributor to PCa metastatic progression and therapeutic resistance in patients treated with the androgen receptor (AR) directed therapies. We previously demonstrated that aberrant TGF-β signaling accelerates prostate tumor progression in the TRAMP mouse model of tumorigenesis via selective effects on EMT. Methods: We hypothesize that the combination of the TGF-β receptor inhibitor, galunisertib (G), and enzalutamide (E) will perturb the interactive signaling between TGF-β and AR signaling affecting the phenotypic landscape of EMT. This perturbation may be exploited in our mouse model, towards enhanced anti-tumor efficacy in advanced castration-resistant PCa (CRPC). We treated 2-week old mice for two weeks with the G (75mg/kg) and/or E (30mg/kg) in combination and as single agents. Results: Treatment with G alone or in combination with E resulted in a significant reduction in prostate tumor weight without affecting total body weight. Immunohistochemical (IHC) and Western blot analysis showed that, while treatment with the G alone led to increased apoptosis and decreased cell proliferation, combination of G and E had significantly higher efficacy in inducing apoptosis and inhibiting cell proliferation than either E or G alone. As expected treatment with the G decreased the levels of nuclear Smad4 protein; the combination of G and E further decreased nuclear Smad4 expression. Furthermore the combination of G and E reversed phenotypic EMT to MET (mesenchymal-epithelial-transition), as assessed by the increase in E-cadherin among the prostate tumor cell populations. IHC and Western blot analysis also revealed that the combined treatment of G and E led to a significant decrease in nuclear AR levels compared to E-only-treated or vehicle-control tumors. Conclusions: These results provide significant insights as to the therapeutic impact of G to effectively impair the TGF-β signaling and overcome resistance of PCa patients to E by reversing EMT to potentially sensitize tumors to the antiandrogen effect. This study has major translational relevance; the combination of G and E may lead to synergistic anti-tumor impact in patients with CRPC.
Nationwide analysis of genitourinary expert opinions on active surveillance for localized prostate cancer.
Authors: McClelland Shearwood , Sandler Kiri A , Degnin Catherine , Chen Yiyi , Mitin Timur 
Published: February 2018

29 Background: The ProtecT trial has provided Level 1 evidence supporting active surveillance for prostate cancer patients with low-risk and intermediate risk disease. The impact of these findings on the opinions of North American genitourinary (GU) experts regarding the role of active surveillance for these patients has not been previously examined. Methods: A survey was distributed to 88 practicing North American GU physicians serving on decision-making committees of cooperative group research organizations. Questions pertained to knowledge about and personal opinions on the role of active surveillance in patients with low-risk and intermediate-risk (Gleason 3+4) disease. Opinions regarding active surveillance were correlated with practice patterns using Fisher’s exact test. Results: Analysis was conducted on 42 radiation oncologist respondents. Forty percent have been in practice for 20+ years; 90% practice at an academic center. Forty-five percent see 20+ patients/month in consultation. More than 95% recommended active surveillance for Gleason 6 disease, while only 17% recommended active surveillance for Gleason 3+4 disease. There were no significant demographic differences between supporters or opponents of active surveillance regarding monthly patient volume, practice type, self-identification as an expert brachytherapist, belief in advanced imaging techniques, or preferred default EBRT dose/fractionation for low-risk or intermediate-risk disease. However, opposition to active surveillance for Gleason 3+4 disease approached significance for experts having practiced 10+ years versus < 10 years (p = 0.085). Conclusions: Active surveillance is well-regarded among North American GU experts for low-risk but not intermediate-risk prostate cancer, despite the results of the ProtecT trial providing Level 1 evidentiary support for active surveillance in both risk groups. There were no significant differences between experts supporting versus opposing active surveillance for either low-risk or intermediate-risk disease. These preferences may affect the design of future clinical studies, influencing the adoption of active surveillance in North American clinical practice.
Post marketing surveillance study of cabazitaxel (CBZ) in Japanese patients with castration resistant prostate cancer (CRPC) in real world settings.
Authors: Matsuyama Hideyasu , Matsubara Nobuaki , Taguchi Tomoyuki , Seto Takeshi , Suzuki Kazuhiro 
Published: February 2018

