bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2930: Global chromatin profiling reveals NSD2 mutation in pediatric ALL
Authors: Chan Ho Man , Jaffe Jacob D. , Wang Yan , Zhang Jinghui , Huether Robert , Kryukov Gregory V. , Bhang Hyo-eun C. , Taylor Jordan E. , Hu Min , Englund Nathan P. , Yan Feng , Wang Zhaofu , McDonald E Robert , Wei Lei , Ma Jing , Easton John , Yu Zhengtian , deBeaumount Rosalie , Gibaja Veronica , Venkatesan Kavitha , Schlegel Robert , Sellers William R. , Keen Nicholas , Liu Jun , Caponigro Giordano , Barretina Jordi , Cooke Vesselina G. , Mullighan Charles , Carr Steven A. , Downing James R. , Garraway Levi A. , Stegmeier Frank 
Published: May 2015

Abstract
Epigenetic dysregulation is an emerging hallmark of cancers. We developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancers. When applied to 115 lines of the Cancer Cell Line Encyclopedia1, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased H3K36 dimethylation, exhibited by several lines harboring NSD2 translocations. A novel NSD2 p.E1099K variant was identified in non-translocated acute lymphoblastic leukemia (ALL) lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of &gt;1000 pediatric cancer genomes identified the NSD2 p.E1099K mutation in 14% of t(12;21)[ETV6-RUNX1]-containing ALLs. These findings identify NSD2 as a potential therapeutic target for pediatric ALL and provide a general framework for the functional annotation of cancer epigenomes.
1.
Barretina,J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607 (2012).
Citation Format: Ho Man Chan, Jacob D. Jaffe, Yan Wang, Jinghui Zhang, Robert Huether, Gregory V. Kryukov, Hyo-eun C. Bhang, Jordan E. Taylor, Min Hu, Nathan P. Englund, Feng Yan, Zhaofu Wang, E Robert McDonald III, Lei Wei, Jing Ma, John Easton, Zhengtian Yu, Rosalie deBeaumount, Veronica Gibaja, Kavitha Venkatesan, Robert Schlegel, William R. Sellers, Nicholas Keen, Jun Liu, Giordano Caponigro, Jordi Barretina, Vesselina G. Cooke, Charles Mullighan, Steven A. Carr, James R. Downing, Levi A. Garraway, Frank Stegmeier. Global chromatin profiling reveals NSD2 mutation in pediatric ALL. [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 2930. doi:10.1158/1538-7445.AM2014-2930
Abstract 2933: Assessment of ABT-263 activity across a comprehensive cancer cell line collection leads to a novel, potent combination therapy for small cell lung cancer
Authors: Faber Anthony C. , Costa Carlotta , Dastur Anahita , Benes Cyril , Engelman Jeffrey 
Published: May 2015

Abstract
BH3 mimetics like ABT-263 induce apoptosis in subsets of cancer. However, they have shown limited clinical efficacy as single agents, and rational combination strategies remain underexplored. Toward the development of a novel combined therapy, we examined efficacy of ABT-263 across 331 cancer cell lines. Cell lines with high expression levels of the pro-apoptotic gene BIM were more sensitive to ABT-263 activity. This was particularly evident in small cell lung cancer (SCLC), which tends to have higher BIM levels and is among the most sensitive to ABT-263. However, MCL-1 expression mitigated the impact of ABT-263-induced apoptosis by sequestering BIM released from BCL-2 and BCL-XL. Since MCL-1 expression is dependent on TORC1 activity in some cancers, we attempted to overcome the apoptotic block in SCLC by combining ABT-263 with the TORC1/2 inhibitor AZD8055. AZD8055 treatment alone downregulated MCL-1 expression; combination AZD8055 and ABT-263 induced marked apoptosis and growth arrest in vitro, as well as tumor regressions in multiple SCLC xenograft models. Strikingly, low-dose AZD8055 was sufficient to promote tumor regressions in the combination strategy. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve single-agent ABT-263 activity in SCLC.
