bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3367: BMP-6 regulates expression of androgen receptor via NF-κB signaling pathway and activated macrophages
Authors: Wilcox Emma , Kwon Seok Joo , Lee Geun Taek , Kim Isaac Yi 
Published: August 2015

Abstract
Prostate cancer (CaP) is the most common non-cutaneous cancer among men in the United States (US). Recent report estimated that around 233,000 new CaP cases will be occurred in 2014 and about 29,480 men will be death because of CaP in the US. Despite recent progress in CaP treatment, metastatic CaP patients still have a poor prognosis due to the inevitable emergence of castration resistant prostate cancer (CRPC). It has been reported that androgen hypersensitivity and tumor microenvironment were critical factors for developing CRPC. In the present study, we investigate the role of BMP-6 on androgen hypersensitivity in the context of macrophages. Initially, we co-cultured androgen responsive murine CaP cell lines TRAMP-C1 and PTEN-CaP8 with RAW 264.7 murine macrophage cell lines and treated with BMP-6. We found that androgen receptor (AR) expression was increased in both cell lines by treatment of BMP-6 and BAY 11-7082 NF-κB inhibitor neutralized this augmentation. The result indicates that NF-κB signaling pathway is involved in up-regulation of AR in CaP cells. To find which NF-κB is activated, we analyzed NF-κB signaling pathway with immunoblot and found that canonical NF-κB pathway was activated in CaP cells. Cytokines such as IL-6 and TNF-α are potential inducer of NF-κB signaling pathway and these cytokines were up-regulated in RAW cells in our co-culture system. Based on these observations, we suggest that BMP-6 potentially regulates expression of AR in CaP cells via activated macrophages and canonical NF-κB pathway.
Citation Format: Emma Wilcox, Seok Joo Kwon, Geun Taek Lee, Isaac Yi Kim. BMP-6 regulates expression of androgen receptor via NF-κB signaling pathway and activated macrophages. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3367. doi:10.1158/1538-7445.AM2015-3367
Abstract 3369: Nuclear hormone receptor profiling of skin cancer-associated fibroblasts for targeted pharmacological modulation of skin squamous cell carcinoma
Authors: Chan Jeremy Soon Kiat , Sng Ming Keat , Teo Zi Qiang , Tan Nguan Soon 
Published: August 2015

Abstract
Background: Cutaneous squamous cell carcinoma (SCC) is the second-most frequently diagnosed non-melanoma skin cancer that commonly manifests in sun-exposed areas of the skin, resulting in permanent disfigurement and potentially death when untreated. The development and malignant progression of skin SCC is dependent not only on the properties of the tumor epithelia but also the effects of the tumor stroma. Cancer associated fibroblasts (CAFs) are enriched in the stroma of skin SCC tumors and supply paracrine factors that encourage tumor growth. However, the transcription regulatory networks enabling this pro-tumor secretory phenotype of CAFs remain largely unknown. Nuclear receptors, being ligand-inducible transcription factors, are relevant therapeutic candidates for modulation of CAF-dependent SCC tumor advancement.
Materials and methods: Laser capture microdissected CAFs from archived patient SCC biopsies were profiled for their expression of 48 known nuclear receptors. siRNA knockdown and overexpression of specific nuclear receptors in CAFs was performed, and their impact on the SCC transcriptome and phenotype was evaluated in a co-culture system. Co-administration of nuclear receptor ligands and conventional anticancer chemotherapeutics was also carried out in a 3D-organotypic skin tumor model to investigate synergistic and sensitizing effects on SCC.
Findings and conclusions: Our study is the first to define a nuclear receptor profile for SCC CAFs, wherein the expression of 5 nuclear receptors was unchanged, 18 nuclear receptors were highly expressed and 3 nuclear receptors were lowly expressed in CAFs relative to normal fibroblasts. We showed that SCC tumor epithelia are transcriptionally and functionally sensitive to this nuclear receptor profile of CAFs. Simultaneous and differential attenuation of multiple aggressive SCC phenotypes was possible through the manipulation of specific nuclear receptor expression and activity in CAFs. Our results highlight the utility of CAF nuclear receptor profiling and a role for nuclear receptor-directed drugs in the multimodal treatment of skin SCC.
Citation Format: Jeremy Soon Kiat Chan, Ming Keat Sng, Zi Qiang Teo, Nguan Soon Tan. Nuclear hormone receptor profiling of skin cancer-associated fibroblasts for targeted pharmacological modulation of skin squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3369. doi:10.1158/1538-7445.AM2015-3369
Abstract 3372: Molecular characteristics of cancer-associated adipocytes in breast cancer
Authors: Moon Hyeong-Gon , Lee Jiwoo , Lee Han-Byoel , Ryu Han Suk , Han Wonshik , Noh Dong-Young 
Published: August 2015

