bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 456: ERG regulation of intracrine androgen production and castration-resistant prostate cancer progression
Authors: Powell Katelyn A. , Semaan Louie , Maddipati Krishna R. , Conley-Lacomb Katie (Mary) , Li Yanfeng , Cher Michael , Chinni Sreenivasa R. 
Published: May 2015

Abstract
Introduction and Objective: Intratumoral androgen synthesis in prostate cancer (PC) contributes to the development of castration-resistant prostate cancer (CRPC). Several enzymes responsible for androgen biosynthesis have been shown to be overexpressed in CRPC, thus, contributing to CRPC in a castrated environment. However, little is known regarding their mode of regulation and expression in this context. The TMPRSS2-ERG transcription factor has been shown to be present in primary PC tumors as well as CRPC tumors; however, its biological function contributing to the development CRPC in the context of intratumoral androgen synthesis is not known. We hypothesize that TMPRSS2-ERG fusions regulate androgen biosynthetic enzyme (ABE) gene expression and the production of androgens, which contributes to the development of CRPC.
Methods: We used a variety of methods including lentiviral knockdown and overexpression of ERG, qPCR, Western blot, ChIP-PCR, and Mass Spectrometry.
Results: We found that (a) shRNA knockdown of ERG in VCaP PC cells significantly reduces the expression of ABE's AKR1C3, HSD17B6, and HSD17B4; (b) overexpression of truncated ERG or wild-type ERG in LNCaP PC cells significantly increases the expression of AKR1C3 and HSD17B6; (c) ERG binds to the AKR1C3 gene in VCaP PC cells; and (d) DHT synthesis is reduced in VCaP shERG cells treated with 5α-Androstanedione, a DHT precursor metabolite, compared to VCaP shScrambled controls.
Conclusions: These data suggest that AKR1C3 catalyzes the biochemical reduction of 5α-Androstanedione to DHT in PC cells, and that ERG may regulate this step through upregulation of AKR1C3 expression. Elucidation of ERG regulation of ABEs in CRPC may help to stratify TMPRSS2-ERG fusion-positive PC patients in the clinic for anti-hormone driven therapies. Additionally, not all PC tumors express CYP17A1 enzyme, therefore this study emphasizes the importance of investigating ABEs other than CYP17A1, such as AKR1C3 and HSD17B6. In summary, this study addresses alternative ABE drug targets as well as possible drug resistance modes in PC treatment.
Citation Format: Katelyn A. Powell, Louie Semaan, Krishna R. Maddipati, Katie (Mary) Conley-Lacomb, Yanfeng Li, Michael Cher, Sreenivasa R. Chinni. ERG regulation of intracrine androgen production and castration-resistant prostate cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 456. doi:10.1158/1538-7445.AM2014-456
Abstract 4566: Fusarochromanone inhibits cell proliferation and induces cell death in COS7 cells
Authors: Gu Ying , Jiang Shanxiang , Mahdavian Elahe , Huang Shile 
Published: May 2015

Abstract
Fusarochromanone (FC101) is a mycotoxin produced by Fusarium equiseti. Contamination of FC101 occurs frequently in grains and feedstuffs, which has been found to cause tibial dyschondroplasia in chickens and Kashin-Beck disease in children. However, little is known about the toxicity of FC101 in the kidney. In this study, we found that FC101 inhibited cell proliferation and induced cell death in monkey kidney fibroblasts (COS7) in a concentration-dependent manner. Furthermore, we found that FC101 inhibited cell proliferation by arresting cells in G1 phase of the cell cycle, which was associated with reduced expression of CDK4, cyclin D1, and Cdc25A, as well as decreased phosphorylation of Rb. FC101 induced cell death by downregulating expression of Bcl-2, Bcl-xl and survivin, and upregulating expression of Bad, leading to increased cleavages of caspase 3 and PARP. Also, FC101 induced translocation of apoptosis inducing factor (AIF) from the cytosol to the nucleus. Furthermore, FC101 activation of JNK cascade also contributed to cell death, as inhibition of JNK with SP600125 or expression of dominant negative c-Jun attenuated FC101-induced cell death. In addition, we observed that FC101-induced cell death linked to induction of reactive oxygen species (ROS) in the cells, since addition of antioxidants (co-enzyme Q10 and N-acetyl-cysteine) attenuated the toxic effect of FC101 on the cells. Our findings suggest that FC101 may exert its toxicity in COS7 cells through oxidative stress.
