bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2663: Characterization of the pharmacodynamic immune response to a novel immunotherapeutic agent, ALKS 4230, in mice and non-human primates
Authors: Lopes Jared E. , Losey Heather C. , Dean Reginald L. , Flick Heather L. , Huff Michael R. , Moroso Rosemarie A. , Sun Lei , Alvarez Juan C. 
Published: July 2017

Abstract
ALKS 4230 is a selective agonist of the intermediate-affinity IL-2 receptor (IL-2R). A phase 1 study is ongoing to evaluate the safety and tolerability of ALKS 4230 in the treatment of patients with refractory solid tumors. The selectivity of ALKS 4230 is achieved through the stable fusion of circularly permuted IL-2 to the extracellular portion of the IL-2Rα chain, CD25. The resulting fusion protein is sterically prevented from binding to the high-affinity IL-2R complex, comprised of IL-2Rα, IL-2Rβ, and common gamma chain, expressed preferentially on CD4+ FOXP3+ regulatory T cells (CD4+ Tregs) yet retains full ability to signal through the intermediate-affinity IL-2R complex, comprised of IL-2Rβ and common gamma chain, expressed on memory CD8+ T cells and NK cells. Repeated dosing of ALKS 4230 drives the significant expansion of various CD8+ T cell and NK cell populations without activation and minimal expansion of CD4+ Tregs in mice and non-human primates (NHP). The kinetics of the immunological responses in mice and NHP demonstrate that the pharmacodynamic effects persist beyond systemic exposure of ALKS 4230. Data demonstrating the effects of ALKS 4230 on tumor-infiltrating lymphocyte populations in syngeneic tumor models will also be presented.
Citation Format: Jared E. Lopes, Heather C. Losey, Reginald L. Dean, Heather L. Flick, Michael R. Huff, Rosemarie A. Moroso, Lei Sun, Juan C. Alvarez. Characterization of the pharmacodynamic immune response to a novel immunotherapeutic agent, ALKS 4230, in mice and non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2663. doi:10.1158/1538-7445.AM2017-2663
Abstract 2667: In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1
Authors: Youssef Sawsan , Abdiche Yasmina , Nguyen HoangKim , Chou Joyce , Chin Sherman Michael , Kamperschroer Cris , Schneider Patricia A. , Kraynov Eugenia , Krupka Heike I. , Rajpal Arvind , Lin John 
Published: July 2017

Abstract
Monoclonal-antibody-based therapies targeting the immune checkpoint receptors have become the new standard of care in many cancers. Antibodies that specifically target programmed death receptor-1 (PD-1) or its cognate ligand, programmed death receptor ligand-1 (PD-L1), alone or in combination, have yielded clinical benefits and durable responses in patient subsets with various cancers (including metastatic melanoma, NSCLC, RCC, urothelial cancer, cHL and others). Here we report on the biophysical characteristics and non-clinical antagonistic activities of PF-06801591. PF-06801591 is a humanized anti-PD-1 antibody of human IgG4 isotype, that binds selectively and with similar potency to human and cynomolgus monkey PD-1 receptor (EC50 ~50 pM) and blocks its interaction with its cognate ligands PD-L1 and PD-L2 (IC50 &lt; 1 nM) with no detectable Fc effector function. The interaction of PF-06801591 to PD-1 rescues T cell suppression and exhaustion that translates into NFAT activation, IL-2 and IFN-gamma secretion and T cell proliferation both in vitro cultures and in vivo using an acute xeno GvHD model with human PBMC transfer. Binding of PF-068001591 to human and cynomolgus PD-1 is characterized by the formation of a very stable complex (T1/2 = 2 h) as measured by SPR at 37 C, resulting in high affinity (KD ~20 pM) as measured in solution by KinExA at 23 C. In addition, we explored therapeutic potential of anti-PD-1 in combination with other immunotherapy agents using surrogate antibodies in non-clinical tumor models. The data presented here support future development of PF-06801591 as a single agent or in combination with other immunotherapies.
Citation Format: Sawsan Youssef, Yasmina Abdiche, HoangKim Nguyen, Joyce Chou, Sherman Michael Chin, Cris Kamperschroer, Patricia A. Schneider, Eugenia Kraynov, Heike I. Krupka, Arvind Rajpal, John Lin. In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2667. doi:10.1158/1538-7445.AM2017-2667
Abstract 2674: Fusobacterium nucleatum subspecies animalis influences pro-inflammatory cytokine expression and monocyte activation in human colorectal tumors
Authors: Ye Xiangcang , Wang Rui , Bhattacharya Rajat , Boulbes Delphine R. , Fan Fan , Xia Ling , Harish Adoni , Ajami Nadim J. , Wong Matthew C. , Smith Daniel P. , Petrosino Joseph F. , Venable Susan , Qiao Wei , Baladandayuthapani Veera , Maru Dipen , Ellis Lee M. 
Published: July 2017