Abstract
Adipose tissue in the tumor microenvironment is now regarded to be an active player in cancer development and progression. Recent studies have suggested critical roles of the cancer-associated adipocytes in breast cancer proliferation and invasion. However, unlike the well-known cancer-associated fibroblasts, the molecular profiles of cancer-associated adipocytes are largely unknown.
We studied the histo-morphologic changes in adipose tissue adjacent to the breast cancer cells in human tissues. Adipocytes had smaller fat droplets and often associated with immune cell infiltration. We investigated the changes of mRNA expression profiles of differentiated adipocytes when they were cultured with breast cancer cells (MCF-7 and MDA-MB-231) by using the NIH-3T3-L1 cell line. Indirect coculture with cancer cells resulted in significantly altered expression of genes involved in immune response, extracellular matrix remodeling, angiogenesis, metabolism, and apoptosis. IL6 and its downstream genes, transcription factors such as RUNX1, as well as PTX3 and TIMP1 were most unregulated genes. Increased secretion of IL6 was further validated in the culture media by ELISA. Also, the gene expression data showed that adipocytes cocultured with cancer cells showed decreased adipocyte-differentiation genes suggesting the cells underwent de-differentiation process. Microscopic examination of co-cultured adipocytes showed smaller fat droplets similar to human specimens. The co-cultured adipocytes showed different effect on cancer cells according to the molecular subtypes of the breast cancer cells. The conditioned media from co-cultured adipocytes resulted in increased proliferation of ER+ breast cancer cells, suggesting a subtype-dependent effect of co-cultured adipocytes in breast cancer.
Our results suggest that cancer-associated adipocytes show increased expression of genes involved in immune response, extracellular matrix remodeling, angiogenesis, metabolism, and apoptosis. Futhermore, these cancer-associated adipocytes show features toward the preadipocyte state suggesting the possibility of de-differentiation of adipocyte under the influence of adjacent cancer cells. The functional impact of the cancer-associated adipocyte seem to vary according to the molecular subtype of epithelial cancer cells.
Citation Format: Hyeong-Gon Moon, Jiwoo Lee, Han-Byoel Lee, Han Suk Ryu, Wonshik Han, Dong-Young Noh. Molecular characteristics of cancer-associated adipocytes in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3372. doi:10.1158/1538-7445.AM2015-3372
Abstract 3392: Ex vivo analysis of RAD51 foci induction in fresh tumor tissue: a promising new tool for the identification of homologous recombination-deficient tumors
Authors: Vreeswijk Maaike , Meijers M. , Naipal K.A.T. , Verkaik N.S. , Kanaar R. , Hoeijmakers J.H.J. , Jager A. , van Gent D.C. , Gaarenstroom K.N. , Smit V.T.H.B.M. , Vrieling H. 
Published: August 2015