Citation Format: Ying Gu, Shanxiang Jiang, Elahe Mahdavian, Shile Huang. Fusarochromanone inhibits cell proliferation and induces cell death in COS7 cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4566. doi:10.1158/1538-7445.AM2014-4566
Abstract 4569: Digitizing single-cell expression patterns in urine for prostate cancer detection
Authors: Lin Chun-Lin , Chen Chun-Liang , Wang Chiou-Miin , Liu Joseph , Huang Susan , Huang Tim 
Published: May 2015

Abstract
Gene expression profiles of microdissected tissue are frequently used to stratify cancer subtypes and to predict patients' clinical outcome. This type of analysis usually operates under the assumption that uniform gene expression is present in a cancer cell population. However, high fluctuation of gene expression in single cells stemming from intra-clonal heterogeneity within a cancer cell population can lead to misinterpretation of the data. An important challenge then lies in developing approaches to decipher this expression chaos for cancer diagnostic and/or prognostic strategies.
We have developed a novel digitizing approach to analyze single-cell gene expression in exfoliated prostate cells isolated from urine sediment. In analyzing 1220 single cells, we observed a panel of genes with dichotomous expression patterns (DEP) and further digitized their expression levels to either 1 for high or 0 for low expression. Of 35 androgen-responsive genes examined, 6 genes exhibited DEP characteristics. When aligning the dichotomous numbers of these genes in the order of CXCL6-TGFBR2-GSK3B-CDKN1C-GATA3-EIF4EBP1, we identified 64 (26) types of code; e.g., 1-0-1-0-1-0. With the conversion from original expression levels to a series of dichotomous numbers, these new codes not only reduced the complexity associated with single cell expression, they also enabled us to decipher expression heterogeneity in the samples by considering multiple gene expression codes simultaneously.
Importantly, these digitized codes identified distinct clonal prostate cell populations in the urine samples. At the single-cell level, high volumes of cells with the same code (common codes) in a collection of cells suggested the presence of a large clonal cell population. By examining the types of code and the size of clonal populations, we found that increasing clonal size of cells carrying common codes was associated with high-grade cancers. Certain common codes were also found in cells from patients diagnosed with benign prostate hyperplasia and prostatic intraepithelial neoplasia. On the other hand, digitized code types appeared to be highly diverse in normal cell populations.
Our data suggest that digitizing single-cell expression can stratify benign, low grade and high grade prostate cancer. This analysis pipeline has a wider application for disease diagnosis/prognosis using cancer cells isolated by non-invasive means from biological fluids or washes from biopsy needles and surgical blades.
Citation Format: Chun-Lin Lin, Chun-Liang Chen, Chiou-Miin Wang, Joseph Liu, Susan Huang, Tim Huang. Digitizing single-cell expression patterns in urine for prostate cancer detection. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4569. doi:10.1158/1538-7445.AM2014-4569
Abstract 4570: Role of ERRalpha in ovarian cancer
Authors: Stevens Ellen V. , Whitaker Regina , Guinet Audrey , Chang Ching-Yi , Grenier Carole , Marks Jeffrey , McDonnell Donald P. , Murphy Susan K. , Berchuck Andrew , Gaillard Stephanie 
Published: May 2015

Abstract
Objective. The estrogen receptor-related receptor-alpha (ERRα, encoded by ESRRA) has emerged as a key transcriptional regulator of mitochondrial function and has been implicated as a prognostic marker in many cancers, including epithelial ovarian cancer. ERRα has shown promise as a therapeutic target in breast cancer where ERRα transcriptional activity regulates growth of breast cancer cells. This study aims to evaluate whether ERRα expression in ovarian cancer correlates with patient outcomes, determine the effect of inhibiting ERRα transcriptional activity on ovarian cancer cell growth, and identify molecular signaling pathways regulated by ERRα in ovarian cancer cells.