Abstract
Chronic infection and associated inflammation have long been suspected to promote human carcinogenesis. Recently, certain gut bacteria, including some in the Fusobacterium genus, have been implicated in playing a role in human colorectal cancer (CRC) development. However, the Fusobacterium species and subspecies involved and their oncogenic mechanisms remain to be determined. We sought to identify the specific Fusobacterium spp. and ssp. in clinical CRC specimens by targeted sequencing of Fusobacterium 16S ribosomal RNA gene. Five Fusobacterium spp. were identified in clinical CRC specimens. Additional analyses confirmed that Fusobacterium nucleatum ssp. animalis was the most prevalent F. nucleatum subspecies in human CRCs. We also assessed inflammatory cytokines in CRC specimens using immunoassays and found that expression of the cytokines interleukin-17A and tumor necrosis factor-alpha was markedly increased but interleukin-21 decreased in the colorectal tumors. Furthermore, the chemokine (C-C motif) ligand 20 was differentially expressed in colorectal tumors at all stages. In in vitro co-culture assays, F. nucleatum ssp. animalis induced CCL20 expression in CRC cells and monocytes. It also stimulated the monocyte/macrophage activation and migration. Our observations suggested that infection with F. nucleatum ssp. animalis in colorectal tissue could induce inflammatory response and promote CRC development. Further studies are warranted to determine if F. nucleatum ssp. animalis could be a novel target for CRC prevention and treatment.
Citation Format: Xiangcang Ye, Rui Wang, Rajat Bhattacharya, Delphine R. Boulbes, Fan Fan, Ling Xia, Adoni Harish, Nadim J. Ajami, Matthew C. Wong, Daniel P. Smith, Joseph F. Petrosino, Susan Venable, Wei Qiao, Veera Baladandayuthapani, Dipen Maru, Lee M. Ellis. Fusobacterium nucleatum subspecies animalis influences pro-inflammatory cytokine expression and monocyte activation in human colorectal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2674. doi:10.1158/1538-7445.AM2017-2674
Abstract 2685: Modulating tumor microenvironments through inflammasome and IL-1 pathways
Authors: Guo Beichu , Zhang Jinyu , Fu Shun-Jun 
Published: July 2017

Abstract
Chronic Inflammation has been shown to play important roles at all stages of tumor development including initiation, growth, invasion and metastasis. The inflammasome is an important innate immune pathway critical for the production of active IL-1β, a potent inflammatory cytokine. While extensive evidence indicates that inflammasomes are involved in infections and autoimmune diseases, the role of inflammasomes in tumor development remains controversial. To dissect the roles of the inflammasome and IL-1 pathway in tumor development, we utilized the MMTV-PyMT transgenic model, which develops mammary gland tumors with a high incidence of lung metastasis. Our results have demonstrated that inflammasome and IL-1β play a critical role in promoting tumor growth and metastasis. We found that tumor growth was associated with inflammasome activation and elevated levels of IL-1β in tumor microenvironments in mouse mammary tumor models and in human breast cancer tissues. Mice deficient for inflammasome components or IL-1R signaling exhibit significantly reduced lung metastasis. Our data also show that inflammasome activation led to the accumulation of myeloid cells, such as such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in tumor microenvironments. Furthermore, blocking IL-1R signaling with IL-1R antagonist (IL-Ra) or anti-IL-1R antibody inhibited tumor growth and metastasis. Our results suggest that targeting the tumor microenvironment through inflammasome and IL-1 blockade may provide a novel approach for the treatment of breast cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Beichu Guo, Jinyu Zhang, Shun-Jun Fu. Modulating tumor microenvironments through inflammasome and IL-1 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2685. doi:10.1158/1538-7445.AM2017-2685
Abstract 2695: Role of tumor generated acidity in immune stromal interactions during prostate carcinogenesis
Authors: El-Kenawi Asmaa , Dhillon Jasreman , Ibrahim-Hashim Arig , Abrahams Dominique , Pilon-Thomas Shari , Ruffell Brian , Gatenby Robert , Gillies Robert 
Published: July 2017