Abstract
Purpose. BRCA1 and BRCA2 related breast and ovarian tumors respond very well to treatment with PARP inhibitors (PARPi) because of their deficiency in homologous recombination (HR). We have indications that a substantial number of ovarian tumors might have deficiencies in HR unrelated to germline mutations in BRCA1 or BRCA2. A functional assay to assess HR efficacy might therefore allow identification of additional ovarian cancer patients that could benefit from PARPi treatment.
Experimental procedure. Unselected fresh ovarian tumor samples were collected from patients undergoing surgery or ascites/pleural fluid drainage. Samples were irradiated with ionizing radiation ex vivo, fixed after 2 hours and embedded in paraffin. Sections were stained with hematoxylin and eosin and examined by pathologist. The presence of RAD51 foci in replicating cells as visualized by immunofluorescence was used as a functional read out for HR proficiency.
Results. We determined the ability to induce RAD51 foci following radiation in ex vivo cultured ovarian tumor samples that contained sufficient numbers of replicating cells (n = 13). RAD51 foci formation was absent (&lt;20% replicating cells showed RAD51 foci) in 46% of the samples. In one tumor sample that did not form RAD51 foci in replicating cells upon ionizing radiation, a pathogenic mutation in BRCA1 was identified (c.5277+1G&gt;A). Genetic and epigenetic analyses of the other samples are ongoing.
Conclusion. The ex vivo analysis of RAD51 foci induction in fresh tumor tissue is a promising new tool to identify HR deficient tumors. Not only is it an important time saving strategy compared to BRCA1/BRCA2 mutation analysis, it may also identify a much broader patient population that will be eligible for the treatment with PARP inhibitors.
Citation Format: Maaike Vreeswijk, M. Meijers, K.A.T. Naipal, N.S. Verkaik, R. Kanaar, J.H.J. Hoeijmakers, A. Jager, D.C. van Gent, K.N. Gaarenstroom, V.T.H.B.M. Smit, H. Vrieling. Ex vivo analysis of RAD51 foci induction in fresh tumor tissue: a promising new tool for the identification of homologous recombination-deficient tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3392. doi:10.1158/1538-7445.AM2015-3392
Abstract 3393: Using protein microarray technology to screen anti-PD-1 monoclonal antibodies for specificity and applications in anatomic pathology
Authors: Chen Caiwei , Tang Yanlin , Wei Haitao , Yuan Kehu , Wu Guiyin , Chen Jian , Chu Boyang , Wang Guangli , Shu Youmin , He Wei-Wu , Ma Donghui 
Published: August 2015

Abstract
Programmed death-1 (PD-1) expresses in many tumors in response to inflammation. It is up-regulated in activated T lymphocytes and inhibits T-cell function upon binding to its ligands PD-L1 and PDL2 and serves as a key checkpoint of the immune system. Pembrolizumab is the first anti-PD-1 therapy approved in the United States and received FDA's Breakthrough Therapy designation for advanced melanoma. Thus, to evaluate PD1 protein levels in formalin-fixed paraffin-embedded tissue samples, a high quality monoclonal antibody validated for immunohistochemistry (IHC) is needed.
To develop the best monoclonal antibody for PD-1 IHC analysis, 41 monoclonal antibodies were generated. 8 of them work for IHC application on FFPE tissue sections. To identify clones that are mono-specific on target, only two clones passed our high density protein microarray chip tests. Other immunoassays and species cross-reactivity tests were also explored.
In summary, two newly generated monoclonal antibodies demonstrated ultra-specificity against PD-1 protein and superior performance for IHC analyses. These two clones could be utilized as companion diagnostic reagents to stratify cancer patients before pembrolizumab prescription.
Citation Format: Caiwei Chen, Yanlin Tang, Haitao Wei, Kehu Yuan, Guiyin Wu, Jian Chen, Boyang Chu, Guangli Wang, Youmin Shu, Wei-Wu He, Donghui Ma. Using protein microarray technology to screen anti-PD-1 monoclonal antibodies for specificity and applications in anatomic pathology. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3393. doi:10.1158/1538-7445.AM2015-3393
Abstract 3402: Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer
Authors: Togashi Yosuke , Kogita Akihiro , Sakamoto Hiroki , Hayashi Hidetoshi , Terashima Masato , de Velasco Marco A. , Sakai Kazuko , Fujita Yoshihiko , Tomida Shuta , Kitano Masayuki , Kudo Masatoshi , Nishio Kazuto 
Published: August 2015

Abstract
Purpose: We previously reported that activin produces a signal with a tumor suppressive role in pancreatic cancer (PC). Here, the association between plasma activin A and survival in patients with advanced PC was investigated.
Experimental Design: The plasma activin A concentrations of patients with advanced PC were determined using an ELISA. The influence of ligands on PC cell lines was evaluated using an MTT assay and western blot analyses. The INHBA gene (beta subunit of inhibin) was overexpressed in PC cell lines, and this phenotype was investigated.
Results: Contrary to our expectations, patients with high plasma activin A levels had a significantly shorter survival period than those with low levels (median survival, 314 days vs. 482 days, P = 0.034). The cellular growth of the MIA PaCa-2 cell line was greatly enhanced by activin A via non-SMAD pathways. The cellular growth and colony formation of an INHBA-overexpressed cell line were also enhanced. In a xenograft study, INHBA-overexpressed cells tended to result in a larger tumor volume, compared with a control. The bodyweights of mice inoculated with INHBA-overexpressed cells decreased dramatically, and these mice all died at an early stage, suggesting the occurrence of activin-induced cachexia.
Conclusions: Our findings indicated that the activin signal can promote cancer progression in a subset of PC and might be involved in cachexia and that plasma activin A can be a novel prognostic factor in patients with advanced PC. The activin signal might be a novel target for the treatment of PC.
Citation Format: Yosuke Togashi, Akihiro Kogita, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio. Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3402. doi:10.1158/1538-7445.AM2015-3402
Abstract 3438: Whole pelvis versus prostate-only radiotherapy with or without short course androgen deprivation therapy and mortality risk
Authors: Braunstein Lior Z. , Chen Ming-Hui , Dosoretz Daniel E. , Salenius Sharon , Katin Michael , Nanda Akash , D'Amico Anthony V. 
Published: August 2015

