bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1329: Identification of neoantigens recognized by autoantibodies in chemotherapy-treated pancreatic cancer patients
Authors: Mandili Giorgia , Mazza Emanuela , Capello Michela , Giordano Daniele , Cappello Paola , Novelli Francesco 
Published: August 2015

Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult cancer to treat, both for lack of effective screening method and for resistance phenomenon. At present surgical resection is the only potentially curative option, but the absence of early symptoms or clinical-pathological markers results in diagnosis at a late, inoperable stage in mostly of cases. Once diagnosed, a number of chemotherapy, radiation and combination therapy regimens are usually used to treat patients, but responses remain poor. However, chemotherapy is able to enhance tumor immunogenicity. Thus more immunogenic neo-antigens can be induced by chemotherapy and targeted by passive or active immunotherapy. We have previously identified a number of Tumor Associated Antigens (TAA) that are recognized by autoantibodies in PDAC patients. One of these, alpha-enolase, was found to have good antigen capability and immunization with DNA coding for alpha-enolase effectively enhanced the survival of genetically engineered mice that develop spontaneously PDAC. To discover neo-antigens that might be selected for immunotherapy, we have analysed antibody response in PDAC patients’ sera before and after chemotherapy. The reactivity of PDAC patients’ sera obtained before and after two rounds of chemotherapy was analysed on 2-dimensional gel electrophoresis proteome map of CF-PAC pancreatic cancer cell line and the antigens recognized by autoantibodies were identified by mass spectrometry. A number of antigens, mainly metabolic enzymes, proteins involved in transcription and structural proteins, were recognized by autoantibody only after one or two rounds of chemotherapy. The identification of common and individual antigens from chemotherapy treated-patients formed the platform for ongoing immunological studies aimed to assess the ability of these neo-antigens, compared to that identified before chemotherapy treatment, to induce specific helper and cytotoxic response to PDAC. A stronger and sustained immune response correlated to survival is expected to be induced by neo-antigens. Validation of these neo-antigens will allow to develop specific immunotherapy combined with chemotherapy.
Citation Format: Giorgia Mandili, Emanuela Mazza, Michela Capello, Daniele Giordano, Paola Cappello, Francesco Novelli. Identification of neoantigens recognized by autoantibodies in chemotherapy-treated pancreatic cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1329. doi:10.1158/1538-7445.AM2015-1329
Abstract 1331: Targeting CD47 triggers macrophage-dependent brain tumor destruction in a clinical relevant model
Authors: Zhu Huaiyang , Yang Ning , Leiss Lina , Rygh Cecilie B , Mitra Siddhartha S , Cheshier Samuel H , Huang Bin , Bjerkvig Rolf , Enger Per Ø , Weissman Irving L , Li Xingang , Wang Jian 
Published: August 2015

Abstract
Glioblastoma multiform (GMB), as a major unsolved clinical challenge, remains among the most aggressive malignancies in human brain with poor prognosis around 10-14.6 months survival. Due to their infiltrative character in the limited space, it is very difficult to be completely resected surgically. Although radiotherapy and chemotherapy that were given to patients after surgery may improve overall survival, the treatment outcomes in general are poor. The tumors eventually recur. Thus, new therapeutic strategy for GBM is urgently needed. It has been shown that CD47, a tumor cell surface marker, through binding its receptor SIRPα on macrophages plays as “don't eat me signal” and thus, by blocking the interaction of CD47 with SIRPα could lead to tumor destruction. So, we developed a standardized protocol for a novel xenograft surgical resection model which mimicked the process of operation in clinic. We hypothesized that the mechanical surgical procedure of tumor resection may create an inflammatory tumor environment, leading to recruitment of immune cells including macrophages. We believed the presence of these macrophages was needed to mediate the anti-tumor effects of the CD47 antibody which we administered postoperatively. The aims of the project are: 1) Translating brain tumour immunotherapy from the lab bench via preclinical studies to the clinic; 2) Establishing a novel xenograft surgical resection model to mimic the clinical setting of tumour recurrence in patients. Specifically, we will: 1) In vitro quantify and functionally characterize tumour-associated macrophages from treated vs. untreated tumours; 2) Using our clinical relevant animal models we want to determine the efficacy of targeting CD47 therapy.