Abstract
Insufficiency in tumor perfusion and high rate glycolysis combine to reduce the pH of tumor microenvironment. In a TRAMP model of prostate cancer, we had shown that carcinogenesis is associated with increasing acidification of the microenvironment and that neutralization of this acidity can prevent cancer emergence or metastases. Carcinogenesis in the TRAMP model is also associated with increased fibrosis and immune cells infiltration. We thus sought to determine if fibrosis drives immune infiltration in early tumorigenesis or vice-versa; and whether this dynamics is affected by tumor acidity. To investigate this, we harvested prostates from TRAMP mice or their matching non-transgenic controls at different time points and stained serial prostate tissue sections with F4/80 (macrophages), SMA (cancer-associated fibroblasts, CAFs), and Masson’s Trichome (collagen). Quantitative image analysis reveals that increase in fibrosis occur prior to macrophage infiltration and that both events preceded tumor development. However, the relative amount of collagen fibers was unchanged across all time points. Notably, neither fibrosis nor macrophage infiltration occurred in mice treated with buffer, suggesting an involvement of acidity in this immune stromal interactions. Interestingly, macrophages isolated from latter time points in the untreated group as well as macrophages co-cultured with prostate tumor cells at acidic pH, possessed an M2-like phenotype by expressing immunosuppressive genes (e.g. Arginase 1, Arg1) and a range of scavenging receptors (e.g. mannose receptor, Cd206), as well as releasing more angiogenic factors (e.g. VEGF and MMPs). Similar results were recapitulated when M2 macrophages were stimulated at acidic pH by showing enhanced Cd206 and Arg1 expression. On the functional level, macrophages activated at acidic pH had a higher ability to uptake fluorescently labelled ovalbumin and collagen, as examples of mannosylated ligands that prevail the fibrotic microenvironment. In summary, these results suggest that tumor acidity may promote fibrosis, with subsequent macrophage infiltration and phenotypic switching, leading to increased collagen turnover. It is suspected that this extracellular matrix remodeling may be permissive for tumor progression.
Citation Format: Asmaa El-Kenawi, Jasreman Dhillon, Arig Ibrahim-Hashim, Dominique Abrahams, Shari Pilon-Thomas, Brian Ruffell, Robert Gatenby, Robert Gillies. Role of tumor generated acidity in immune stromal interactions during prostate carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2695. doi:10.1158/1538-7445.AM2017-2695
Abstract 2699: NFATc2 in non-small cell lung cancer mediates inhibition of peripheral blood mononuclear cell proliferation
Authors: Lam Ian K. , Xiao Zhi-Jie , Tin Vicky P. , Huang Fang Ping , Wong Maria P. 
Published: July 2017