Abstract
Purpose: To determine whether extent of prostate radiotherapy (i.e. whole-pelvic radiotherapy (WPRT) versus prostate/seminal-vesicle radiotherapy [PSVRT]) is associated with all-cause mortality (ACM) in men treated with or without androgen deprivation therapy (ADT).
Methods: A multi-institutional cohort of 3,709 prostate cancer patients was prospectively assembled from 1991-2006. Median age was 72 years and all patients had T1c-T3N0M0 adenocarcinoma of the prostate. Patients were treated with WPRT or PSVRT followed by a brachytherapy boost, with or without neoadjuvant ADT (median duration 4.2months). 70% of patients had unfavorable-risk disease (Gleason ≥7; PSA ≥10ng/mL; or stage ≥T2b). Cox regression was applied to determine whether the radiation treatment volume affected the risk of ACM. A test for interaction between radiation volume and ADT use was conducted.
Results: After a median follow-up of 3.3 years, 561 deaths were observed. A decreased risk of ACM was noted with the use of WPRT versus PSVRT (adjusted hazard ratio [AHR] 0.58; 95% confidence interval [CI] 0.38-0.89; p = 0.01), or with ADT (AHR 0.71; 95%CI 0.58-0.90; p = 0.004). However, combining WPRT and ADT did not further improve ACM in comparison to either WPRT alone or PSVRT with ADT. Moreover, there was a significant interaction between the RT treatment volume and ADT (AHR 1.61; 95%CI 1.004-2.58; p = 0.048).
Conclusions: Treatment with WPRT or short-course ADT is associated with a decreased risk of ACM, though combining the two does not yield greater benefit. This observation suggests a shared mechanism for this risk-reduction which we hypothesize to be sterilization of micrometastatic disease within the pelvic lymph nodes.
Citation Format: Lior Z. Braunstein, Ming-Hui Chen, Daniel E. Dosoretz, Sharon Salenius, Michael Katin, Akash Nanda, Anthony V. D'Amico. Whole pelvis versus prostate-only radiotherapy with or without short course androgen deprivation therapy and mortality risk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3438. doi:10.1158/1538-7445.AM2015-3438
Abstract 3497: Mechanism-based scheduling of triple therapy gemcitabine/CHK1i/WEE1i in pancreatic cancer at submaximal yet synergistic concentrations
Authors: Koh Siang-Boon , Richards Frances M. , Rodriguez Esther , Lyons Scott K. , Jodrell Duncan I. 
Published: August 2015