Citation Format: Anthony C. Faber, Carlotta Costa, Anahita Dastur, Cyril Benes, Jeffrey Engelman. Assessment of ABT-263 activity across a comprehensive cancer cell line collection leads to a novel, potent combination therapy for small cell 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 2933. doi:10.1158/1538-7445.AM2014-2933
Abstract 2968: FTY720 inhibits mutant Kras-induced lung cancer via disrupting Stat3-S1PR1 vicious cycle and downregulating tumor PD-L1 expression
Authors: Yeh Hsuan-Heng , Hsu Tsung-I , Hung Jan-Jong , Su Wen-Pin , Su Wu-Chou 
Published: May 2015

Abstract
Aberrant activation of signal transducer and activator of transcription 3 (Stat3) occurs in many cancers and plays a critical role in tumor progression. The system that Stat3-induced Sphingosine-1-phosphate receptor 1 (S1PR1) expression and the S1P-S1PR1 pathway reciprocally regulate Stat3 activity was considered a major positive feedback loop for persistent Stat3 activation in cancer cells and the cells of tumor microenvironment. Tumor cells expressing the ligand for the receptor programmed death-1 (PD-1), PD-L1, have been shown to increase apoptosis of antigen-specific human T-cell to evade the immune system. In this study, we determined the influence of disrupting Stat3-S1PR1 vicious cycle on tumor formation and PD-L1 expression in lung cancer. We have established mutant Kras-induced lung cancer mice model and found that Stat3 phosphorylation was elevated in tumor tissues of lung cancer. Treatment of lung cancer cells with AG490 (JAK2 inhibitor) inhibited Stat3 activation and AG490 administration to the mice decreased the numbers of lung cancer nodules, indicating that blockage of Stat3 activation could inhibit mutant Kras-induced lung cancer in mice. Similar effects were also detected by using Stat3 inhibitor, S3I-201. We found that lung cancer cells expressed more pStat3 showed higher PD-L1 expression levels than that of lower pStat3 expressing cells. Inhibition of Stat3 activation by AG490 decreased PD-L1 expression in vitro and in vivo, indicating that PD-L1 expression could be regulated by Stat3. Moreover, FTY720 (S1P antagonist) could inhibit S1PR1 expression, down-regulate Stat3 activity, pJAK1 expression and inhibit IL-6 secretion in lung cancer cell lines and causes inhibition of the mutant Kras-induced lung cancer in mice. Furthermore, FTY720 administration dose-dependently suppressed tumor PD-L1 expression in mice lung cancer tissues. Taken together, our study indicated that FTY720 could suppress mutant Kras induced-lung cancer formation via inhibiting persistent Stat3 activation and down-regulating tumor PD-L1 expression.
Citation Format: Hsuan-Heng Yeh, Tsung-I Hsu, Jan-Jong Hung, Wen-Pin Su, Wu-Chou Su. FTY720 inhibits mutant Kras-induced lung cancer via disrupting Stat3-S1PR1 vicious cycle and downregulating tumor PD-L1 expression. [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 2968. doi:10.1158/1538-7445.AM2014-2968
Abstract 2980: Maximizing the efficacy of anti-angiogenesis cancer therapy: A multi-targeting strategy by tyrosine kinase inhibitors
Authors: Nakazawa Youya , Kawano Satoshi , Matsui Junji , Funahashi Yasuhiro , Tohyama Osamu , Muto Hiroki , Nakagawa Takayuki , Matsushima Tomohiro 
Published: May 2015

Abstract
Although vascular endothelial growth factor (VEGF) inhibitors provide significant clinical benefit, they often require dose reductions or even withdrawals due to their severe toxicities. Furthermore, almost all cancers show intrinsic and/or evasive resistance to VEGF inhibitors by multiple mechanisms. Serum angiopoietin-2 (Ang2) level has been proposed as a potential biomarker of VEGF inhibitor response in several cancers. Response to lenvatinib (E7080; VEGFR1-3 inhibitor) is also reported to correlate with low Ang2 level in differentiated thyroid cancer and endometrial cancer. From these clinical observations, Ang2 and its receptor Tie2 has been focused as promising targets. Here, we demonstrated mechanisms of resistance induced by Ang2 and a novel strategy to circumvent the resistance by combination of multi-tyrosine kinase inhibitors (TKIs), lenvatinib and golvatinib (E7050; c-Met, Tie2, EphB4 inhibitor). Tie2 defines a highly pro-angiogenic macrophage subset, Tie2-expressing macrophage (TEM). Ang-Tie2 and EphB4-EphrinB2 signaling play critical roles in pericyte-mediated vessel stabilization. Ectopic expression of Ang2 in thyroid cancer conferred resistance to lenvatinib and enhanced pericyte-associated endothelial network development and TEM infiltration. In vitro analyses suggested that golvatinib/lenvatinib combination inhibited pericyte-mediated vessel stabilization and TEM differentiation. In thyroid and endometrial cancer models, golvatinib/lenvatinib combination inhibited pericyte network development and TEM infiltration, resulting in severe perfusion disorder and massive apoptosis. Body weight loss was tolerable in mice, and no macroscopic change was observed. These results suggest that modulation of tumor microenvironment by strategic and well-tolerated combination of multi-targeting TKIs sensitizes cancer to VEGF inhibitors, which warrants further clinical investigation to determine the clinical benefit of anti-angiogenesis cancer therapy.