Abstract
Lung cancer is the leading cause of cancer death worldwide. While genetic mutations that provide growth advantages to cancer cells are fundamental to malignant transformation, ability to evade the immune system is also crucial in tumorigenesis. We have previously shown that human lung cancers with high expression of nuclear factor of activated T cells, cytoplasmic 2, (NFATc2) are associated with reduced recurrence-free and overall survival. NFATc2 is expressed in most immune cells and has been extensively studied in immune cells. However, its function in cancer development is not completely understood. In this study, the role of NFATc2 in lung cancer on immune escape is explored. Lung cancer cell lines with high NFATc2 expression were co-cultured with peripheral blood mononuclear cells (PBMC) and a significant inhibition of PBMC proliferation was observed compared to PBMC only control. However, the inhibitory effect of PBMC proliferation was reversed in co-culture with NFATc2 knockdown cancer cells. When cancer cells and PBMC were separated by a membrane using Transwell inserts, the anti-proliferative effect on PBMC was not observed suggesting that cell-cell contact was required for the NFATc2-mediated inhibition. Moreover, interleukin-2 (IL-2) was produced by PBMC irrespective of the presence or absence of lung cancer cells. These results showed that the inhibition of proliferation was independent of the activation of PBMC. Taken together, we have shown NFATc2 in lung cancer plays a role in immune modulation by inhibiting PBMC proliferation and this could be a novel mechanism of immune evasion in lung cancer.
Citation Format: Ian K. Lam, Zhi-Jie Xiao, Vicky P. Tin, Fang Ping Huang, Maria P. Wong. NFATc2 in non-small cell lung cancer mediates inhibition of peripheral blood mononuclear cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2699. doi:10.1158/1538-7445.AM2017-2699
Abstract 2711: Whole exome sequencing analyses of colorectal cancers associated with liver metastasis
Authors: Ma Yanlei , Weng Wenhao , Yang Yongzhi , Wei Qing , Cai Sanjun 
Published: July 2017

Abstract
Purpose: Liver metastasis is one of the major causes of death in colorectal cancer (CRC) patients. But the process is still unknown. Here, we analyzed genetic differences between primary tumors associated with liver metastasis and those without liver metastasis and predicted clinical significance.
Experimental design: Eight primary tumors associated with liver metastasis and twelve without liver metastasis of CRC were analyzed by whole-exome sequencing. The functional characterisation for the role of metastatic-related genes was investigated through in vitro migration and invasion assays. For clinical relevance, TMAs were used for immunohistochemistry assay.
Results: The mutation spectrum was similar to that of previous studies. TP53, APC and KRAS were the three most frequently mutated genes, with no significant difference of mutation frequency between primary tumors from patients with liver metastasis and those from other patients. Notably, four recurrently mutated genes (FBXW7, EDIL3, KCNK9 and PCDHGA7) were identified exclusively in the tumors associated with liver metastasis. Furthermore, in vitro analyses showed that EDIL3 and KCNK9 overexpression resulted in enhanced cell migration and invasion, while CRISPR-mediated deletion of FBXW7 and PCDHGA7 exhibited enhanced migratory and invasive properties as well. For clinical relevance, highly expressed EDIL3 and KCNK9 was significantly associated with liver metastasis, whereas the expression of FBXW7 and PCDHGA7 negatively correlated with it in our cohorts. Pathway enrichment analysis also indicated a role for cell adhesion signaling in liver metastasis of CRC patients.
Conclusion: Our study identified candidate genes, which might response to the initiation of metastasis, exclusively mutated in tumors associated with liver metastasis. These findings also provided potential therapeutic targets for personalized treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Yanlei Ma, Wenhao Weng, Yongzhi Yang, Qing Wei, Sanjun Cai. Whole exome sequencing analyses of colorectal cancers associated with liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2711. doi:10.1158/1538-7445.AM2017-2711
Abstract 2722: Next generation targeted sequencing reveals four unknown mutations in the Mexican population with Gorlin syndrome
Authors: Veronica Fragoso , Espinosa Natalia , Dominguez Julieta , Vaca-Paniagua Felipe , Herrera Luis A. , Alvarez Rosa M. 
Published: July 2017

