bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2674: Stroma biology identifies heparins as differentiating agents in neuroblastoma
Authors: Knelson Erik H. , Gaviglio Angela L. , Nee Jasmine C. , Starr Mark D. , Nixon Andrew B. , Marcus Stephen G. , Blobe Gerard C. 
Published: May 2015

Abstract
The neuroblastoma tumor stroma is thought to suppress neuroblast growth via release of soluble differentiating factors. Here we identify these factors and design a novel therapy based on their mechanism of action. We show that expression of heparan-sulfate proteoglycan co-receptors (HSPGs), including TβRIII, GPC1, GPC3, SDC3, and SDC4, is decreased in neuroblasts, localized to the stroma and correlates with improved prognosis. Treatment with soluble HSPGs promoted neuroblast differentiation via FGFR1, Erk, and Id1. HSPGs also enhanced differentiation from FGF2 released by the stroma. The anticoagulant heparin had similar differentiating effects, leading to decreased neuroblast proliferation. Dissection of individual sulfation sites identified 2-O, 3-O-de-sulfated heparin (ODSH) as a differentiating agent that suppressed orthotopic xenograft growth while avoiding anticoagulation. These studies uncover the critical components of the differentiating stroma secretome in neuroblastoma and the central mechanism by which they act. We translate these biologic insights into novel prognostic and therapeutic biomarkers, as well as therapeutic differentiation strategies for clinical development. More generally, our work demonstrates that tumor stroma biology can inform design of targeted molecular therapeutics.
Citation Format: Erik H. Knelson, Angela L. Gaviglio, Jasmine C. Nee, Mark D. Starr, Andrew B. Nixon, Stephen G. Marcus, Gerard C. Blobe. Stroma biology identifies heparins as differentiating agents in neuroblastoma. [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 2674. doi:10.1158/1538-7445.AM2014-2674
Abstract 2680: Inhibition of activin-like kinases 4 and 5 attenuates cancer cachexia associated muscle wasting
Authors: Levolger Stef , Bruin Ron W.F. de , IJzermans Jan N.M. 
Published: May 2015

Abstract
Background: Cancer cachexia has a detrimental effect on patient survival. Cachectic patients experience reduced quality of life and have a decreased survival time. The underlying mechanism behind cancer cachexia is not yet fully understood. Recent experimental data suggests myostatin signaling may be a key contributor in the pathogenesis of cancer cachexia. Activin receptor IIB / activin-like kinase 4/5 heterodimer activation by myostatin leads to catabolic muscle degradation. SB-431542 is a potent inhibitor of activin-like kinases 4 and 5. We aimed to assess its potential in the treatment of cancer cachexia in an experimental rodent model.
Methods: All experiments were approved by the local Animal Ethics Committee. 24 CD2F1 were inoculated subcutaneously with 0.5 x 106 colon-26 murine adenocarcinoma cells to induce cachexia. The mice were allocated randomly into one of four experimental groups: healthy control, tumor-bearing control, tumor-bearing vehicle treated and tumor-bearing SB-431542 treated. All mice were weighed daily. Tumor size was assessed every other day, starting day 9 post inoculation. Four-paw grip strength was determined weekly using a grip-strength meter. SB-431542 was reconstituted in DMSO 1 mg/mL. From day 5 post inoculation, allocated mice received 10 mg/kg SB-431542, or vehicle intraperitoneally until sacrifice on day 20.
Results: All tumor-bearing mice had a reduction in body weight compared to controls, 21.1 ± 2.1 g versus 30.0 ± 1.3 g respectively (p &lt; 0.0001). No differences in body weight were found between the tumor-bearing groups. Despite weight loss, SB-431542 treated animals had no reduction in grip strength. Grip strength directly after tumor inoculation was 200.9 ± 11.3 g, and on day 14 211.3 ± 20.4 g. Vehicle treated animals showed a reduction from 204.0 ± 19.1 g to 174.8 ± 13.7 g (p = 0.0158). Mean wet muscle weight of the m. tibialis anterior was significantly preserved in SB-431542 treated animals versus tumor-bearing vehicle treated animals (53.8 mg vs. 40.5 mg, p = 0.0171) as well as tumor-bearing untreated animals (53.8 mg vs. 34.7 mg, p = 0.0002).
Conclusion: These findings suggest that inhibition of activin-like kinases 4 and 5 by SB-431542 attenuates cancer cachexia associated muscle loss and loss of muscle force in experimental cancer cachexia, and further emphasizes the role of myostatin/activin signaling.
Citation Format: Stef Levolger, Ron W.F. de Bruin, Jan N.M. IJzermans. Inhibition of activin-like kinases 4 and 5 attenuates cancer cachexia associated muscle wasting. [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 2680. doi:10.1158/1538-7445.AM2014-2680
Abstract 2682: ELTD1 as a target for anti-cancer therapy in rodent gliomas
Authors: Towner Rheal A. , Pody Richard , Smith Nataliya , Saunders Debra , Njoku Charity , Wren Jonathan D. 
Published: May 2015

