bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2067: BMN 673 potentiates efficacy of temozolomide in sensitive and resistant glioblastoma models.
Authors: Kizilbash Sani H. , Kawashima Ryo , Gupta Shiv , Mladek Ann C. , Shen Yuqiao , Sarkaria Jann N. 
Published: August 2014

Abstract
Poly (ADP-ribose) polymerase (PARP) plays an important role in several DNA repair processes, and previous studies with various PARP inhibitors have demonstrated robust enhancement of sensitivity to temozolomide (TMZ) chemotherapy in pre-clinical models of glioblastoma multiforme (GBM). The focus of this study was to evaluate the antitumor effects of a novel PARP inhibitor, BMN 673, as a single agent and in combination with TMZ in the established U251 glioma cell line, neurosphere cultures from the primary Mayo GBM xenograft line GBM12, and TMZ-resistant cells derived from either line (U251TMZ, GBM12TMZ(MGMT high) and GBM12TMZ(MGMT low)). In a biochemical assay of PARP inhibition, BMN 673 potently suppressed poly-ADP-ribosylation of cellular proteins at concentrations of 3 nM following hydrogen peroxide treatment of U251 cells. Single agent treatment had modest anti-tumor activity with 30 nM BMN 673 reducing absorbance in a CyQUANT cell proliferation assay relative to control treatment in both U251 and U251TMZ cells (Table 1). BMN 673 co-treatment also enhanced the efficacy of TMZ in both U251-derivative lines at a clinically relevant concentration of TMZ. Similarly, treatment with BMN673 alone or in combination with TMZ inhibited primary neurosphere formation in all three GBM12 models. Notably, the addition BMN 673 clearly re-sensitized both resistant GBM12 sub-lines to relatively low concentrations of TMZ. Consistent with a mechanism involving disruption of DNA repair, combined treatment with BMN 673 and TMZ resulted in robust activation of ATM-mediated KAP1 phosphorylation (Ser824) and ATR-mediated Chk1 phosphorylation (Ser345) as compared to TMZ or BMN 673 alone 24 hours after treatment. In conclusion, BMN673 is a promising PARP inhibitor with high potency and cytotoxicity in vitro against both TMZ sensitive and TMZ resistant GBM cells.
Table 1 - In vitro antitumor effects of TMZ combined with BMN673 TMZ, microM 0 nM BMN673 30 nM BMN673 CyQUANT U251 Relative absorbance Relative absorbance 0 1.00 0.58 30 0.80 0.30 U251TMZ 0 1.00 0.69 30 1.02 0.21 Primary Neurosphere Assay GBM12 Relative Count Relative Count 0 1.00 0.66 5 0.32 0 10 0.01 0 GBM12TMZ (MGMT high) 0 1.00 0.32 5 1.11 0.02 10 1.04 0.01 GBM12TMZ (MGMT low) 0 1.00 0.25 5 0.86 0.03 10 0.75 0
Citation Format: Sani H. Kizilbash, Ryo Kawashima, Shiv Gupta, Ann C. Mladek, Yuqiao Shen, Jann N. Sarkaria. BMN 673 potentiates efficacy of temozolomide in sensitive and resistant glioblastoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2067. doi:10.1158/1538-7445.AM2013-2067
Abstract 2097: Targeting aneuploidy with NMS-P153, a tight binder inhibitor of the spindle assembly checkpoint MPS1 (TTK) kinase.
Authors: Colombo Riccardo , Caldarelli Marina , Giorgini Maria Laura , Degrassi Anna , Ciomei Marina , Pezzetta Daniele , Ballinari Dario , Montagnoli Alessia , Pesenti Enrico , Donati Daniele , Galvani Arturo 
Published: August 2014

Abstract
Aneuploidy is one of the major hallmarks of cancer and is a unique property of tumoral cells. Targeting of the molecular mechanisms required for growth of aneuploid cells is a potential strategy for developing new therapies with preferential activity against cancer.