Citation Format: Youya Nakazawa, Satoshi Kawano, Junji Matsui, Yasuhiro Funahashi, Osamu Tohyama, Hiroki Muto, Takayuki Nakagawa, Tomohiro Matsushima. Maximizing the efficacy of anti-angiogenesis cancer therapy: A multi-targeting strategy by tyrosine kinase inhibitors. [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 2980. doi:10.1158/1538-7445.AM2014-2980
Abstract 2983: Bisphosphonates: New strategies for targeting angiogenesis in ovarian cancer
Authors: Dalton Heather J. , Reusser Nicole M. , Zien Alexander , Jackson David , Previs Rebecca , Rupaimoole Rajesha , Zand Behrouz , Lopez-Berestein Gabriel , Coleman Robert L. , Sood Anil K. 
Published: May 2015

Abstract
Objectives:
Bisphosphonates, known to have beneficial effects on bone and soft tissue metastases in breast cancer, are potent inhibitors of macrophages, but effects on the microenvironment are not fully understood. We investigated the biological effect of clodronate on macrophage and endothelial cell-driven angiogenesis in ovarian cancer.
Methods:
Using the FDA Adverse Event Reporting System (FAERS), we examined the effects of bisphosphonate use on overall cancer mortality. We examined the in vitro (endothelial cell migration, capillary formation and cytokine secretion) and in vivo (orthotopic mouse models) effects of clodronate on angiogenesis, macrophage infiltration, and tumor growth.
Results:
Using (FAERS) data, out of ∼17,000 patients with a cancer diagnosis co-medicated with a bisphosphonate, overall reported death rate was 36% lower (17.6% vs 27.7%, p&lt;0.0001) than those not receiving bisphosphonates, independent of anti-tumor therapy. In vitro, treatment with clodronate resulted in decreased endothelial cell secretion of IL-6 (p &lt; 0.001), IL-8 (p &lt; 0.001), and a 2.5-fold reduction in cell migration compared to controls (p &lt; 0.001), with only partial recovery after VEGF stimulation. Clodronate reduced capillary formation by 1.5-fold compared to controls. In the ID8-VEGF model, clodronate-treated mice had a 5-fold decrease in tumor weight (0.05g vs. 0.3g, p &lt; 0.001) compared to controls. In the SKOV3ip1 model, clodronate treatment resulted in a 3-fold decrease in tumor weight (0.35g vs. 0.96g, p = 0.003) and tumor nodules (5.2 vs. 16, p=0.005) compared to controls. Immunohistochemical staining of clondronate-treated tumor sections showed a 2-fold and 1.5-fold (ID8-VEGF and SKOV3ip1, respectively) reduction in macrophage density (p=0.001 and p &lt; 0.001, respectively) compared to controls. Clodronate-treated tumor sections showed a 3-fold decrease in capillary density (p &lt; 0.001) compared to controls.
Conclusions:
Bisphosphonates modulate tumor angiogenesis through effects on macrophages and endothelial cells and are associated with overall decreased mortality in cancer patients, independent of chemotherapeutic agents. Bisphosphonates represent an unexplored, but attractive clinical strategy in ovarian cancer, with potential for synergistic combination with other anti-angiogenic agents.