Abstract
Despite current therapies, glioblastoma multiforme (GBM) is a devastating cancer with a very poor prognosis. Specific protein biomarkers for GBM enable not only new prognostic avenues to tailor treatment, but valuable therapeutic targets to interfere with GBM growth. We recently discovered a new biomarker for high-grade gliomas, ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1), via a novel bioinformatics approach, GAMMA (Global microarray meta-analysis). ELTD1 was found to be significantly higher (p&lt;0.05) in high-grade gliomas (50 patients) compared with low-grade gliomas (21 patients). ELTD1 gene expression was found to be associated with tumor grade, survival across grade, and an increase in the mesenchymal subtype. From our previous results we hypothesized that ELTD1 may be a potential therapeutic target in high-grade gliomas. We tested the hypothesis in an orthotopic GL261 mouse glioma model in animals treated with an anrti-ELTD1 antibody, compared to those that were treated with an anti-VEGF antibody or an anti-c-Met antibody, and untreated tumors. Tumor volumes were measured by morphological magnetic resonance imaging (MRI). Our data in orthotopic GL261 glioma-bearing mice shows that injection of anti-ELTD1 antibodies lead to a significant decrease in tumor volumes (p&lt;0.0001) and a significant increase in animal survival (p&lt;0.05), superior to that achieved by a mouse anti-VEGF antibody or an antibody against c-Met, when compared to untreated mice. Tumor volumes were obtained at various time-points, and compared at 21 days following intracerebral implantation of GL261 cells in male C57BL6 mice. These tumor volumes at 21 days were 86.03+/-41.54 mm3 for untreated mice (n=5); 13.04+/-5.35 mm3 for anti-ELTD1 treated mice (n=5); 33.16+/-12.48 mm3 for anti-VEGF treated mice (n=4); and 28.49+/-11.11 mm3 for anti-c-Met treated mice (n=5). The mean days of survival for untreated, ELTD1, VEGF or c-Met treatment groups were 23.8+/-1.79, 28.2+/-2.39, 27+/-1.15 or 27+/-1.87 days, respectively. These pre-clinical results indicate that an additional therapy in the form of an anti-ELTD1 antibody either as a sole agent or in combination with current or new therapies could potentially provide high-grade glioma patients with a better prognostic outcome.
Citation Format: Rheal A. Towner, Richard Pody, Nataliya Smith, Debra Saunders, Charity Njoku, Jonathan D. Wren. ELTD1 as a target for anti-cancer therapy in rodent gliomas. [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 2682. doi:10.1158/1538-7445.AM2014-2682
Abstract 2687: CK2 inhibitor CX-4945 modulates AKT, NF-kB, TP53 and MEK inhibitor PD-325901 targets AP1 mediated CK2 inhibitor drug resistance in head and neck cancer
Authors: Bian Yansong , Han Jiawei , Kannabiran Vishnu , Mohan Suresh , Friedman Jay , Anderes Kenna , Chen Zhong , Waes Carter Van 
Published: May 2015

