bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2672: Vinyl sulfone analogues of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma
Authors: Murph Mandi M. , Altman Molly , Jia Wei , Nguyen Duy , Fambrough Jada , Hardman William J. , Jiang Guowei , Madan Damian , Zhang Jianxing , Prestwich Glenn D. 
Published: May 2015

Abstract
Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression and represents a promising area of research with significant translational potential. Since ATX inhibitors may have broad implications for therapy, we sought to create a novel series of inhibitors for use against cancer, especially melanoma. Herein we report on the synthesis and biological activity of a targeted affinity label for the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of vinyl sulfone analogs of ATX that function as irreversible inhibitors of ATX and inactivate the enzyme. We commenced biological testing of this compound with viability assays against multiple cancer cell lines whereby the IC50 values ranged from 6.74 - 0.39 μM, which was consistent with the Ki of the vinyl sulfone (3.50 μM). In addition, this compound was also able to significantly inhibit melanoma cell wound closure and pore migration. Most importantly, the vinyl sulfone significantly inhibited melanoma progression using an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that the vinyl sulfone is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo.
Note: This abstract was not presented at the meeting.
Citation Format: Mandi M. Murph, Molly Altman, Wei Jia, Duy Nguyen, Jada Fambrough, William J. Hardman, Guowei Jiang, Damian Madan, Jianxing Zhang, Glenn D. Prestwich. Vinyl sulfone analogues of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma. [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 2672. doi:10.1158/1538-7445.AM2014-2672
Abstract 2673: A novel ligand-independent peptide inhibitor of TREM-1 attenuates inflammation and suppresses tumor growth in mice
Authors: Sigalov Alexander B. 
Published: May 2015

Abstract
Non-small cell lung cancer (NSCLC) comprises about 85% of all lung cancers, accounting for over 1.5 million new cases annually. Despite advances in therapy, the 5-year survival rate is as low as 15%. The limitations in efficacy and safety associated with available treatments for NSCLC highlight the need for new treatments. As found recently, triggering receptor expressed on myeloid cells (TREM-1) plays a role in NSCLC progression. Inhibition of TREM-1 by short hairpin RNA (shRNA) in macrophages suppresses cancer cell invasion in vitro. In clinical setting, high level of TREM-1 expression in tumor-associated macrophages is associated with cancer recurrence and poor survival of patients with NSCLC. However, the precise function of TREM-1 and the nature of its ligand are not yet known. Here we show that TREM-1 can be specifically silenced in vitro and in vivo using a novel ligand-independent peptide inhibitor, which was designed using a new model of immune signaling, the signaling chain homooligomerization (SCHOOL) model. Blockade of TREM-1 function using non-toxic and non-immunogenic SCHOOL peptide inhibitors: 1) delays tumor growth in xenograft models of human NSCLC and 2) substantially decreases cytokine production in vitro and in vivo. In addition, macrophage-targeted delivery of SCHOOL peptides utilizing lipoprotein-mimicking nanoparticles significantly increased peptide half-life and dosage efficacy. Together, the results suggest that ligand-independent modulation of TREM-1 function using small synthetic peptides might be a suitable treatment for NSCLC and possibly other types of inflammation-associated cancers.
Citation Format: Alexander B. Sigalov. A novel ligand-independent peptide inhibitor of TREM-1 attenuates inflammation and suppresses tumor growth in mice. [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 2673. doi:10.1158/1538-7445.AM2014-2673
Abstract 2676: Inhibition of bmp signaling suppresses metastasis in mammary cancer
Authors: Owens Philip , Pickup Michael W. , Novitskiy Sergey V. , Giltnane Jennifer M. , Gorska Agnes E. , Hopkins Corey R. , Hong Charles C. , Moses Harold L. 
Published: May 2015