Citation Format: Heather J. Dalton, Nicole M. Reusser, Alexander Zien, David Jackson, Rebecca Previs, Rajesha Rupaimoole, Behrouz Zand, Gabriel Lopez-Berestein, Robert L. Coleman, Anil K. Sood. Bisphosphonates: New strategies for targeting angiogenesis in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2983. doi:10.1158/1538-7445.AM2014-2983
Abstract 2985: In vivo evaluation of regorafenib and liposomal-doxorubicin in a panel of low passage uterine START-PDX tumor models
Authors: Meade Justin , Wick Michael J. , Vaught Teresa , Gamez Lizette , Chavez Roger , Tolcher Anthony , Rasco Drew , Patnaik Amita , White Allan J. , Papadopoulos Kyriakos 
Published: May 2015

Abstract
Background: Uterine and ovary cancers account for a majority of gynecologic cancer-related deaths in Western countries. While initial cure rates are high, recurrent disease is often chemoresistant with few treatment options. Regorafenib is a recently approved multi-tyrosine kinase targeting VEGFR2 and Tie2. As Tie2 has been implicated in the pathogenesis of uterine cancers, we evaluated regorafenib as a potential therapy in our panel of uterine PDX models and compared activity to the approved therapy liposomal-doxorubicin.
Methods: PDX uterine models were established in immune-deficient mice from primary or metastatic patient tissue and once established were confirmed by histologic comparative analysis with patient tumor tissue, linked with patient treatment and outcome data and characterized for activating mutations and known amplifications. Drug sensitivity studies were performed in each model evaluating daily oral regorafenib or weekly intravenous liposomal-doxorubicin versus control; group sizes were n=2-3 for control and n=1 for treatment arms. Study endpoints included a set day following treatment initiation with tumor growth inhibition or delay and regression reported at study completion.
Results: For this project we evaluated twenty-five uterine models. Statistically significant (p&lt;0.05) regorafenib activity was reported in a subset of evaluated endometrial models; however, activity was not limited to a particular tumor subtype or mutation profile. Liposomal-doxorubicin also demonstrated differential but significant tumor growth inhibition towards models in the evaluated panel.
Conclusion: We have screened preclinical activity of regorafenib and liposomal-doxorubicin towards a panel of uterine START-PDX models and identified sensitive and resistant models. Additional genomic and characterization studies are underway to better understand activity of regorafenib with the goal of identifying a sensitivity profile for patient stratification.
Citation Format: Justin Meade, Michael J. Wick, Teresa Vaught, Lizette Gamez, Roger Chavez, Anthony Tolcher, Drew Rasco, Amita Patnaik, Allan J. White, Kyriakos Papadopoulos. In vivo evaluation of regorafenib and liposomal-doxorubicin in a panel of low passage uterine START-PDX tumor models. [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 2985. doi:10.1158/1538-7445.AM2014-2985
Abstract 2990: Notch1 monoclonal antibody inhibits tumor growth and modulates angiogenesis
Authors: Okamura Heidi , Proia Theresa , Bell Alisa , Liu Qing , Siddiquee Zakir , Lin Jie , Gyuris Jeno 
Published: May 2015

Abstract
AVEO Oncology has developed a series of inducible mouse models of cancer, which through the preservation of critical tumor/stromal interactions, facilitate identification of cell-surface and secreted proteins that represent viable targets for therapeutic antibodies and other biologics. Functional genetic screens performed in vivo in these models identified the Notch pathway as a critical regulator of tumor maintenance. This finding was consistent with emerging evidence that activation of Notch signaling via receptor point mutation, receptor amplification, and elevated receptor and ligand expression, plays a key role in various human cancers. Moreover, the Notch pathway controls diverse aspects of tumorigenesis and tumor maintenance, regulating tumor autonomous processes and interactions with the microenvironment, including angiogenesis. To further understand the role of the Notch pathway in tumor maintenance, and to assess the therapeutic potential of targeting the Notch pathway in cancer, we have generated monoclonal antibodies that inhibit the Notch1 receptor. Characterization of monoclonal antibodies targeting Notch1 through cell-based and biochemical studies demonstrated that the Notch1 monoclonal antibody bound with high affinity and high specificity to the Notch1 receptor, prevented ligand-mediated activation of the target receptor, and specifically repressed Notch-dependent signaling with high potency. Significantly, specific inhibition by the Notch1 monoclonal antibody did not result in the dose-limiting gut toxicity observed with Notch1 mAb resulted in tumor inhibition that was accompanied by increased vascular density, inhibition of Notch target gene expression, and increased expression of angiogenesis-related genes, consistent with expected changes resulting from Notch1/Dll4 pathway inhibition. In addition, several tumor models treated in combination with Notch1 mAb and an investigational VEGF pathway inhibitor, tivozanib, demonstrated increased tumor inhibition compared to either agent alone. Interestingly, combination treatment resulted in decreased vascular density and downregulated expression of angiogenesis genes, similar to treatment with VEGF inhibitor alone. Collectively, our work suggests that combination therapy of Notch1 antibodies with VEGF inhibitors should be evaluated as a potential viable therapeutic option for VEGF-resistant tumors.