Abstract
We previously identified upregulated kinase CK2 as an activator of NF-B and repressor of TP53 in promoting the malignant phenotype of head and neck squamous cell carcinoma (HNSCC). Here, we investigate the anti-tumor effects of a small molecule CK2 inhibitor CX-4945, alone and in combination with MEK inhibitor PD-0325901 (PD-901), in human HNSCC models in vitro and in vivo. CX-4945 IC50s ranged from 3.4 µM to 11.9 µM in 9 UMSCC cell lines. CX-4945 caused S and G2/M cell cycle arrest, and induced sub-G0 DNA fragments, indicating cell death. CX-4945 inhibited NF-B and BcL-XL prosurvival reporter genes in wild type (wt) TP53 (UMSCC1) and mutant (mt) TP53 (UMSCC46) cell lines, and concurrently upregulated proapoptotic TP53, p21 and prosurvival AP-1 activity only in the wtTP53 cell line. Correspondingly, CK2 phosphorylation of AKT S129 as well as T308 and S473 prosurvival signaling was reduced in both cell lines, but AP-1 inducing p-Erk1/2Thr202/204 was increased in the wtTP53 cell line. In the UMSCC1 xenografts, CX-4945 treatment significantly decreased PI3K/Akt/mTOR pathway signaling by immunostaining. While CX-4945 increased TP53 and TUNEL apoptosis marker staining at early time points (13 days after CX4945 treatment), an opposing increase in p-Erk, FosL1, cJun, JunB, and proliferation (Ki67) were also observed. Consistent with these opposing effects, no significant tumor reduction or improvement in survival was observed by CX-4945 alone. However, combination of CX-4945 with MEK/ERK inhibitor PD-901 exhibited significant synergistic anti-proliferative effects in vitro. Significant anti-tumor effects were observed with MEK inhibitor alone and in combination with CX-4945 in vivo, further supporting a role for MEK/ERK/AP-1 in resistance to CX-4945 in this HNSCC model.
Supported by NIH Medical Research Scholars Program and NIDCD intramural projects ZIA-DC-000016, 73 and 74.
Citation Format: Yansong Bian, Jiawei Han, Vishnu Kannabiran, Suresh Mohan, Jay Friedman, Kenna Anderes, Zhong Chen, Carter Van Waes. CK2 inhibitor CX-4945 modulates AKT, NF-kB, TP53 and MEK inhibitor PD-325901 targets AP1 mediated CK2 inhibitor drug resistance in head and neck 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 2687. doi:10.1158/1538-7445.AM2014-2687
Abstract 2698: Degrasyn-like symmetrical compounds: Possible therapeutic agents for multiple myeloma (MM-I)
Authors: Bornmann William G. , Peng Zhenghong , Maxwell David , Sun Duoli , Bhanu Basvoju A. , Talpaz Moshe , Donato Nicholas , Levitzki Alexander 
Published: May 2015

Abstract
A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents.
Citation Format: William G. Bornmann, Zhenghong Peng, David Maxwell, Duoli Sun, Basvoju A. Bhanu, Moshe Talpaz, Nicholas Donato, Alexander Levitzki. Degrasyn-like symmetrical compounds: Possible therapeutic agents for multiple myeloma (MM-I). [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 2698. doi:10.1158/1538-7445.AM2014-2698
Abstract 2717: DMH1, a small molecule inhibitor of BMP type I receptors, suppresses growth and invasion of lung cancer
Authors: Huang Ying , Lee Rachel , Chang Andy , Fan Jeffery , Labib Chantelle , Parsa Cyrus , Orlando Robert , Andresen Bradley , Hao Jijun 
Published: May 2015

Abstract
Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and their biological activity is mediated by the formation of heterodimeric complexes of BMP type I and type II receptors of serine/threonine kinases. BMPs play an important role in regulating cell proliferation, differentiation and migration, processes that are involved in carcinogenesis of many types of cancer. BMP-2 has been shown overexpressed in human non-small cell lung cancer (NSCLC) and enhances lung tumorigenesis, suggesting that blocking the BMP signaling may be an effective therapeutic approach for NSCLC. Although previous work demonstrated that known protein-based BMP antagonists such as Noggin may reduce lung tumor growth, their clinical application could be limited by short half-lives and poor intra-tumor delivery. In a previous zebrafish embryo-based structure and activity study, we identified DMH1, a highly selective small molecule inhibitor which specifically antagonize the intracellular kinase domains of BMP type I receptors, the critical mediators of BMP signaling. In the present study, we found that DMH1 potently reduced lung cell proliferation, promoted cell death, and decreased cell migration and invasion in vitro by blocking the BMP signaling, as indicated by the reduction of Smad 1/5/8 phosphorylation and gene expression of Id1, Id2 and Id3 in A549 and H460 cells. In an in vivo study, treatment by intraperitoneal injection of DMH1 (5 mg/kg) for four weeks significantly reduced the growth of A549-derived xenograft in SCID mice. In conclusion, our study indicates that small molecule inhibitors of BMP type I receptors may offer a promising novel therapeutic strategy for lung cancer.
Citation Format: Ying Huang, Rachel Lee, Andy Chang, Jeffery Fan, Chantelle Labib, Cyrus Parsa, Robert Orlando, Bradley Andresen, Jijun Hao. DMH1, a small molecule inhibitor of BMP type I receptors, suppresses growth and invasion of lung 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 2717. doi:10.1158/1538-7445.AM2014-2717
Abstract 2720: In vitro evaluation of a novel chemotherapeutic agent, NecroX-7, in human Burkitt lymphoma cells
Authors: Kim Eun- Jung , Lee Eun Sol , Im Keon- Il , Kim Soon H. , Lim Jung- Yeon , Kim Nayoun , Cho Seok- Goo 
Published: May 2015