Abstract
Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors that play differing roles in cancer. BMPs are overexpressed in human breast cancers, but loss of BMP signaling in mammary carcinomas can accelerate metastasis. We show that human breast cancers display active BMP signaling, which is rarely downregulated or homozygously deleted. We hypothesized that systemic inhibition of BMP signaling in both the tumor and the surrounding microenvironment could prevent tumor progression and metastasis. To test this hypothesis, we used DMH1, a BMP antagonist in MMTV.PyVmT expressing mice. Treatment with DMH1 reduced lung metastasis and the tumors were less proliferative and more apoptotic. In the surrounding tumor microenvironment, treatment with DMH1 altered fibroblasts, lymphatic vessels and macrophages to be less tumor promoting. These results indicate that inhibition of BMP signaling may successfully target both the tumor and the surrounding microenvironment to reduce tumor burden and metastasis.
Citation Format: Philip Owens, Michael W. Pickup, Sergey V. Novitskiy, Jennifer M. Giltnane, Agnes E. Gorska, Corey R. Hopkins, Charles C. Hong, Harold L. Moses. Inhibition of bmp signaling suppresses metastasis in mammary 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 2676. doi:10.1158/1538-7445.AM2014-2676
Abstract 2681: 4-methylumbelliferone: Dietary supplement turned chemo-preventive and anti-metastatic agent for prostate cancer
Authors: Yates Travis , Alonzo David , Lokeshwar Soum , Hoye Kelly , Lopez Luis E. , Hupe Marie , Lokeshwar Vinata 
Published: May 2015

Abstract
INTRODUCTION: Hyaluronic acid (HA), a glycosaminoglycan, is associated with prostate cancer (PCa) progression and metastasis. 4-methylumbelliferone (4-MU) is dietary supplement that inhibits HA-synthesis. In this study we evaluated chemopreventive and therapeutic efficacy of 4-MU to prevent PCa growth and metastasis in three PCa models.
METHODS: Efficacy of daily oral gavage of 4-MU was evaluated in 3 PCa models: Model 1: TRAMP mice (n = 8-20/group) were treated with vehicle or 4-MU (450 mg/kg) by starting stage-specific treatment at 8 (PIN stage), 12 (adenocarcinoma) and 22 (invasive carcinoma) wks of age. Model 2: Mice were treated with 4-MU (200 mg/kg or 450 mg/kg) following intracardiac injection of Luciferase expressing PC3-ML cells. 3. Palpable DU145 xenografts were treated with 4-MU (200 and 450 mg/kg). Effect of 4-MU on EMT markers, HA receptors was evaluated by Q-PCR, immunoblotting and/or immunohistochemistry in PCa cells and xenograft tissues. HA add back and overexpression studies were conducted to evaluate the mechanism of action of 4-MU.
RESULTS: In the TRAMP model, at 28 wks, 100% of vehicle treated mice developed PCa, but tumor growth and progression was inhibited in all 4-MU treated groups; P+SV weight (g): vehicle: 3.2±2.9; 8 wk: 0.43±0.14; 12 wk: 0.35±0.04; 22 wk: 1.0±0.35 g. The P+SV weight in TRAMP mice at 22 wks of age was 0.9±0.04, showing that late stage administration of 4-MU halted further tumor progression. Animals in 8, 12 and 22 wk groups remained tumor free until 52, 44 and 34 wks respectively, even after stopping treatment at 28 wks. While 55% of vehicle treated animals developed metastasis, none of the treated groups had metastasis. In the PC3-ML intracardiac model, 100% of the mice in the vehicle group but none in the treatment group developed skeletal metastasis. In the DU145 model, 4-MU inhibited tumor growth. No serum/organ toxicity or weight loss was observed in any treatment groups. In all models, 4-MU treatment downregulated HA, HA receptors (CD44, RHAMM) and EMT markers (β-catenin, Zeb2) by &gt;2-fold) but up-regulated E-cadherin. HA addition and overexpression of myristoylated AKt inhibited 4-MU effects.
CONCLUSION: 4-MU is a potent non-toxic, oral chemopreventive agent, which inhibits PCa growth and metastasis by abrogating HA-signaling and reversing EMT.
Support: R01 CA 123063-04 (VBL); R01 CA 72821-11 (VBL)
Note: This abstract was not presented at the meeting.
Citation Format: Travis Yates, David Alonzo, Soum Lokeshwar, Kelly Hoye, Luis E. Lopez, Marie Hupe, Vinata Lokeshwar. 4-methylumbelliferone: Dietary supplement turned chemo-preventive and anti-metastatic agent for prostate 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 2681. doi:10.1158/1538-7445.AM2014-2681
Abstract 2684: Inhibition of tumor growth and angiogenesis by SP-2, an anti-LGALS3BP antibody
Authors: Piccolo Enza , Trani Sara , Tinari Nicola , Rossi Cosmo , Sorda Rossana L. , Lattanzio Rossano , D'Egidio Maurizia , Risio Annalisa D. , Grassadonia Antonino , Spinella Francesca , Bagnato Anna , Piantelli Mauro , Natoli Clara , Iacobelli Stefano 
Published: May 2015