In this study, we have developed a standardized protocol for a novel xenograft surgical resection model to parallel the treatment seen in glioma patients. The model accounts for the therapeutic benefit of surgical resection in pre-clinical models and demonstrates that recurrent tumors show higher proliferation and angiogenesis comparing to non-resected tumors. Moreover, the resection site is highly infiltrated by both CD68 and pSTAT1 positive macrophages. CD47 antibody treatment group has longer survival time than other groups.
Citation Format: Huaiyang Zhu, Ning Yang, Lina Leiss, Cecilie B Rygh, Siddhartha S Mitra, Samuel H Cheshier, Bin Huang, Rolf Bjerkvig, Per Ø Enger, Irving L Weissman, Xingang Li, Jian Wang. Targeting CD47 triggers macrophage-dependent brain tumor destruction in a clinical relevant model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1331. doi:10.1158/1538-7445.AM2015-1331
Abstract 1340: Antitumor effector B cells directly kill tumor cells involving the CXCL12/CXCR4 pathway and their therapeutic efficacy is enhanced by IL-2
Authors: Xia Yang , Tao Huimin , Hu Yangyang , Zhou Li , Bao Yangyi , Lundy Steven K , Huang Shiang , Li Qiao , Chang Alfred E 
Published: August 2015

Abstract
In cancer immunotherapy, effector B cells can inhibit spontaneous tumor metastases as well as local tumor growth in animal models. We have previously reported that antitumor effector B cells generated from tumor-draining lymph node (TDLN) could directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. Trafficking of TDLN B cells in vivo suggested that they were recruited to the tumor and lung as well as secondary lymphoid organs. The number of TDLN B cells increased following transfer. As a result, adoptive transfer of TDLN B cells conferred tumor regression in a spontaneous pulmonary metastasis mouse model of breast cancer, 4T1. Removal of IL-10, either by using IL-10-/- TDLN B cells or by systemic neutralization of IL-10 using anti-IL-10 antibody, significantly augmented the therapeutic efficacy of adoptively transferred TDLN B cells. In recent studies, we found that tumor cell death mediated by effector B cells involves the CXCR4/CXCL12 as well as Fas/FasL interactions. Blockade of CXCR4 and FasL using a CXCR4-specific inhibitor, AMD3100, and anti-FasL antibody, respectively, reduced the killing of 4T1 tumor cells by 4T1 TDLN B cells. Of note, blockade of CXCR4 and FasL concurrently inhibited B cell-mediated direct killing of tumor cells in an additive fashion, suggesting that both CXCL12/CXCR4 and Fas/FasL pathways are involved in the direct killing of 4T1 tumor cells by 4T1 TDLN B cells. In other experiments, we found that TDLN B cells express IL-2 receptors (IL-2R) and the ability of the TDLN B cells to inhibit metastasis was significantly enhanced with exogenous IL-2 administration. Besides our previously reported Fas/FasL pathway and IL-10-mediated suppression, our recently identified CXCL12/CXCR4 pathway and IL-2-mediated augmentation of the biological function of effector B cells suggests these B cells may represent an important component of the host immune response against tumor.