Methods. Affymetrix U133A gene expression microarray analysis from frozen tumor specimens of serous epithelial ovarian cancer was used to compare ESRRA transcripts levels in patients with short-term (&lt;3 years) verses long-term survival (&gt;7 years). ESRRA transcript levels were also measured in normal ovarian surface and fallopian tube epithelial tissues. Protein expression levels were assessed in ovarian cancer cell lines and patient tumor samples. Overall survival was estimated using the Kaplan-Meier Method. The effect of ERRα inhibition on proliferation and anchorage-independent growth was determined after treatment with the ERRα antagonist, XCT790. The activity of 49 different phospho-receptor tyrosine kinases (RTKs) was analyzed after down-regulation of ERRα with shRNA.
Results. ESRRA expression was significantly higher in cancer tissues verses normal ovarian surface and fallopian tube epithelial tissues. Expression was also higher in patients with short-term versus long-term survival. Inhibition of ERRα with XCT790 led to a &gt;50% reduction in proliferation and anchorage-independent growth. The induced knockdown of ERRα decreased the phosphorylation of RTKs, including HER2, suggesting that important growth promoting pathways are downstream of ERRα.
Conclusions. In this study we determined that higher expression of ESRRA correlates with worse survival in ovarian cancer patients. However, inhibition of ERRα results in decreased growth potential. This effect may be manifest through the regulation of receptor tyrosine kinase activity. Thus, ERRα may be an important therapeutic target for the treatment of ovarian cancer and warrants future studies to determine the role of ERRα regulated signaling networks in ovarian oncogenesis.
Citation Format: Ellen V. Stevens, Regina Whitaker, Audrey Guinet, Ching-Yi Chang, Carole Grenier, Jeffrey Marks, Donald P. McDonnell, Susan K. Murphy, Andrew Berchuck, Stephanie Gaillard. Role of ERRalpha in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4570. doi:10.1158/1538-7445.AM2014-4570
Abstract 4573: A novel bispecific Fap-Dr5 antibody inducing potent and tumor-specific death receptor 5 (Dr5) activation by fibroblast activation protein (Fap)-dependent crosslinking
Authors: Wartha Katharina , Weiser Barbara , Friess Thomas , Majety Meher , Runza Valeria , Herting Frank , Weber Thomas , Scheuer Werner , Harring Suzana Vega , Sade Hadassah , Niu Huifeng , Bruenker Peter 
Published: May 2015

Abstract
Background:
Activation of the extrinsic apoptosis pathway in tumor cells through agonistic death receptor 5 (DR5) antibodies has been evaluated in the clinic with limited success so far. In this context, several reports show that DR5 activation is strongly dependent on receptor hyperclustering on the cell surface. Therefore a therapeutic principle that induces DR5 hyperclustering specifically at the tumor site may provide superior efficacy, potency and safety compared to conventional DR5 agonistic antibodies. Fibroblast activation protein (FAP) is a marker for activated fibroblasts and abundantly expressed in cancer associated fibroblasts of various epithelial tumor indications and as a tumor antigen on tumors of mesenchymal origin. Due to its relative absence from normal tissues, FAP can be used as a tumor targeting antigen. Here, we are using the broad expression of FAP in tumor stroma for crosslinking of DR5 by a bispecific antibody.
Aim:
In order to achieve superior tumor targeting and tumor located DR5 hyperclustering we have generated a bispecific antibody, RG7386, comprised of an agonistic DR5 binder and a FAP targeting moiety.
Results:
RG7386 shows potent and selective binding to FAP and DR5 and can simultaneously bind to both targets. In in vitro co-culture assays, using human DLD-1 colon cancer cells and FAP expressing fibroblasts, RG7386 induces potent, FAP dependent DR5 hyperclustering and apoptosis induction in DR5 positive tumor cells (IC50: 0.05 nM). In preclinical in vivo models with co-injection of DLD-1 tumor cells and fibroblasts as well as patient-derived colorectal cancer models, RG7386 shows FAP dependent efficacy and apoptosis induction superior to conventional DR5 antibodies. Furthermore the superior induction of apoptosis could be confirmed by in vivo and ex vivo analysis of cleaved Caspase-3 with imaging, Luminex and histopathology.
Conclusion:
RG7386 is a promising novel therapeutic entity for the treatment of solid tumors with FAP positive tumor stroma inducing DR5 activation by FAP dependent DR5 hypercrosslinking which results in potent anti-tumor activity.
