bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug Repurposing for Gastrointestinal Stromal Tumor
Authors: Pessetto Ziyan Y. , Weir Scott J. , Sethi Geetika , Broward Melinda A. , Godwin Andrew K. 
Published: May 2013

Abstract
Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25 to 30 million people in the United States alone. Given the costs associated with the discovery, development, and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, “drug repurposing” or “repositioning,” has emerged as an alternative to the traditional drug development process. In this study, we screened 796 U.S. Food and Drug Administration (FDA)-approved drugs and found that two of these compounds, auranofin (Ridaura) and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs, including imatinib-resistant cells. One of the most notable drug hits, auranofin, an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis, was found to inhibit thioredoxin reductase activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anticancer activity associated with auranofin was independent of imatinib-resistant status, but was closely related to the endogenous and inducible levels of ROS. Coupled with the fact that auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for patients with GIST, particularly in those suffering from imatinib-resistant and recurrent forms of this disease. Mol Cancer Ther; 12(7); 1299–309. ©2013 AACR.
NF-κB Inhibition by Bortezomib Permits IFN-γ–Activated RIP1 Kinase–Dependent Necrosis in Renal Cell Carcinoma
Authors: Thapa Roshan J. , Chen Peirong , Cheung Mitchell , Nogusa Shoko , Pei Jianming , Peri Suraj , Testa Joseph R. , Balachandran Siddharth 
Published: May 2013

AbstractAdvanced renal cell carcinoma (RCC) is an invariably fatal cancer. Currently, small-molecule inhibitors that target cell growth, angiogenesis, or nutrient-sensing pathways represent the primary pharmacologic interventions for this disease, but these inhibitors only delay tumor progression and are not curative. The cytokine IFN-γ showed the potential to provide lasting remission in several phase I/II trials for advanced RCCs, but subsequent trials, including a multicenter phase III study using IFN-γ as a monotherapy for RCCs, were less promising. Notably, these trials were designed to exploit the indirect immunomodulatory effects of IFN-γ, whereas its direct antitumor properties—including its ability to trigger programmed cell death in tumors—remain mostly untapped. Here, we show that the proteasome inhibitor bortezomib (PS-341, Velcade) sensitizes otherwise resistant RCC cells to direct necrotic death by IFN-γ. Mechanistically, we show that bortezomib functions, at least in part, by inhibiting prosurvival NF-κB signaling. In the absence of this signal, IFN-γ triggers programmed necrosis (or “necroptosis”) dependent on the kinase RIP1. When taken together with the observation that NF-κB signaling is elevated in RCCs, these results provide rationale for the combined use of IFN-γ and bortezomib in the treatment of metastatic RCCs. Mol Cancer Ther; 12(8); 1568–78. ©2013 AACR.
Abstract A17: Antagonizing HOX function triggers apoptosis in prostate cancer cells
Authors: Morgan Richard , Simpson Guy , Boxall Angela , Michael Agnieszka , Pandha Hardev 
Published: May 2013

Abstract
The HOX genes are a family of transcription factors that determine the identity of cells and tissues during embryonic development and in adult stem cell maturation, and are known to have an oncogenic function in a number of hematological and solid malignancies. HOX genes are also highly expressed in prostate tumors relative to normal prostate tissue, but the redundant nature of HOX function has made the significance of these observations hard to assess by conventional gene knock out studies. Here we use the previously characterized antagonist HXR9 to target the post translational association of HOX proteins with the PBX co-factor and show that this is sufficient to trigger apoptosis in the prostate derived cell lines LNCaP, PC3 and DU145, in vitro. Furthermore HXR9 causes tumor shrinkage in murine and CAM models of prostate cancer. These results suggest that the interaction between HOX proteins and their PBX cofactor might be a therapeutic target in prostate cancer.
Note: This abstract was not presented at the conference because the presenter was unable to attend.
Citation Format: Richard Morgan, Guy Simpson, Angela Boxall, Agnieszka Michael, Hardev Pandha. Antagonizing HOX function triggers apoptosis in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A17.
Abstract A2: A Study of the effects of MDV3100 in the tumor microenvironment of bone metastatic castrate resistant prostate cancer (bmCRPC)
Authors: Efstathiou Eleni , Troncoso Patricia , Mohler James , Logothetis Christopher J. , Titus Mark , Tsavachidou Dimitra , Wen Sijin , Hoang Anh , Ashe Robynne , Karlou Maria , Berman Craig 
Published: May 2013