Abstract
Background: Accumulating evidence indicates that serum and tissue levels of the lectin galactoside-binding soluble 3 binding protein (LGALS3BP), a secreted glycoprotein, are elevated in human cancer. Recently, we have identified LGALS3BP as a factor capable of stimulating angiogenesis of microvascular endothelial cells in culture as well as in vivo. However, the potential therapeutic implications of LGALS3BP function blockade, has not been explored yet.
Methods: Here we tested the ability of an anti-LGALS3BP monoclonal antibody, named SP-2, to antagonize LGALS3BP-induced angiogenesis and tumor growth.
Results: SP-2 dose-dependently inhibited HUVEC tubulogenesis induced by either conditioned medium of breast cancer and melanoma cells or purified recombinant LGALS3BP. This was accompanied by inhibition of FAK, Akt and ERKs phosphorylation as well as FAK recruitment to membrane sites and actin remodeling. In vivo, SP-2 inhibited LGALS3BP-stimulated angiogenesis and restrained growth of different xenograft models of human cancer. Finally, the combination of SP-2 with low-dose Bevacizumab was more effective than either agent alone in suppressing angiogenesis and tumor growth.
Conclusions: Targeting LGALS3BP with SP-2 could represent a promising therapeutic approach for LGALS3BP expressing tumors.
Citation Format: Enza Piccolo, Sara Trani, Nicola Tinari, Cosmo Rossi, Rossana La Sorda, Rossano Lattanzio, Maurizia D'Egidio, Annalisa Di Risio, Antonino Grassadonia, Francesca Spinella, Anna Bagnato, Mauro Piantelli, Clara Natoli, Stefano Iacobelli. Inhibition of tumor growth and angiogenesis by SP-2, an anti-LGALS3BP antibody. [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 2684. doi:10.1158/1538-7445.AM2014-2684
Abstract 2685: Regulation of Ras stability via inhibition of Wnt/β-catenin pathway as a potential therapeutic strategy to treat colorectal cancers
Authors: Cha Pu-Hyeon , Cho Yong-Hee , Jeong Woo-Jeong , Kim Hyun-Yi , Choi Kang-Yell 
Published: May 2015

Abstract
Ras is a well-characterized proto-oncogene, and its various mutations contribute to transformation and tumorigenesis in a wide variety of human cancers. Although the GTP/GDP loading switch is known as a major regulatory mechanism of Ras, other mechanisms affecting Ras activity are poorly understood. Here, we report a mechanism for controlling Ras activity by regulating its degradation and describe this regulatory mechanism in the suppression of cellular transformation and tumors induced by Ras mutations. We found that negative regulators of Wnt/β-catenin signaling contributed to the polyubiquitin-dependent degradation of Ras following phosphorylation by glycogen synthase kinase 3β (GSK3β) and subsequent recruitment of β-TrCP-E3 ligase. We found a positive association between tumorigenesis and Ras stabilization due to the aberrant activation of Wnt/β-catenin signaling. Our results indicate an essential role for phosphorylation and degradation of Ras and suppression of Ras-induced transformation via the Wnt/β-catenin pathway and provide insight into the role of this novel regulatory mechanism for Ras in tumorigenesis of colorectal cancers (CRCs). Because both Ras and Wnt/β-catenin pathways are frequently activated in CRCs, these results suggest that the regulation of Ras stability through inhibition of the Wnt/β-catenin pathway could be an ideal therapeutic approach for treatment of CRC.
Citation Format: Pu-Hyeon Cha, Yong-Hee Cho, Woo-Jeong Jeong, Hyun-Yi Kim, Kang-Yell Choi. Regulation of Ras stability via inhibition of Wnt/β-catenin pathway as a potential therapeutic strategy to treat colorectal cancers. [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 2685. doi:10.1158/1538-7445.AM2014-2685
Abstract 2688: Drugging MYCN through an allosteric transition in Aurora A kinase
Authors: Gustafson William C. , Meyerowitz Justin G. , Nekritz Erin A. , Charron Elise A. , Chanthery Yvan , Simonds Erin , Matthay Katherine , Hertz Nicholas , Shokat Kevan , Weiss William A. 
Published: May 2015