290 Background: The study evaluated safety and efficacy of CBZ in Japanese patients (pts) with CRPC in real world settings. Methods: This prospective, observational study targeted all CRPC pts receiving CBZ in daily practice between September 2014 and June 2015. Observation period was 1 year after first dose of CBZ given. Adverse drug reactions (ADRs) were evaluated for safety by CTCAE 4.0. Overall survival (OS), time to treatment failure (TTF) and prostate specific antigen (PSA) response rate (≥30% PSA decrease) were the efficacy endpoints. Two groups, those given 25mg/m2 of CBZ as initial dose (C25) and those given 20mg/m2 of CBZ (C20), were comparatively analyzed. This study was supported by Sanofi. Results: Of 662 enrolled pts with CRPC treated with CBZ, 660 pts were analyzed. ADRs occurred in 511 pts (77.4%). Most frequent all grade ADRs were neutropenia (49.2%), febrile neutropenia (18.0%) and anemia (14.2%). Median OS and TTF were 319 and 116 days, respectively. Of 540 PSA evaluable pts, 158 (29.3%) achieved PSA response. Populations for post hoc analysis were 159 pts for C25 and 190 pts for C20. Patient characteristics were similar C25 and C20 groups. Statistical significant differences were observed between C25 and C20 groups for OS (Hazzard Ratio [HR] = 0.71) and TTF (HR = 0.78) in favor of C25 group. Initial dose of CBZ remained as the independent prognostic factor for OS and TTF in univariate and multivariate analysis. There was no significant difference for PSA response rate. ≥ Grade 3 ADRs with C25 and C20 occurred in 129 pts (81.1%) and 116 pts (61.1%), respectively. Conclusions: Safety profile of CBZ was generally consistent with clinical studies conducted before approval in Japan. Although there are some limitations of studies done in real world settings, there were significant differences for OS and TTF between C25 and C20. Less ADRs occurred with C20. [Table: see text]
Epidemiology and survival disparities of prostate cancer in Appalachian Kentucky.
Authors: Myint Zin , Huang Bin , Chen Quan , Wang Peng 
Published: February 2018

292 Background: Prostate cancer is the most common cancer in men in the United States. When comparing the incidence and mortality rates of prostate cancer in Appalachian Kentucky and general population in the United States, Appalachian Kentucky had lower incidence (113 per 100,000 rate vs. 137 per 100,000) but higher mortality rate (23.08% vs. 21.79%) from Surveillance Epidemiology and End Results (SEER) data in 2005-2014. The aim of our study is to further characterize the epidemiology and survival disparities of prostate cancer between Appalachian and non-Appalachian Kentucky. Methods: All stages of prostate cancer patients diagnosed between 2007-2011 were identified through Kentucky Cancer Registry (KCR). Baseline characteristics and survival outcome were compared between Appalachian Kentucky and non-Appalachian Kentucky. Kaplan-Meier plots and cox regression analyses were performed in this population-based study. Results: Out of 12871 patients studied, 3482 patients (26.8%) were Appalachian Kentucky whereas 8489 patients (73.2%) were non-Appalachian Kentucky. Caucasians were the most predominant in both groups. Most Appalachian Kentucky patients fell in the age group between 65-74. Appalachian Kentucky had high Gleason score, high prostate specific antigen (PSA), aggressive histologic grade, more distant disease, high comorbidity score, low high school education and high poverty rate compared to non-Appalachian Kentucky. There was a 5-year survival difference between Appalachian Kentucky and non-Appalachian Kentucky in unadjusted analysis (p < 0.0001). After adjusting with cox regression analysis, no survival difference was seen (p = 0.3866). However, statistical significance in survival was seen in high GLS, high PSA, distant stage, high charlson comorbidity score, and low high school education (p < 0.0001). Conclusions: Our study shows a significant difference in prostate cancer survival between Appalachian and non-Appalachian Kentucky. The difference was not related to geographic location, rather it was more related to high comorbidity score, high poverty rate, low education and less knowledge of health care. Additional research is needed to understand the health care in Appalachia.