Abstract
Background: Androgen signaling remains a central driver in castrate-resistant prostate cancer. We performed a study to determine the effect of the antiandrogen MDV 3100 on bone marrow infiltrating CRPC.
Methods: From February 2010 to June 2011, we performed an open-label, observational study of 60 bmCRPC patients (pts), who underwent transilial bone marrow biopsy (BMB) at baseline, 8 weeks and end of study. Pts received MDV3100 160mg orally once daily. The primary objective was to evaluate androgen signaling in bone marrow infiltrating cancer and testosterone in blood (BT) and bone marrow (BMT) and correlate findings with clinical observations. Androgen receptor (AR) c-terminus n-terminus, AR Variant 7 (ARV7), ERG, CYP17, phospho Src (pSrc), expression and mitotic index (Ki67 ) were assessed by immunohistochemistry, AR copy number by qPCR and BT and BMT by liquid chromatography mass spectrometry.
Initial Findings: Maximal PSA decline of ≥50% occurred in 29 (48%) of 60 pts, and ≥90% in 13 (22%). Tumor involvement in BMB was detected in 28 (47%) pretreatment BMBs. Paired tumor infiltrated BMBs were found in 23 (38%) pts. Increased androgen receptor expression (n-terminal antibody used for IHC) was observed at pretreatment with heterogeneous CYP17 and pSrc extent of expression.
Pretreatment intense nuclear AR expression combined with ≥10% CYP17 tumor expression or increased BMT correlate with ≥50% PSA decline (p value 0.02). AR subcellular localization shift from dominant nuclear to cytoplasmic and regression of bone marrow tumor infiltration correlate with ≥50% PSA decline (p value 0.05). Increased pretreatment p-Src expression is associated with lack of PSA decline (p value 0.002). Increase in BMT and BT is observed after 8 weeks of MDV3100 (mean pretreatment BMT 0.026 ng/ml, Wk8 BMT 0.04 in 33pts, p value 0.0001) (pretreatment BT 0.041, wk8 BT 0.066 in 37 pts, p value &lt;0.0001).
Interpretation: Pretreatment expression profile is consistent with persistent androgen signaling in bmCRPC. MDV3100 induces pharmacodynamic changes in androgen signaling. AR changes likely account for the reported therapeutic effect of MDV3100. These data prompt exploratory combinations of MDV3100 with androgen biosynthesis inhibitors and src inhibitors.
Citation Format: Eleni Efstathiou, Patricia Troncoso, James Mohler, Christopher J. Logothetis, Mark Titus, Dimitra Tsavachidou, Sijin Wen, Anh Hoang, Robynne Ashe, Maria Karlou, Craig Berman. A study of the effects of MDV3100 in the tumor microenvironment of bone metastatic castrate-resistant prostate cancer (bmCRPC) [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A2.
Abstract A32: A urinary mRNA profile to increase the specificity of PSA and reduce the number of unnecessary biopsies
Authors: Rigau Marina , Altadill Tatiana , Doll Andreas , Sequeiros Tamara , Olivan Mireia , Garcia Marta , Sanchez Alex , Montes Melania , Ortega Israel , Morote Juan , Reventos Jaume 
Published: May 2013