Abstract
MYC genes contribute to a range of cancers including neuroblastoma, where amplification of MYCN confers a poor prognosis. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora kinase A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and causes degradation of MYCN protein across MYCN-expressing neuroblastoma cell lines. Comparison of co-crystal structures with structure- activity relationships across multiple inhibitors and chemotypes, coupled with mechanistic studies and biochemical assays, delineates an Aurora A conformation-specific effect on proteolytic degradation of MYCN, rather than simple nanomolar-level inhibition of Aurora A kinase activity. This new class of inhibitors, which disrupts stabilizing interactions between Aurora A and MYCN, represents candidate agents to target MYCN-driven and potentially MYC-driven cancers.
Citation Format: William C. Gustafson, Justin G. Meyerowitz, Erin A. Nekritz, Elise A. Charron, Yvan Chanthery, Erin Simonds, Katherine Matthay, Nicholas Hertz, Kevan Shokat, William A. Weiss. Drugging MYCN through an allosteric transition in Aurora A kinase. [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 2688. doi:10.1158/1538-7445.AM2014-2688
Abstract 2696: PPAR beta/delta is a novel therapeutic target in acute myeloid leukemia
Authors: Hu Sophia , Wald David , Parameswaran Reshmi 
Published: May 2015

Abstract
Acute myeloid leukemia (AML) is characterized by the differentiation arrest and rapid proliferation of abnormal white blood cells. Current therapeutics involves the use of chemotherapeutic agents, which possess high toxicities and poor efficacies. Thus, there is an unparalleled need to identify low-toxicity therapies to improve the mortality of these patients. Facilitating the maturation of acute myeloid leukemia cells induces their growth arrest and death without the need for high doses of overt toxicity from chemotherapies. Therefore, we seek to identify differentiating agents capable of inducing monocytic differentiation without deleterious side-effects on normal hematopoietic tissues. One possible approach to promote AML cellular differentiation is manipulating the activity or expression of proteins, such as PPAR delta, that are known to modulate cellular growth processes. PPAR delta is part of a family of nuclear hormone receptors that function as transcription factors to induce the activation of genes related to cellular growth, development, and metabolism. PPAR alpha and PPAR gamma have been extensively characterized in the context of leukemia. However, little is known about PPAR delta. In the current study, we sought to delineate the role of PPAR delta in AML and analyze whether inhibiting the PPAR delta pathway would induce differentiation in AML cells. Inhibiting PPAR delta led to a significant increase in monocytic differentiation in AML cell lines in vitro, as measured by immunophenotyping by flow cytometry and NBT reduction assays. For instance, we observed 3% CD11b expression in untreated HL60, OCI, NB4, and U937 cell lines and 40% CD11b expression after PPAR inhibition. Importantly, PPAR delta does not lead to toxic effects on non-leukemic cells at similar doses. These results were further supported by morphological evidence of monocytic differentiation seen from Wright-Giemsa staining and a 40% decrease in AML cell proliferation following PPAR delta inhibition using the MTT cell proliferation assay. A 34% decrease in self-renewal capabilities of leukemic cells after PPAR delta inhibition suggests permanent effects on differentiation and growth arrest, as determined by colony assays. Consistent with growth inhibition, treatment with PPAR delta inhibitors induced the expression of cell cycle and proliferation-related genes such c-Myc, p21, and p27 in a dose-dependent manner. Overall, our findings suggest that PPAR delta inhibitors may possess promising clinical relevance as potential candidates for non-toxic alternatives to chemotherapy.
Note: This abstract was not presented at the meeting.
Citation Format: Sophia Hu, David Wald, Reshmi Parameswaran. PPAR beta/delta is a novel therapeutic target in acute myeloid leukemia. [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 2696. doi:10.1158/1538-7445.AM2014-2696
Abstract 2699: Identification and characterization of active components of antrodia cinnamomea mycelia on targeting cancer initiating cells
Authors: Wu Meng-Chia , Lo Jeng-Fan 
Published: May 2015