Citation Format: Katharina Wartha, Barbara Weiser, Thomas Friess, Meher Majety, Valeria Runza, Frank Herting, Thomas Weber, Werner Scheuer, Suzana Vega Harring, Hadassah Sade, Huifeng Niu, Peter Bruenker. A novel bispecific Fap-Dr5 antibody inducing potent and tumor-specific death receptor 5 (Dr5) activation by fibroblast activation protein (Fap)-dependent crosslinking. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4573. doi:10.1158/1538-7445.AM2014-4573
Abstract 4581: A novel modular polymer platform for the treatment of oral and head and neck carcinoma
Authors: Lin Yuan , Sharma Sherven , Dubinett Steven M. , Wu Ben , John Maie St. 
Published: May 2015

Abstract
Objective: Head and neck Squamous cell carcinoma (HNSCC) is difficult to resect completely by surgery due to complicated context and therefore exhibits high recurrence rate in the patient. To reduce tumor recurrence after surgery, we developed a biodegradable polymer to deliver CCL21 cytokine and cisplatin, and evaluate its efficacy in a partially resected xenograft animal model of HNSCC.
Study Design: in vivo study.
Setting: Academic research laboratory.
Subjects and Methods: After xenograft HNSCC tumors were established by subcutaneous injection, C3H/HeJ mice underwent surgery to debulk their tumors to a size of 0.5x0.5x0.5 cm3 and received different polymer implantation. For cytokine studies, mice were grouped into: (1) no polymer; (2) plain polymer; (3) plain polymer with intratumoral injection of recombinant CCL21 twice a week; (4) polymer containing parental dendritic cells; (5) polymer containing dendritic cells secreting CCL21 (DC-CCL21). For cisplatin studies, mice were randomized to receive implantation of (1) no polymer; (2) plain polymer; (3) plain polymer with local cisplatin injection; (4) cisplatin polymer. The two groups of mice implanted with cisplatin polymer or no polymer were further randomized to receive (1) 4 Grays external beam radiation for 4 days; (2) no radiation. Tumor size was measured until the mice were euthanized. At necropsy, the tumors were excised and weighed.
Results: Our results using this novel polymer platform demonstrate a significant reduction in tumor growth. The DC-CCL21 polymer reduced SCCVII/SF tumors in the C3H/HeJ mice by over 41% compared to the control groups (p&lt;0.01). The cisplatin secreting polymer effectively reduced SCCVII/SF tumors in the C3H/HeJ mice by over 16-fold (P &lt; 0.01) as compared to control, plain polymer group. We also observed a statistically significant lower tumor weight among mice treated with cisplatin polymer and concomitant CCL21 compared to the control group.
Conclusion: Herein we demonstrate the efficacy of a novel polymer platform in delivering cisplatin and cytokines to a partially resected SCC in a murine model. We also demonstrate that we can effectively grow dendritic cells in the polymer that can actively secrete CCL21. Our results indicate that this polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized we will plan for validation in the context of a prospective trial in patients with unresectable advanced or recurrent HNSCC.
Citation Format: Yuan Lin, Sherven Sharma, Steven M. Dubinett, Ben Wu, Maie St. John. A novel modular polymer platform for the treatment of oral and head and neck carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4581. doi:10.1158/1538-7445.AM2014-4581
Abstract 4591: The folate receptor-targeted agents, vintafolide and etarfolatide, are not substrates for the reduced folate carrier or the proton-coupled folate transporter
Authors: Parker Nikki , Cherian Christina , Matherly Larry , Leamon Christopher P. 