Citation Format: Heidi Okamura, Theresa Proia, Alisa Bell, Qing Liu, Zakir Siddiquee, Jie Lin, Jeno Gyuris. Notch1 monoclonal antibody inhibits tumor growth and modulates angiogenesis. [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 2990. doi:10.1158/1538-7445.AM2014-2990
Abstract 2991: Triple combination of bevacizumab, anti-DLL4 (delta like ligand 4) and trebananib gives enhanced therapeutic effects in three xenograft tumor models
Authors: Mattson Bethany , Moriguchi Jodi , Jun H. Toni , Coxon Angela , Cordover Dave , Kaufman Steve , Oliner Jon , Starnes Charlie 
Published: May 2015

Abstract
Bevacizumab is a monoclonal antibody targeting VEGF that is clinically approved for the treatment of multiple indications in oncology, including colorectal, lung and renal cancer as well as glioblastoma. Clinical activity has also been demonstrated in breast and ovarian cancer as well, however, the time periods of benefit for all of these indications is in months (1-5). Multiple pathways are known to participate in the process of angiogenesis, and the limited effects of bevacizumab may represent the maximum activity of targeting just one of them. The purpose of the present study was to examine the effect of simultaneously targeting multiple angiogenic axes including angiopoietins 1 and 2, Dll4 and VEGF. Trebananib is a recombinant peptide-Fc fusion protein that selectively blocks the Tie2 interactions of both Ang1 and Ang2. Trebananib, as well as a recombinant antibody to Dll4 were produced at Amgen, Inc., Thousand Oaks, CA. Bevacizumab was purchased from a local pharmacy. These reagents were employed in the combination treatment of three different preclinical murine tumor models (U87, glioblastoma; MiaPaca and BxPC3, pancreatic carcinoma), one of which (BxPC3) was specifically selected for its relative resistance to VEGF/KDR inhibition. Harlan Athymic nu/nu female mice at 6-7 weeks of age were injected subcutaneously on the right flank with 5 x 106 tumor cells in the presence of Matrigel and treated when the tumors were approximately 300 mm3. The results, as supported by histomorphometric analysis (percent blood vessel area, viable tumor burden), demonstrate that under conditions of optimal biological dosing, the addition of trebananib to a two-way combination of bevacizumab and anti-Dll4 resulted in a statistically significant enhancement of therapeutic effect for the three-way combination, an observation made consistently over 3 different tumor models and 3 different dose levels of bevacizumab and anti-Dll4 (p = or &lt; 0.0024; RMANOVA). Furthermore, the therapeutic effect in all three models approximated prolonged stasis, the ultimate theoretical goal of antiangiogenesis in the treatment of cancer.
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Citation Format: Bethany Mattson, Jodi Moriguchi, H. Toni Jun, Angela Coxon, Dave Cordover, Steve Kaufman, Jon Oliner, Charlie Starnes. Triple combination of bevacizumab, anti-DLL4 (delta like ligand 4) and trebananib gives enhanced therapeutic effects in three xenograft tumor models. [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 2991. doi:10.1158/1538-7445.AM2014-2991