Citation Format: Yang Xia, Huimin Tao, Yangyang Hu, Li Zhou, Yangyi Bao, Steven K Lundy, Shiang Huang, Qiao Li, Alfred E Chang. Antitumor effector B cells directly kill tumor cells involving the CXCL12/CXCR4 pathway and their therapeutic efficacy is enhanced by IL-2. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1340. doi:10.1158/1538-7445.AM2015-1340
Abstract 1350: The combination of a murine iNKT cell-activating antibody and IL-12 exhibits antitumor activity in a mouse melanoma model
Authors: Yuan Weiming , Wen Xiangshu 
Published: August 2015

Abstract
Invariant natural killer T (iNKT) cells are innate-like T cells with an invariant iTCR with potent anti-tumor activity. Current anti-tumor clinical trials using the iNKT cell ligand, a-galactosylceramide (a-GalCer) have had limited success. One major limitation of a-GalCer-based therapies is the bioavailability of lipid drugs and current therapies require isolation and a-GalCer loading of dendritic cells prior to administration (Richter et al Blood 121:423, 2013). We have engineered a murine iNKT TCR-targeting monoclonal antibody (NKT14m) that activates iNKT cells directly without dendritic cells or glycolipids. We have evaluated the in vivo anti-tumor efficacy with the established B16 mouse melanoma model. Based on preliminary results that the potency of NKT14m is less than that of a-GalCer, we reasoned that the addition of IL-12 stimulation would be beneficial for iNKT cell activation (Yue et al PNAS 102:11811, 2005). Currently, the toxicity of IL-12 has restricted its use in clinical trials. We evaluated a non-toxic dose of IL-12 alone and in combination with NKT14m. C57BL/6 mice were injected with 400K B16F10 melanoma cells on Day 0. On Day 2 they were divided into untreated, IL-12 treated (0.1 ug/mouse/day for 12 days), NKT14m treated (100 ug/mouse once on Day 2) and the combination of NKT14m+IL-12 using the same dose regimens. On Day 14 mice were sacrificed and lung tumors counted. We detected a synergistic effect in the combination of NKT14m+IL-12 (Table 1). These findings represent a new paradigm of iNKT cell activation for their anti-tumor function.
Table 1 - Lung Tumors in Treatment GroupsExperimental GroupsControlIL-12NKT14mIL-12+NKT14mNumbers of metastatic tumors150+/-67117+/-2555+/-2923+/-10
Citation Format: Weiming Yuan, Xiangshu Wen. The combination of a murine iNKT cell-activating antibody and IL-12 exhibits antitumor activity in a mouse melanoma model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1350. doi:10.1158/1538-7445.AM2015-1350
Abstract 1366: Mdm2 antagonist RG7388 does not interfere with tumor angiogenesis in vitro and in vivo
Authors: Lehmann Christian , Friess Thomas , Lorenzon Erica , Herting Frank , Dangl Markus 
Published: August 2015

Abstract
MDM2 interacts with the transcription factor p53 via its N-terminal domain and is the most prominent and best described natural inhibitor of the p53 tumor suppressor pathway. Apart from this very well investigated function, MDM2 has been reported to be involved in angiogenesis via various mechanisms. Published data indicate that MDM2 interacts directly with and activates HIF1a but can also display HIF1a independent effects such as VEGF mRNA stabilization or regulation of ERK1/2 signaling. Taken together, these reports suggest that MDM2 antagonists might have the potential to inhibit tumor-angiogenesis or age-related macular degeneration.
In order to test the potential anti-angiogenic activity of interfering with MDM2-p53 binding, we utilized the highly selective, clinical stage MDM2 antagonist RG7388. First, it was tested if RG7388 influences the induction of response to hypoxic conditions using a HRE-reporter cell line, followed by analyzing the interference of RG7388 with human endothelial cell tubule formation. The in-vitro results showed no statistically significant inhibition of HIF1a facilitated GFP reporter activation nor any effect on HUVEC tubule formation, viability or proliferation. In a mouse cornea pocket assay in-vivo, systemic administration of a MDM2 antagonist did not prevent VEGF-A or FGF-2 induced vessel formation. Finally, RG7388 and vehicle treated SJSA xenograft tumors were explanted and analyzed in detail for changes in vessel architecture. No effects on microvascular density or vessel structure were observed. Taken together, these data indicate that RG7388, a highly selective MDM2 antagonist that binds to the p53-binding pocket of MDM2 and prevents interaction of MDM2 with p53, is not suitable for anti-angiogenic treatment. One possible explanation for the lack of anti-angiogenic activity is the increased potency/specificity of RG7388 resulting in higher selectivity and fewer off target effects compared to Nutlin-3a.