Abstract
Background: Cancer initiating cells (CICs) are a subtype of cancer cells, which have the enhanced stemness properties and tumorigenic abilities. CICs are also considered to render resistance of chemotherapy, then, result in recurrence and metastasis. Recent researches and our discovery show that elevated activity of aldehyde dehydrogenase (ALDH) is closely related to CICs. Development of drugs that can specific target cancer initiating cells as a therapeutic method to against the disease would benefit for treatment of cancer patients.
Methods: We first used the ALDH assay to screen for purified compounds of the myceluim from Antrodia Cinnamomea with inhibitory activity in cancer cells. Then, we find out 4-acetylantroquinonol B (4-AAQN B) significantly down regulated the ALDH activity after its administration. Further, the anticancer activity of 4-AAQN B by targeting CICs will be identified both in vitro and in vivo.
Results: Our results showed that ALDH activity and stemness marker CD44, uPAR, CCN1 significantly decreased after 4-AAQN B administration. We also observed the decreased cell viability in cancer cells. On note, 4-AQQN B reduced ROS high cells, which are considered as activated CICs.
Conclusion: The anticancer activity of has been reported before. However, we are the first group to confirm that 4-AAQN B can selectively target CICs. The abovementioned findings provide an alternative therapeutics for future cancer treatment in combination with conventional chemotherapy.
Citation Format: Meng-Chia Wu, Jeng-Fan Lo. Identification and characterization of active components of antrodia cinnamomea mycelia on targeting cancer initiating 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 2699. doi:10.1158/1538-7445.AM2014-2699
Abstract 27: Label-free, real-time analysis of endothelial cell morphogenesis using iPSC-derived endothelial cells
Authors: Mann David , Belair David , Carlson Coby , Thompson Arne , Abassi Yama , Irelan Jeff 
Published: May 2015

Abstract
Endothelial cell (EC) morphogenesis during the early stages of angiogenesis is a highly dynamic process tightly regulated by growth factor activity in the extracellular milieu. Other in vitro models for the analysis of EC morphogenesis have previously been developed to understand the cellular processes and the impact of soluble cues and pharmacological inhibitors. However, these assays typically utilize end-point analysis of primary endothelial cells (eg. HUVEC), which are a physiologically relevant vascular cell type but do exhibit variability from the diversity of donors. Additionally, current methods for measuring morphogenesis (eg. proliferation and migration) only capture a snapshot of cell function owing to potentially destructive labeling of the cells and do not capture the complexity of cellular processes involved in EC morphogenesis Here, we describe use of a real-time system for monitoring of cellular processes using electronic cell sensor array technology. The cellular model tested on this impedance-based platform was a well-defined human induced pluripotent stem cell (iPSC)-derived endothelial cells. Following assay optimization and workflow improvement, we assessed the impact of serum, growth factors (e.g. VEGF, EGF, FGF-2), and small-molecule angiogenesis inhibitors (e.g. Sunitinib, SU1498) on the proliferation, migration, and invasion of iPSC-derived ECs compared to primary cells. We observed that real-time monitoring of such cellular processes offers distinct and important advantages over traditional end-point assays - specifically, the ability to measure receptor activation and quantify morphologic and adhesive remodeling of EC upon growth factor activation or signaling inhibition. By better understanding cellular morphogenesis in vitro, we can generate a picture of what soluble cues regulate the process and how pharmacological agents can modulate the different cell fates underlying morphogenesis. The use of iPSC-derived endothelial cells provides a robust and reproducible source of cells that perform equivalently to the standard that is HUVEC. The combination of iPSC-derived EC together with a real time monitoring system provides a biologically relevant human model system.
Citation Format: David Mann, David Belair, Coby Carlson, Arne Thompson, Yama Abassi, Jeff Irelan. Label-free, real-time analysis of endothelial cell morphogenesis using iPSC-derived endothelial 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 27. doi:10.1158/1538-7445.AM2014-27