The Spindle Assembly Checkpoint (SAC) is a mitotic mechanism required for proper chromosomal segregation, ensuring that cells do not divide until all sister chromatids correctly align to the metaphase plate. The SAC is a complex machinery regulated by a number of members which are rarely mutated in tumors. Rather, checkpoint components have been found to be upregulated in aneuploid tumor cells, suggesting a potential tumor “addiction” to SAC functions.
MPS1 kinase, (also known as TTK) is an essential enzyme of the SAC complex which is aberrantly overexpressed in a wide range of tumors and necessary for tumor cell proliferation. We previously reported the identification of NMS-P715, a selective and orally bioavailable MPS1 inhibitor, capable of promoting mitotic acceleration, thereby causing massive aneuploidy and cancer cell death both in vitro and in vivo and which promotes tumor growth inhibition in preclinical cancer models. Supported by these results, a lead optimization program was then undertaken which led to the identification of NMS-P153, an optimized product candidate for clinical development.
NMS-P153 is selective, shows high in vitro enzymatic potency on MPS1 (IC50 of 3 nM) and a prolonged residence binding time.
More than 100 cell lines have been analyzed against NMS-P153 in proliferation studies and several distinct xenograft models have been tested in vivo, allowing the identification of potential genetic contexts of sensitivity. Potent anti-proliferative activity, good tumor growth inhibition associated with tumor regression and biomarker modulation was observed in sensitive xenograft models.
A favorable ADME profile, associated with permissive therapeutic safety margins observed in different species at efficacious exposures, indicate that NMS-P153 is suitable for further development, with the potential for being a first-in-class drug targeting MPS1 kinase.
Citation Format: Riccardo Colombo, Marina Caldarelli, Maria Laura Giorgini, Anna Degrassi, Marina Ciomei, Daniele Pezzetta, Dario Ballinari, Alessia Montagnoli, Enrico Pesenti, Daniele Donati, Arturo Galvani. Targeting aneuploidy with NMS-P153, a tight binder inhibitor of the spindle assembly checkpoint MPS1 (TTK) kinase. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2097. doi:10.1158/1538-7445.AM2013-2097
Abstract 2114: Docosahexaenoic acid induces degradation of human papillomavirus E6 and E7 oncoproteins through activation of the ROS-mediated ubiquitin-proteasome system in cervical cancer cells.
Authors: Jing Kaipeng , Shin Soyeon , Jeong Soyeon , Park Ji-Hoon , Seo Kang-Sik , Heo Jun-Young , Han Jeongsu , Park Jong-Il , Kweon Gi-Ryang , Park Seung-Kiel , Yoon Wan-Hee , Hwang Byung-Doo , Lim Kyu 
Published: August 2014

Abstract
Sustained expression of high risk human papillomavirus (HR-HPV) E6/E7 oncogenes is essential for the maintenance of cervical cancer. We have previously reported that docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, triggers apoptosis in HR-HPV positive cervical cancer cells. The aim of present study was to investigate whether and how the DHA-induced apoptosis is associated with modulation of E6/E7 viral oncoproteins in HR-HPV positive HeLa and SiHa cells. We found that DHA diminished E6/E7 protein levels in a time-dependent manner and restored the function of known E6/E7 binding targets, p53 and retinoblastoma (Rb) tumor suppressors. DHA increased the ubiquitination and proteasomal degradation of E6/E7 oncoproteins as well as three different ubiquitin-proteasome system (UPS) reporter substrates (GFP-CL1, GFP-ODC and UbG76V-GFP), supporting that DHA degrades E6/E7 viral proteins via the UPS. Using HeLa cells constitutively expressing UbG76V-GFP reporter, we confirmed these effects of DHA and further observed that similar to DHA, hydrogen peroxide (H2O2) was also able to accelerate E6/E7 degradation through promoting the UPS activity. In addition, reactive oxygen species (ROS) scavengers significantly prevented the UPS-mediated reduction in E6/E7 viral proteins and apoptosis caused by DHA and H2O2, suggesting that the augmented UPS activity and E6/E7 degradation caused by DHA depend on its effect on ROS generation. Together, our results show that DHA induces degradation of HPV E6/E7 oncoproteins through activation of the ROS-mediated UPS, and provide novel insights into the mechanism by which DHA exerts its inhibitory effect on virus-associated cancer. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by Korea government (2012-0005767, 2012-0005456 and 2011-0003060)].