Abstract
NecroX-7 is a novel small molecule of the NecroX series, its chemical compound is C25H32N4O4S2 with molecular weight 516.67 based on the indole-moiety. It prevents from oxidative stress-induced cell death. NecroX-7 prevented the release of HMGB1 or ameliorated hepatic IR injury. It is shown that NecroX-7 can inhibit NAPDH oxidase activity and osteoclast differentiation. Furthermore, NecroX-7 protected against APAP-induced hepatic injury by directly binding to NAPQI. However, the function and the underlying mechanisms of NecroX-7 in cancer cell growth have not been well established. This study was aimed at evaluating the efficacy as anticancer agent in human lymphoma cells.
Human Burkitt lymphoma cell lines were treated NecroX-7 in vitro. The effects of NecroX-7 treatment were evaluated using MTS assay for cell viability and annexin-V/propidium iodide labeling for apoptosis. Cell cycle was analyzed by Flow cytometry. Western blotting was used to look for NecroX-7 induced protein changes.
As results, NecroX-7 treatment efficiently inhibited cell growth at dose- and time- dependent and induced apoptosis in cell lines. Apoptosis was showed by accumulation of annexin-V and PI-positive cells, caspase-3 activation and induction of PARP cleavage. The IC50 values of NecoX-7 in cell lines were around 50 uM. NecroX-7 induced G2/M phase cell cycle arrest in Ramos and Daudi cells.These results suggest that NecroX-7 is a potential anticancer agent for treatment of human Burkitt lymphoma cells and provide a rational for preclinical and clinical evaluation of NecoX-7 for lymphoma therapy.
Citation Format: Eun- Jung Kim, Eun Sol Lee, Keon- Il Im, Soon Ha Kim, Jung- Yeon Lim, Nayoun Kim, Seok- Goo Cho. In vitro evaluation of a novel chemotherapeutic agent, NecroX-7, in human Burkitt lymphoma 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 2720. doi:10.1158/1538-7445.AM2014-2720
Abstract 2722: Suppression of breast cancer cell migration by novel inhibitors that target transient receptor potential-melastatin-like 7 (Trpm7) kinase activity
Authors: Kaoud Tamer Saad , Park Jihyun , Tavares Clint D.J. , Mitra Shreya , Cano Micael , Tseng Chun-Chia , Dalby Kevin N. 
Published: May 2015

Abstract
TRPM7 (transient receptor potential melastatin 7) encodes a calcium permeable non-selective cation channel implicated in cell adhesion and magnesium homoeostasis. The TRPM7 gene encodes for a protein kinase whose activity is linked to the control of actomyosin contractility. TRPM7 mediates adhesion and migration of MDA-MB-231 breast cancer cells and recently has been reported to promote breast tumor cell metastasis. The lack of cell-permeable pharmacological inhibitors of the kinase domain represents a barrier to fully understanding kinase function. Herein, we describe the discovery of several compounds that target TRPM7 kinase activity and which were shown to decrease the binding of Myosin IIB to TRPM7 in HEK293 cells and MDA-MB-231 breast cancer cells transfected with pCMV6-TRPM7. Interestingly, two of the inhibitors potentially inhibited MDA-MB-231 breast cancer cells migration that have been reported to be regulated by TRPM7 kinase activity. Finally, magnesium starvation, which promotes TRPM7 kinase activity, induces phosphorylation of eEF2. Treatment of cells with several of the compounds decreased eEF2 phosphorylation under conditions of magnesium starvation, consistent with the notion that they inhibit TRPM7 kinase activity in cells.
Citation Format: Tamer Saad Kaoud, Jihyun Park, Clint D.J. Tavares, Shreya Mitra, Micael Cano, Chun-Chia Tseng, Kevin N. Dalby. Suppression of breast cancer cell migration by novel inhibitors that target transient receptor potential-melastatin-like 7 (Trpm7) kinase activity. [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 2722. doi:10.1158/1538-7445.AM2014-2722
Abstract 2723: Breast cancer type 1 susceptibility protein mimetics induce specific estrogen receptor confirmations and inhibit MCF7 breast cancer cell proliferation
Authors: Asare Bethany Kristen , Katche Christ Ange , Rajnarayanan Rajendram V. 
Published: May 2015