Abstract
Background: Several studies have demonstrated the usefulness of monitoring an RNA transcript, such as PCA3, in post-prostate massage (PM) urine for increasing the specificity of prostate-specific antigen (PSA) in the detection of prostate cancer (PCa). However, a single marker may not necessarily reflect the multifactorial nature of PCa.
Methods: We analyzed post-PM urine samples from 154 consecutive patients, who presented for prostate biopsies because of elevated serum PSA (&gt;4 ng/ml) and/or abnormal digital rectal exam. We tested whether the putative PCa biomarkers PSMA, PSGR, and PCA3 could be detected by quantitative real-time PCR in post-PM urine sediment. We combined these findings with PSAD to test if a combination of these biomarkers could improve the specificity of actual diagnosis. Afterwards, we specifically tested our model for clinical usefulness in the PSA diagnostic “gray zone” (4–10 ng/ml) on a target subset of 82 men with no prior biopsy.
Results: By univariate analysis, we found that the PSMA, PSGR, PCA3 and PSAD scores were significant predictors of PCa. Using a multiplex model, the area under the multireceiver operating characteristic curve was 0.80 versus 0.89 in the diagnostic gray zone. Fixing the sensitivity at 96%, we obtained a specificity of 40% and 62% in the gray zone. By this approach it would be possible to save approximately 35% of unnecessary biopsies with a sensitivity of 95%.
Conclusions: Taken together, these results provide a strategy for the development of a more accurate model for PCa diagnosis. In the future, a multiplexed, urine-based diagnostic test for PCa with a higher specificity, but the same sensitivity as the serum-PSA test, could be used to determine better which patients should undergo biopsy.
Citation Format: Marina Rigau, Tatiana Altadill, Andreas Doll, Tamara Sequeiros, Mireia Olivan, Marta Garcia, Alex Sanchez, Melania Montes, Israel Ortega, Juan Morote, Jaume Reventos. A urinary mRNA profile to increase the specificity of PSA and reduce the number of unnecessary biopsies [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A32.
Abstract A42: In vitro proliferation, apoptosis, cell cycle progression, and gene analysis for 25- hydroxyvitamin D-1α-hydroxylase (1α-OHase) transfected LNCaP cells.
Authors: Banks Mara , Holick Michael F. 
Published: May 2013

Abstract
Vitamin D is converted to 25(OH)D, which is the major vitamin D metabolite in circulating blood. However, 25(OH)D must be converted to 1α,25(OH)2D for most of its biological actions. 25- hydroxyvitamin D-1α-hydroxylase (1α-OHase) is the enzyme that hydroxylates the1-alpha position of 25(OH)D and creates the biologically active form of vitamin D, 1α,25(OH)2D. 1α,25(OH)2D has been shown to induce cell cycle regulation, apoptosis and inhibit proliferation in prostate cancer cells. Previous studies have demonstrated that prostate and some prostate cancer cells have the ability to convert 25(OH) D to 1α,25(OH)2D. This ability along with epidemiological evidence correlating an inverse relationship between serum 25(OH)D levels and prostate cancer risk suggests that vitamin D and its metabolizing enzymes may be important for prostate cancer prevention. Since LNCaP cells are androgen sensitive, possess a functional vitamin D receptor, have 24-OHase activity but lack 1α-OHase activity, this cell line was the model used to transfect 1α-OHase and determine what the effects local conversion to 1α,25(OH)2D had on prostate cancer cells. LNCaP cells transfected with the sense strand of 1α-OHase have been designated 1α-S. We hypothesize that local intracellular conversion of 25(OH) D to 1α,25(OH)2D is important to the anti-carcinogenic autocrine/paracrine functions of vitamin D. Cellular proliferation, apoptosis and cell cycle progression were assessed using 3[H]-thymidine incorporation, DNA fragmentation and fluorescence activated cell sorting, respectively. Gene analysis was done using Real Time PCR to elucidate the molecular mechanism(s) involved in vitamin D's anti-carcinogenic effects. A dose dependent decrease in 3[H]-thymidine incorporation in 1α-S cells was observed with 25(OH)D at 10−6M concentration having the greatest decrease (54.1± 9.0%). In 1α-S cells treated with 25(OH)D at 10−6M, there was 2.1 times more DNA fragmentation than untreated LNCaP cells or LNCaP treated with 25(OH) D at 10−6M. Cell cycle progression was also analyzed with 10−6M 25(OH)D treatment in 1α-S resulted in 94.9% of cells being in the G1 phase. Gene expression analysis showed an increase in cell cycle regulatory genes; p21 (14.1±0.5 fold), p27 (5.2±0.4 fold) and p53 (3.8±0.4 fold). Apoptotic gene expression, bax and bcl-2, were induced (3.8±0.4 fold) and suppressed (0.04±0.3 fold) in 1α-S cells, respectively. This study supports the idea that the local intracellular conversion to 1α,25(OH)2D is important to prostate cancer prevention.
Citation Format: Mara Banks, Michael F. Holick. In vitro proliferation, apoptosis, cell cycle progression, and gene analysis for 25- hydroxyvitamin D-1α-hydroxylase (1α-OHase) transfected LNCaP cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A42.
Abstract A46: A new transgenic mouse model of prostate cancer that displays rapid progression from prostate intraepithelial neoplasia to invasive carcinoma.
Authors: Bjerke Glen , Yang Chun-Song , Frierson Henry , Paschal Bryce , Wotton David 
Published: May 2013