Citation Format: Kaipeng Jing, Soyeon Shin, Soyeon Jeong, Ji-Hoon Park, Kang-Sik Seo, Jun-Young Heo, Jeongsu Han, Jong-Il Park, Gi-Ryang Kweon, Seung-Kiel Park, Wan-Hee Yoon, Byung-Doo Hwang, Kyu Lim. Docosahexaenoic acid induces degradation of human papillomavirus E6 and E7 oncoproteins through activation of the ROS-mediated ubiquitin-proteasome system in cervical cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2114. doi:10.1158/1538-7445.AM2013-2114
Abstract 2119: Silencing of KCNJ2, a potassium influx channel, increases cisplatin-induced cell death in oral cancer.
Authors: Li Yen Liang 
Published: August 2014

Abstract
Oral cancer is the sixth leading cancer in the world. Cisplatin is the first-line of chemotherapeutic drug for the treatment of oral cancer, however, cancer with cisplatin resistance is a significant cause of treatment failure. To investigate the mechanism of cisplatin resistance, we established cisplatin-resistant (CR) subline cells from SAS, CGHNC8, and CGHNC9 oral cancer cell lines. The transcriptomic profiling analysis was performed between parental and CR subline cells to global survey and identify cisplatin-resistant genes. Total of 345 genes were differentially expressed in both SAS and CGHNC8 cells, in which 16 genes were confirmed. KCNJ2 was shown highest over-expression in both CR subline cells, and was selected for further investigation. KCNJ2 is a molecular potassium influx channel, which allows potassium flowing into cells to maintain ion homeostasis. To determine potential effect of KCNJ2, we have established KCNJ2 stable knocked down cells. Results showed that KCNJ2 knockdown cells were more sensitive to cisplatin treatment, as demonstrated by significantly reduced potassium influx, accelerated apoptosis by increasing caspase activity, and led to reduced cellular clonogenic survival. Taking together, we have profiled transcriptomes and identified at least 16 genes which may associate with cisplatin resistance in oral cancer cells. KCNJ2 silencing sensitizes cisplatin-resistant cells, through suppression of potassium influx. This study serves as knowledge foundation for clinical application in the prediction or prognosis of cisplatin treatment for oral cancer.
Citation Format: Yen Liang Li. Silencing of KCNJ2, a potassium influx channel, increases cisplatin-induced cell death in oral cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2119. doi:10.1158/1538-7445.AM2013-2119
Abstract 2134: Bone-targeted MMP inhibitors for the treatment of multiple myeloma.
Authors: Shay Gemma , Tauro Marilena , Laghezza Antonio , Tortorella Paolo , Hazlehurst Lori A. , Lynch Conor C. 
Published: August 2014

Abstract
Multiple Myeloma (MM) is a plasma cell malignancy that is hallmarked by areas of extensive bone destruction. Our group, and others have recently shown that individual host or tumor derived MMP-2 and MMP-9 play an important role in the progression of many cancers in the bone microenvironment, including MM. These data support the design of selective inhibitors of individual MMPs for the treatment of multiple myeloma. Previous clinical trials with broad-spectrum matrix metalloproteinase (MMP) inhibitors failed, arguably because the precise roles of individual MMPs had not been fully appreciated. Therefore, in the current study, we have developed novel bone seeking MMP inhibitors (BMMPIs) that are highly selective to MMP-2 and structurally are based on the bone targeting bisphosphonate, Tiludronate. In vitro, BMMPIs showed greater enzyme inhibition, and specificity for MMP-2 than previously synthesized bisphosphonates (e.g. Zoledronate, Etidronate and Tiludronate) with Ki values in the nanomolar range. Further treatment of the 5TGM1 mouse MM cell line with low micromolar concentrations of the BMMPI inhibitors significantly reduced cell viability through inhibition of cell growth (p&lt;0.05). In vivo, 5TGMI tumor-bearing mice receiving BMMP inhibitors three times a week, showed significant increase in overall survival compared to vehicle and tiludronate treated mice over 80 days (p&lt;0.05). This was associated with a reduction in tumor burden and protection from tumor-associated bone loss compared to vehicle treated mice as measured by x-ray and histomorphometry. These data suggest that given the roles for MMPs in tumor progression in bone, that our novel BMMPIs may be effective in the treatment of MM. We predict that MMP-2 specific BMMPIs may be more effective than current clinically used bisphosphonates for the treatment of MM, and may eliminate undesirable side effects of broad-spectrum MMP inhibitors due to their high specificity and bone seeking nature. We are currently continuing to characterize these BMMPI both as single agents, and in combination with existing MM treatments (eg. Bortezomib) for the treatment and eradication of MM.