Abstract
The human Estrogen Receptor (hER) is present in 70% of breast cancers, and dysregulation of hER signaling can lead to aberrant cell growth and proliferation. Known anti-estrogens used in treatments of breast cancer today, tamoxifen and raloxifene cause hER to undergo conformational changes and inhibit normal hER signaling by directly binding to the ligand binding pocket. However, often breast cancer cells become resistant to tamoxifen, and prolonged tamoxifen treatment can lead to endometrial cancers. Breast Cancer Type 1 Susceptibility protein (BRCA1) is a well characterized inhibitor of breast cancer cell growth. BRCA1 plays an important role in maintaining genomic stability through various DNA repair mechanisms. It is mutated in approximately 50% of breast cancer cases that are associated with heredity. While the majority of breast cancer cases are “sporadic” or unassociated with heredity, BRCA1 is expressed 30 to 40 % less in sporadic breast cancers. BRCA1 has also been shown to associate directly with hER, and inhibit transactivation of hER. This association and inhibition of hER transcriptional activity is reversed by cyclin D1. This, in conjunction with studies that have shown that cyclin D1 gene and protein levels are amplified and overexpressed respectively in breast cancers suggest that the normal regulation of hER by BRCA1 and cyclin D1 may be shifted in breast cancers to primarily regulation (activation) by cyclin D1 and other coactivators. A decrease in BRCA1 is associated with acquired tamoxifen resistance, suggesting that BRCA1 may play a critical role in maintaining breast cancer cells sensitivity to tamoxifen. The hER binding region of BRCA1 contains the known corepressor binding motif LXXIIXXXL (amino acids 78-95). Here we present a study of several small molecules identified based on pharmacophoric features of previously found conformation sensing BRCA1 peptides. BRCA1 mimetics induce unique ER conformations and inhibit breast cancer cell growth (MCF7). Further development of these compounds could lead to viable alternative breast cancer treatments as well as supplemental treatments in the anti-estrogen resistant cases.
Acknowledgements: This research was supported via funds from the New York State, National Institutes of Health (5P20MD002725), through the NCMHD -RIMI program (RVR) and NSF LSAMP Bridge to Doctorate grant (BKA).
Citation Format: Bethany Kristen Asare, Christ Ange Katche, Rajendram V. Rajnarayanan. Breast cancer type 1 susceptibility protein mimetics induce specific estrogen receptor confirmations and inhibit MCF7 breast cancer cell proliferation. [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 2723. doi:10.1158/1538-7445.AM2014-2723
Abstract 2732: Identification of a small molecule selectively kill mismatch repair deficient tumors
Authors: Myung Kyungjae 
Published: May 2015

Abstract
Lynch Syndrome, a genetic disorder caused by defects in the DNA mismatch repair (MMR) pathway, accounts for approximately 5% of all colon cancer cases. Lynch Syndrome tumors have proven to be resistant to most conventional chemotherapeutic agents, making surgery the best treatment option available. Here we screened NIH small molecule library for their ability to selectively kill cells with mutations in the MSH2 gene, and identified a small molecule that could target MMR-deficient cancer cells. This small molecule intercalates DNA, trigering a DNA damage response in MSH2-proficeint cells. In MSH2-deficient cells, continued replication in the presence of this small molecule leads to the formation of DNA double-strand breaks and ultimately results in apoptosis in the G2/M phase of the cell cycle. In addition, this small molecule is not mutagenic. Our results suggest that this small molecule may offer an improved treatment option for patients with tumors characterized mutations in the MMR pathway.
Citation Format: Kyungjae Myung. Identification of a small molecule selectively kill mismatch repair deficient tumors. [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 2732. doi:10.1158/1538-7445.AM2014-2732