Abstract
Sensitization of cancer cells to gemcitabine has been shown with checkpoint kinase CHK1 and WEE1 inhibitors. To rationalize and optimize the concomitant use of these three agents, we first performed growth inhibition assays on MIA PaCa-2 pancreatic cancer cells using gemcitabine in combination with either CHIR-124 (CHK1 inhibitor) or MK-1775 (WEE1 inhibitor). In silico analysis with three mathematical models (Bliss Independence, Loewe and Highest Single Agent) identified synergistic growth inhibition at submaximal (i.e. &lt;GI50) concentrations of the single agents (10nM gemcitabine, 20nM CHIR-124, 300nM MK-1775) in MIA PaCa-2 cells. At these concentrations of gemcitabine+CHIR-124, quantitative image-based cytometry demonstrated S-phase redistribution, with 31% of &gt;8000 individual cells undergoing extensive fork collapse (compared to 0-1% with single agents) as evidenced by co-staining of yH2AX and hyper-phosphorylated RPA32. Conversely, submaximal gemcitabine+MK-1775 induced clear reduction of inhibitory CDK1 Y15 level compared to single agents. Consistent with this G2/M abrogation, in a Fucci-based CDT1/geminin-expressing MIA PaCa-2 stable cell line, gemcitabine+MK-1775 partially reversed the accumulation of the geminin-expressing (S/G2) population induced by gemcitabine alone. This was accompanied by an increase in the CDT1-expressing (G1) population, alongside aberrant mitotic cells with features of perturbed kinetochore-microtubule integrity. Based on these findings, we performed a series of long-term, kinetic live-cell imaging assays to determine the optimal scheduling for gemcitabine/CHK1i/WEE1i as a triplet at synergistic concentrations. In contrast to the widely proposed scheduling regimen, we found that delayed administration of CHK1i (at 24 hours), relative to gemcitabine, did not lead to synergy. However, concurrent administration yielded durable growth inhibition, even when the two agents were removed after 24 hours. This inhibition was further enhanced with the subsequent addition of WEE1i at 24 hours, but not continuation of a CHK1i. Together, our results illustrate differential mechanistic effects of CHK1 and WEE1 inhibitors with gemcitabine, when combined at sub-GI50 concentrations, and propose a novel triple agent schedule that will be evaluated in vivo.
Citation Format: Siang-Boon Koh, Frances M. Richards, Esther Rodriguez, Scott K. Lyons, Duncan I. Jodrell. Mechanism-based scheduling of triple therapy gemcitabine/CHK1i/WEE1i in pancreatic cancer at submaximal yet synergistic concentrations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3497. doi:10.1158/1538-7445.AM2015-3497
Abstract 3500: Combinations of ARQ087 with chemotherapeutic agents are safe and show a striking antitumor activity in different xenograft models
Authors: Chilà Rosaria , Guffanti Federica , Hall Terence , Ricci Francesca , Broggini Massimo , Damia Giovanna 
Published: August 2015

Abstract
ARQ087 is a non ATP-competitive tyrosine kinase inhibitor with activity against the FGFR receptor family, and currently in Phase I clinical studies for the treatment of advanced solid tumors. It potently inhibits FGFR1, 2, and 3, as well as mutant FGFR2 (N549H) and FGFR3 (K650E/M) with IC50 values in the low nanomolar range in biochemical assays. ARQ 087 has shown potent anti-proliferative activity in a panel of cancer cells with deregulated FGFR1 and FGFR2 pathways and exerted a dose-dependent antitumor activity in in vivo systems with FGFR1/FGFR2-driven xenografts model (H1581 and SNU-16 respectively) and models harboring FGFR2-activating mutation (AN3CA and MFE296). Given orally in a 15 daily administration, ARQ 087 has shown a very safe profile while inducing tumor regressions in FGFR driven models. The feasibility of combining ARQ087 with chemotherapy was investigated in H1581 FGFR1-amplified lung xenograft and in SNU16-FGFR2 driven gastric xenografts. Tumor bearing mice, were randomized to receive vehicle, ARQ087, paclitaxel, carboplatin as single agents, ARQ087 and paclitaxel, ARQ087 and carboplatin, paclitaxel and carboplatin as doublets; and the triple combination of ARQ087 with carboplatin and paclitaxel. Similar experimental setting was applied in nude mice bearing SUN16 xenografts, but instead of paclitaxel, capecitabine was given. The choice of the anticancer agents to be combined with ARQ087 was supported by the fact that these drugs are currently used for the treatment of various cancers clinically. In both experimental settings the drugs given as single agents showed moderate anti-tumor activity. Combination of two agents was more active than the single ones alone and combination of three agents has shown the most antitumor activity. In particular, combination of ARQ 087 with paclitaxel and carboplatin in H1581 bearing mice resulted in tumor regression and only 1/8 tumor re-grew after 30 days from the last drug administration versus 6/8, 4/8 e 5/8 in treatment groups with paclitaxel alone, combination of ARQ087 with paclitaxel, and combination of paclitaxel with carboplatin respectively. Of importance, no toxic deaths nor premature stopping or delaying of drug administration occurred. These data clearly suggest that ARQ087 can be safely combined with chemotherapy and that the combinations are much more active than the monotherapies.
Citation Format: Rosaria Chilà, Federica Guffanti, Terence Hall, Francesca Ricci, Massimo Broggini, Giovanna Damia. Combinations of ARQ087 with chemotherapeutic agents are safe and show a striking antitumor activity in different xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3500. doi:10.1158/1538-7445.AM2015-3500