Citation Format: Gemma Shay, Marilena Tauro, Antonio Laghezza, Paolo Tortorella, Lori A. Hazlehurst, Conor C. Lynch. Bone-targeted MMP inhibitors for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2134. doi:10.1158/1538-7445.AM2013-2134
Abstract 2135: TGFβRI inhibition results in reduced collagen expression in pancreatic ductal adenocarcinoma.
Authors: Whatcott Clifford J. , Dumas Sabrina N. , Watanabe Aprill , LoBello Janine , Von Hoff Daniel D. , Han Haiyong 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a robust stromal component termed the desmoplastic reaction. Transforming growth factor β (TGFβ) has been implicated in the activation of the cancer-associated fibroblast (CAF) that leads to pancreatic desmoplasia and the increased deposition of extracellular matrix proteins. Desmoplasia and its effects are thought to contribute to poor drug efficacy in PDAC treatment. We therefore hypothesized that TGFβ receptor (TGFβR) inhibition may serve to improve the activity of chemotherapeutics in PDAC by reducing the effects of desmoplasia. Using the TGFβRI inhibitors, LY2157299 and SB431542, we assessed the effects of TGFβR inhibition on cell proliferation and collagen production in both mono- and co-cultured pancreatic tumor cells and CAFs. We found that although the TGFβRI inhibitors had moderate effect on the proliferation of PDAC cells and co-cultured CAF cells, they significantly inhibited collagen 1 expression in the co-culture of MIA PaCa-2 and SU86.86 cells with CAFs (2.3 and 6.0-fold at the mRNA level, respectively). Similar qualitative reductions were also observed in immunofluorescence microscopy and immunoblots probing for collagen 1 protein levels. We also sought to determine if TGFβR inhibition would result in a reduction in collagen expression in the more biologically relevant in vivo model for PDAC, the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse. KPC mice were treated orally, b.i.d., with 75mg/kg LY2157299 and by i.p., with gemcitabine (q3dx4) at 80mg/kg. Tumors in KPC mice treated with the combination of LY2157299 and gemcitabine showed a marked reduction in overall stromal content when compared to vehicle-treated mice. Our results suggest that TGFβR inhibition may be an effective means of ameliorating the effects of desmoplasia in PDAC, which may in turn improve the efficacy of current PDAC treatment regimens.
Citation Format: Clifford J. Whatcott, Sabrina N. Dumas, Aprill Watanabe, Janine LoBello, Daniel D. Von Hoff, Haiyong Han. TGFβRI inhibition results in reduced collagen expression in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2135. doi:10.1158/1538-7445.AM2013-2135
Abstract 2138: Targeting cancer-associated fibroblasts using antibodies recognizing fibroblast activation protein-alpha.
Authors: Van Deventer James A. , Wittrup Karl D. 