Abstract
Understanding the molecular, biochemical, and cellular mechanisms that underpin prostate cancer progression will reveal new opportunities for targeted therapies. Our NCI-supported Program Project on “Signaling and Progression in Prostate Cancer” is a team of basic and clinician scientists that share the overall goal of defining how prostate cancer cells subvert signal transduction pathways during progression to androgen independence. Projects and cores within our program are developing new model systems intended to recapitulate human disease progression. Core B in the program (Transgenic Models and Animal Imaging) has developed a new transgenic mouse model by combining mutant alleles of genes known to have important roles in human prostate cancer. The model is based on the phosphatase and tensin homolog (Pten) tumor suppressor, which is mutated in approximately 30% of primary prostate cancers. Prostate-specific deletion of Pten in mice has been shown by multiple groups to cause prostatic intraepithelial neoplasia (PIN), which slowly progresses to invasive cancer. This suggests that Pten loss allows the initiation of cancer, but that progression is subject to restraint mechanisms. We hypothesized that a restraint mechanism might depend on signaling via the TGFβ pathway, owing to the prominent role that TGFβ plays in growth control. We show that conditional deletion of Pten and Tgfbr2, the type II receptor for TGFβ, in prostate epithelium results in large, poorly differentiated prostate tumors with 100% penetrance by 12 weeks of age. Mice with Pten and Tgfbr2 deletions acquire invasive adenocarcinoma and bladder obstruction and most die by 15 weeks of age. Androgen depletion by castration does not provide a survival benefit for these mice. Pten loss causes an increase in expression of the cyclin-dependent kinase inhibitor p27, which likely restrains progression in this setting. However, when both Pten and Tgfbr2 are deleted, p27 levels are reduced and cyclin D levels increase. Our results suggest that Tgfbr2 is an important tumor suppressor in prostate cancer and that its loss allows rapid progression when combined with loss of the Pten tumor suppressor. Disruption of the TGFβ-mediated restraint provides a rapid, penetrant, and physiologically relevant preclinical model that will be helpful for analyzing restraint- and progression-related gene expression and signal transduction changes in Pten-dependent tumorigenesis.
Citation Format: Glen Bjerke, Chun-Song Yang, Henry Frierson, Bryce Paschal, David Wotton. A new transgenic mouse model of prostate cancer that displays rapid progression from prostate intraepithelial neoplasia to invasive carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A46.
Abstract B51: Ligand-independent EphA2 signaling through Akt is preferentially activated in prostate cancer bone metastases and is important for tumor growth
Authors: Petty Aaron , Miao Hui , Guo Hong , Morrissey Colm , Chinnaiyan Arul , Wu Hong , Wang Bingcheng 
Published: May 2013