Citation Format: Christian Lehmann, Thomas Friess, Erica Lorenzon, Frank Herting, Markus Dangl. Mdm2 antagonist RG7388 does not interfere with tumor angiogenesis in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1366. doi:10.1158/1538-7445.AM2015-1366
Abstract 1370: Activin receptor-like kinase 1 ligand trap reduces microvascular density and improves chemotherapy efficiency to various solid tumors
Authors: Hawinkels Lukas JAC , Garcia de Vinuesa Amaya , Paauwe Madelon , Kruithof-de Julio Marianna , Heijkants Renier , Goumans Marie-Jose , ten Hagen Timo , ten Dijke Peter 
Published: August 2015

Abstract
Anti-angiogenic therapy, mostly targeting vascular endothelial growth factor (VEGF), has been clinical applied in cancer patients for the last decade. However, often resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new anti-angiogenic strategies are needed. In this study we analyzed the potential anti-angiogenic effects of activin-receptor-like kinase (ALK)1-Fc protein. ALK1-Fc sequesters bone morphogenetic protein (BMP)-9 and -10 and prevents binding of these ligands to endothelial ALK1, which controls angiogenesis. Treatment of mice with breast cancer, head and neck cancer, or melanomas strongly decreased the tumors’ microvascular density, but this effect was not accompanied by a reduction in tumor volume. In contrast to anti-VEGF therapy, we observed decreased hypoxia, and increased staining for pericytes, consistent with the notion that ALK1-Fc may have induced a normalization of the remaining tumor vessels. Next we found that combined regimen of ALK1-Fc with chemotherapy inhibited tumor growth in the breast- and head and neck cancer models more efficiently than chemotherapy alone. Our results provide strong rational to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase-II clinical trials with ALK1-Fc.
Citation Format: Lukas JAC Hawinkels, Amaya Garcia de Vinuesa, Madelon Paauwe, Marianna Kruithof-de Julio, Renier Heijkants, Marie-Jose Goumans, Timo ten Hagen, Peter ten Dijke. Activin receptor-like kinase 1 ligand trap reduces microvascular density and improves chemotherapy efficiency to various solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1370. doi:10.1158/1538-7445.AM2015-1370
Abstract 1372: Acquired resistance to sunitinib is not associated with functional re-vascularization in 786-O renal cell carcinoma xenografts
Authors: Robinson Simon P. 
Published: August 2015

Abstract
Anti-angiogenic therapy has shown considerable efficacy in metastatic renal cell carcinoma (mRCC). However, the ability of drugs such as sunitinib to delay tumour progression and extend survival is limited, due to both innate and evasive drug resistance, thought to arise through alternative, VEGF-independent mechanisms of tumour re-vascularization. Furthermore, there are no validated biomarkers that predict which mRCC patients will benefit from anti-angiogenic therapy. In investigating the response of 786-O RCC xenografts to sunitinib, a model of acquired resistance has been established with chronic treatment. The aims were to evaluate fractional blood volume (fBV) derived from susceptibility contrast MRI with ultrasmall superparamagnetic iron oxide (USPIO) particles as a non-invasive imaging biomarker of response, and interrogate the vascular phenotype of 786-O xenografts exhibiting acquired resistance to sunitinib.
Mice bearing established xenografts underwent MRI prior to and two weeks after daily treatment with 40mg/kg sunitinib. USPIO particle uptake was reduced in all treated tumours, resulting in a highly significant reduction in fBV in the absence of any change in tumour volume (Table 1). This response was associated with a significant reduction in the uptake of the perfusion marker Hoechst 33342. The average pre-treatment tumour fBV was significantly positively correlated (R2 = 0.92, p&lt;0.0001) with sunitinib-induced changes in tumour fBV across the cohort.