Published: August 2014

Abstract
An expanding body of work suggests that the tumor stroma plays an integral role in the initiation and development of epithelial cancers. Within the stroma, cancer-associated fibroblasts (CAFs) are involved in several functions that form integral aspects of tumor progression, including immune suppression, metabolism, and invasion and metastasis. Despite the demonstrated importance of CAFs within the tumor microenvironment, targeting CAFs in a therapeutic context remains a challenge. The work presented here details the isolation and characterization of antibody fragments targeting multiple epitopes of fibroblast activation protein-alpha (FAP), a membrane-bound protease selectively overexpressed on CAFs in numerous epithelial cancers. The combination of a minimalist antibody fragment library and yeast surface display allowed for the isolation of more than 50 unique antibodies recognizing the human or murine forms of FAP, with close to 30 exhibiting cross-reactivity. To narrow the pool of cross-reactive antibodies to a biologically relevant subset, the fragments were converted to an antibody-like format that could be secreted from yeast. Without purification, the soluble proteins were first used to investigate the abilities of individual fragments to recognize FAP transiently expressed on the surface of HEK293 cells. Proteins for which binding to FAP could be confirmed were then used in combination with antibody fragments displayed on the surface of yeast in order to determine which sets of fragments bind distinct epitopes of FAP. Flow cytometry-based assays revealed that the isolated fragments recognize two or more distinct epitopes of the antigen. A handful of fragments is currently being subjected to affinity maturation and conversion to IgGs, and work to further investigate the in vitro and in vivo characteristics of the proteins is ongoing. These proteins may allow for the ablation of cancer-associated fibroblasts or interference with the proteolytic activity of FAP in the tumor microenvironment, providing biological insights into the roles of CAFs and therapeutic approaches to cancer treatment. Furthermore, the general antibody isolation and characterization approaches used in this work are accessible to many single-investigator laboratories and should be applicable to the targeting of numerous cancer antigens.
Citation Format: James A. Van Deventer, Karl D. Wittrup. Targeting cancer-associated fibroblasts using antibodies recognizing fibroblast activation protein-alpha. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2138. doi:10.1158/1538-7445.AM2013-2138
Abstract 215: Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1.
Authors: Synowitz Michael , Stock Kristin , Kumar Jitender , Petrosino Stefania , Imperatore Roberta , St J Smith Ewan , Wend Peter , Purfürst Bettina , Nuber Ulrike A , Gurok Ulf , Matyash Vitali , Wälzlein Joo-Hee , Chirasani Sridhar R , Dittmar Gunnar , Cravatt Benjamin F , Momma Stefan , Lewin Gary R , Ligresti Alessia , De Petrocellis Luciano , Cristino Luigia , Tonn Joerg Christian , Di Marzo Vincenzo , Kettenmann Helmut , Glass Rainer 
Published: August 2014

Abstract
Primary astrocytomas of grade 3 or 4 according to the classification system of the World Health Organization (high-grade astrocytomas or HGAs) are preponderant among adults and are almost invariably fatal despite the use of multimodal therapy. Here we show that the juvenile brain has an endogenous defense mechanism against HGAs. Neural precursor cells (NPCs) migrate to HGAs, reduce glioma expansion and prolong survival time by releasing endovanilloids that activate the vanilloid receptor (transient receptor potential vanilloid subfamily member-1 or TRPV1) on HGA cells. TRPV1 is highly expressed in tumor and weakly expressed in tumor-free brain. TRPV1 stimulation triggers tumor cell death through the branch of the endoplasmic reticulum stress pathway that is controlled by activating transcription factor-3 (ATF3). The antitumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid arvanil, suggesting that TRPV1 agonists have potential as new HGA therapeutics.
Citation Format: Michael Synowitz, Kristin Stock, Jitender Kumar, Stefania Petrosino, Roberta Imperatore, Ewan St J Smith, Peter Wend, Bettina Purfürst, Ulrike A Nuber, Ulf Gurok, Vitali Matyash, Joo-Hee Wälzlein, Sridhar R Chirasani, Gunnar Dittmar, Benjamin F Cravatt, Stefan Momma, Gary R Lewin, Alessia Ligresti, Luciano De Petrocellis, Luigia Cristino, Joerg Christian Tonn, Vincenzo Di Marzo, Helmut Kettenmann, Rainer Glass. Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 215. doi:10.1158/1538-7445.AM2013-215