Abstract
Prostate cancer progression to castration-resistance (CRPC) and metastasis represent the major challenges to effective prostate cancer therapy. PI3 kinase/Akt pathway activation has been linked to CRPC progression and metastasis, but the precise mechanisms have only been partially determined. Recently, we discovered that ligand-independent activation of the EphA2 receptor tyrosine kinase by Akt on a serine 897 site (S897) promotes cell migration and invasion, while stimulation with its ligand, ephrin-A1, downregulates EphA2 and inhibits migration and invasion. In the current study, we sought to determine whether ligand-independent EphA2 activation by Akt is linked to prostate cancer metastasis and progression to CRPC through biochemical and immunohistochemical analyses. Analysis of a panel of human prostate cancer tissues revealed EphA2 overexpression and increased S897 phosphorylation primarily in bone metastases, the primary metastatic site. Similarly, EphA2 was overexpressed in human cell lines from bone and brain metastases, but not in those from lymph node metastasis or primary tumor. Further analysis in a PTEN-deletion mouse model of aggressive prostate cancer revealed increased S897 phosphorylation in prostate glands from PTEN-null mice, compared to wild type prostate glands. To determine the potential link of EphA2 phosphorylation to CRPC progression, we compared S897 phosphorylation in xenograft tumors from both LAPC9 androgen-dependent and castration-resistant prostate cancer cell lines and found increased S897 phosphorylation in tumors from castration-resistant cells. Finally, abolishing S897 phosphorylation through the S897A point mutation inhibited growth of PC3 prostate cancer cells in a xenograft mouse model. Our study supports a link between ligand-independent EphA2 activation and prostate cancer progression and metastasis to bone, as well as primary tumor growth, highlighting a potential new mechanism involved in malignant prostate cancer progression.
Citation Format: Aaron Petty, Hui Miao, Hong Guo, Colm Morrissey, Arul Chinnaiyan, Hong Wu, Bingcheng Wang. Ligand-independent EphA2 signaling through Akt is preferentially activated in prostate cancer bone metastases and is important for tumor growth [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B51.
Abstract B7: ETS1 overexpression in prostate cancer cells
Authors: Bentel Jacqueline M. , Harvey Jennet , Thomas Marc A. , Rodgers Jamie J. , Rouse Ebony J. , Preece Darren M. , Chai Siaw M. , Epis Michael R. , Cohen Ronald J. , Leedman Peter J. , Roehrig Kimberley 
Published: May 2013

Abstract
The ETS1 transcription factor is overexpressed in human prostate cancers in comparison to nonmalignant prostate and exhibits nuclear, in addition to aberrant cytoplasmic localisation. A previous report has identified direct interaction between ETS1 and the androgen receptor (AR) in the prostate cancer cell line, LNCaP and we have demonstrated that this ligand-dependent interaction is mediated via the ETS (DNA binding) domain of ETS1 and the ligand-binding domain of the AR. In a cohort of 44 prostate cancer cases, mRNA for the full-length ETS1 isoform, p54ETS1 was detected in all prostate tumour and adjacent nonmalignant prostate tissues, while expression of the internally truncated p42ETS1 isoform was very low or undetectable. In protein lysates extracted from the same cases, p54ETS1 was detected in all samples, with expression of a lower molecular weight ETS1 corresponding in size to the dominant negative p27ETS1 isoform also observed. Increased expression of one or both of the ETS1 isoforms was identified in 38 (86%) cases, supporting the elevated expression of ETS1 in human prostate tumours. Both ETS1 and the AR upregulate expression of the prostatic tumour suppressor, NKX3.1 via sequences located in the 5′ promoter and 3′ untranslated region (3′UTR), respectively. Although unresponsive to androgens, the proximal ∼2kb of the NKX3.1 promoter, and in particular a 76bp sequence surrounding the ETS binding site (EBS) become androgen responsive following ETS1 overexpression. In addition, in LNCaP cells that stably overexpress p54ETS1, the biphasic proliferative responses to androgens, where low (≤10−10M) DHT concentrations stimulate proliferation and higher (&gt;10−10M) DHT levels inhibit proliferation, were altered and DHT concentrations as low as 10−12M inhibited proliferation. The findings indicate that the increased expression of ETS1 commonly observed in human prostate tumours may modify the androgen responsiveness of the cancer cells, augmenting AR-mediated regulation of androgen target genes and potentially sensitising prostate cancer cells to the very low androgen levels in men treated with androgen ablation therapies.
Citation Format: Jacqueline M. Bentel, Jennet Harvey, Marc A. Thomas, Jamie J. Rodgers, Ebony J. Rouse, Darren M. Preece, Siaw M. Chai, Michael R. Epis, Ronald J. Cohen, Peter J. Leedman, Kimberley Roehrig. ETS1 overexpression in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B7.