Additional tumour-bearing mice exhibiting acquired resistance to sunitinib (designated 786-O-R) were imaged when their tumours reached at least 4x their volume at commencement of treatment. Resistant 786-O- R xenografts revealed a suppressed fBV whilst still being treated with sunitinib.
Pre-treatment tumour fBV is a predictive biomarker of subsequent response to sunitinib in RCC. Acquired resistance to sunitinib is not associated with functional re-vascularization in 786-O RCC xenografts.
Table 1
786-O (n = 9)786-O-R (n = 4)PrePostPostTumour volume (mm3)153 ± 17148 ± 24471 ± 63fBV (%)8.3 ± 22.4 ± 0.5**2.1 ± 0.5fBV / Tumour volume6.8 ± 22.5 ± 1*0.5 ± 0.1Hoechst 33342 uptake (%)13.5 ± 56.4 ± 1*n.a.
Citation Format: Simon P. Robinson. Acquired resistance to sunitinib is not associated with functional re-vascularization in 786-O renal cell carcinoma xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1372. doi:10.1158/1538-7445.AM2015-1372
Abstract 1383: Phenotype-based development of novel therapies for the treatment of colorectal cancer
Authors: Butler Clare T. , Murphy Adrian , Gallagher William M. , O'Sullivan Jacintha , Kennedy Breandán 
Published: August 2015

Abstract
Introduction: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Treatment of late stage CRC using Bevacizumab®, a targeted anti-VEGF, produces insufficient patient response rates and acquired tumour resistance. There is a clinical need for development of improved treatment options.
Materials and Methods: Previously, anti-angiogenic screens in Tgfli1:EGFP zebrafish identified Quininib, a small molecule drug as effective as Bevacizumab®at reducing tumour volume in vivo and which reduces tumour CD31 expression in xenografted mice. Here, structural analogues of Quininib were synthesised to identify novel chemical entities with higher anti-angiogenic and anti-inflammatory efficacy. Analogues were examined for anti-angiogenic effects in the zebrafish intersegmental-vessel assay. Hits were progressed for safety analysis in cytotoxic assays, anti-angiogenic efficacy in aortic explants, and effects on cell proliferation and tubule formation using HT29_Luc2 and HMEC cells. Leads were then tested in ex vivo human CRC tumour explants to determine effects on angiogenic and inflammatory factor secretion. A CRC-specific murine xeongraft model was created by subcutaneous injection of HT29_Luc2 cells for anti-tumorigenic analysis of the Quininib analogues.
Results and Discussion: Five out of 12 drug candidates (CTB_1, CTB_2, WP_1, WP_2 and WP_11) reduced developmental angiogenesis in fli1:EGFP zebrafish significantly more than Quininib (98% vs 67%, ***P&lt;0.01). These analogues were well-tolerated in human endothelial and CRC cell cytotoxic assays and were more effective than Quininib at reducing tubule formation and angiogenic factor secretion in HMEC cells. Two analogues reduced aortic ring vessel sprouting equally or more effectively than Quininib. Preliminary data suggests that certain analogues can reduce inflammatory and angiogenic factor secretion from ex vivo human CRC explants more so than Quininib. We successfully established a CRC-specific murine tumour xenograft model. Using a ranking efficacy table, we chose analogues to analyse their anti-tumorigenic and anti-metastatic effects, by i/p injection in an optimised model of HT29_Luc2-CRC tumourigenesis in Balb/c nude mice.
Conclusion: We identified 5 analogues which are significantly more effective than Quininib within in vitro and ex vivo models of inflammation and angiogenesis. Our highest ranking analogue will be tested in murine xenografts to determine effects on tumour burden and metastasis.
Citation Format: Clare T. Butler, Adrian Murphy, William M. Gallagher, Jacintha O'Sullivan, Breandán Kennedy. Phenotype-based development of novel therapies for the treatment of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1383. doi:10.1158/1538-7445.AM2015-1383