Published: May 2015

Abstract
Vintafolide (EC145), a folate-targeted small molecule drug conjugate (SMDC) of desacetylvinblastine hydrazide (DAVLBH), and etarfolatide (EC20), a folate-targeted companion imaging agent, are currently being evaluated in global phase 2 and 3 studies for the selection and treatment of patients with folate receptor (FR)-positive tumors. Both of these compounds have been shown to bind with high affinity and specificity to the FR, which is known to be internalized via endocytosis. Though the FR is the major route for delivery of folic acid (an oxidized folate congener) into a cell at physiological pH, two other transporters, the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), play key roles in transporting folates and antifolates across the cell membrane at neutral and acidic pH, respectively. It is not known, however, if these two transporters play any role in the uptake of folic acid-based SMDCs. Therefore, this study was designed to determine whether vintafolide and/or etarfolatide are substrates for active transport by the RFC or PCFT, or whether their cellular uptake is specific only to the FR. To achieve this, we utilized a set of isogenic Chinese hamster ovary cell lines which have been engineered from transporter-null R2 cells to express the RFC, PCFT, or FR-α, to evaluate cellular uptake of 3H-vintafolide and 3H-etarfolatide:Re. The results of the uptake studies showed that no RFC or PCFT-specific transport of either SMDC occurred under the optimal conditions for transporter activity (pH 7.2 for RFC, and pH 5.5 for PCFT). Conversely, 3H-MTX, a known RFC and PCFT substrate, showed significant uptake by both the RFC and PCFT-expressing cells, and uptake was blocked by PT523 (specific inhibitor for RFC) and AG94 (specific inhibitor for PCFT). Though levels of 3H-vintafolide uptake by the RFC-expressing PC43 cells were similar to that of 3H-MTX, no inhibition of 3H-vintafolide uptake was seen with PT523 suggesting that this uptake is not mediated by the RFC. As expected, very high 3H-vintafolide and 3H-etarfolatide:Re binding and uptake was seen in the FRα-expressing RT-16 cells, and this uptake was competable with excess FA indicating that the interaction was specific to the FR. Collectively, these results show that vintafolide and etarfolatide are specifically transported via the FR and are not substrates for the RFC or PCFT.
Citation Format: Nikki Parker, Christina Cherian, Larry Matherly, Christopher P. Leamon. The folate receptor-targeted agents, vintafolide and etarfolatide, are not substrates for the reduced folate carrier or the proton-coupled folate transporter. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4591. doi:10.1158/1538-7445.AM2014-4591
Abstract 4602: Blocking of p14/ARF and DX2 binding by novel small chemical can improve the chemo-sensitivity of small cell lung cancer and non-small cell lung carcinoma
Authors: Oh Ah Young , Jung Youn-Sang , Lee Su-Jin , Jo Jung Hyun , Chun Ho Young , Park Bum-Joon 
Published: May 2015

Abstract
In recent, it has been reported that alternative splicing variant of AIMP2, AIMP2/DX2 (DX2), is frequently expressed in human lung cancer and is related with p53-mediated tumor suppression pathway. Here we show that DX2 can promote tumor progression and increase incidence, cooperatively with oncogenic K-Ras in transgenic mouse model. Moreover, it can induce small cell lung carcinoma (SCLC) as well as contribute to progression of non-small cell lung carcinoma (NSCLC). In fact, DX2 expression is elevated in human small cell lung cancer cell lines. Based on the cellular localization and responsibility of si-DX2, we revealed that DX2 is an inhibitor of p14/ARF. Elimination of DX2 can induce p14/ARF expression and DX2 Transgenic (Tg) mouse cells show the low expression of p19/ARF. Since DX2, but not its original product AIMP2, is selectively interacted with p14/ARF, we screened the specific binding inhibitor and obtained the single compound (SLC36) from about 9000 chemicals. This chemical can block the interaction of p14/ARF-DX2 and also AIMP2-DX2, but not the binding of p14/ARF-p53 or AIMP2-p53. In addition, it can induce p14/ARF expression and cell death in human lung cancer cell lines including SCLC cell lines. In our in vivo study, treatment of SLC36, combined with low dosage of adriamycin (1 mg/kg) can suppress the cancer incidence as well as progression in K-RasLA2 and K-Ras/DX2 double Tg model. These results indicate that DX2 can contribute to lung cancer progression and development, including SCLC, through inhibition of p14/ARF, and blocking of DX2-p14/ARF binding would be useful therapeutic strategy of human lung cancers including SCLC as well as NSCLC.
Citation Format: Ah Young Oh, Youn-Sang Jung, Su-Jin Lee, Jung Hyun Jo, Ho Young Chun, Bum-Joon Park. Blocking of p14/ARF and DX2 binding by novel small chemical can improve the chemo-sensitivity of small cell lung cancer and non-small cell lung carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4602. doi:10.1158/1538-7445.AM2014-4602