Abstract
Aim: Nevoid Basal Cell Carcinoma Syndrome (NBCCS), an autosomal dominant disorder, is characterized by the presence of a variety of developmental anomalies, and predisposition to multiple basal cell carcinomas (BCCs), and other neoplasias. NBCCS mainly results from germinal mutations in the PTCH1 gene, that encodes a transmembrane glycoprotein, component of the hedgehog signalling pathway. The incidence of NBCCS in general population is estimated at 1 in 150000. Data related to NBCCS in Mexican patients is reduced to clinical case reports, without molecular testing. Therefore, we conducted next-generation sequencing (NGS) of PTCH1, in 9 Mexican patients with diagnosis of NBCCS.
Material and methods: NGS of PTCH1 was performed, in the context of a hereditary cancer gene panel. The PTCH1 regions with insufficient coverage (&lt;30× read depth), were complemented by Sanger sequencing, to ensure 100% coverage of the gene. In-silico analysis was perfomed for missenses mutations. The identified pathogenic mutations were verified by capillary sequencing.
Results: Targeted analysis of PTCH1 gene, looking for deletions, insertions, splice-site alterations, nonsense and missense mutations, was done. Four PTCH1 mutations (4/9) were identified: a deletion (c.1044delG); one insertion (c.631dupA); a non-sense mutation (c.3406G&gt;T), and a missense mutation (c.1488C&gt;A). None of the mutations had been previously reported.
Conclusions : NGS of PTCH1 gene in 9 Mexican patients with clinical criteria for NBCCS allowed the identification of four novel pathogenic mutations (44% frequency). This is the first molecular overview of PTCH1 in NBCCS patients of our population. The perspectives of the current study lie in the molecular testing of other genes involved in NBCCS (PTCH2, SUFU), and other mechanisms (whole gene deletion), as well as the review of possible phenotype-genotype correlations.
Citation Format: Fragoso Veronica, Natalia Espinosa, Julieta Dominguez, Felipe Vaca-Paniagua, Luis A. Herrera, Rosa M. Alvarez. Next generation targeted sequencing reveals four unknown mutations in the Mexican population with Gorlin syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2722. doi:10.1158/1538-7445.AM2017-2722
Abstract 2741: Assessing the utility of circulating tumor DNA as a surveillance tool for sarcomas and Li-Fraumeni syndrome using a pre-clinical model
Authors: Paramathas Sangeetha , Lewis Nathan , Guha Tanya , Motala Zainab , Malkin David 
Published: July 2017

Abstract
Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome commonly characterized by the presence of inherited mutations in the tumor suppressor gene TP53. This leads to an early onset of a wide spectrum of tumors in multiple organ systems. Current surveillance protocols for early tumor detection include biochemical screening, MRI and ultrasound scans, colonoscopy and mammography (for adults). While early detection is associated with improved survival, the complexity of testing, potential to ‘misdiagnose’ tumors (false positive/negative) and requirement for multiple imaging modalities makes clinical surveillance challenging to implement and interpret. Liquid biopsies are a recently described diagnostic and prognostic tool that takes advantage of analyzing circulating tumor DNA - fragmented genomic material that are released into the blood from dying tumor cells.
In this proof-of-principle study, we use mouse xenograft tumor models to assess the dynamic relationship between tumor burden and ctDNA concentrations, as well as resolve the sensitivity of capturing the presence of lesions in their earliest stages of growth. Longitudinal analyses of ctDNA from serially collected blood were performed on mice with xenografts of rhabdomyosarcoma (Rh4 and Rh30), osteosarcoma (HOS) and non-small cell lung carcinoma (H1975) of both localized and simulated metastatic tumors. We characterized ctDNA using droplet digital PCR (ddPCR) for known gene mutations that were specific for the cancer cell lines used. We observe obvious increases in ctDNA with increased tumor burden and a complete clearance of ctDNA after tumor resection. In addition, using the metastatic model, we have conducted synchronized imaging and blood-based biopsies to determine the smallest lesion able to be detected in the blood by ctDNA.
These studies provide the foundation for early tumor detection with ctDNA in Trp53 mutant mice that develop spontaneous tumors analogous to LFS. This model will help further our understanding on the utility of ctDNA as a surveillance and diagnostic tool for LFS as well as assess its potential for clinical use.
Citation Format: Sangeetha Paramathas, Nathan Lewis, Tanya Guha, Zainab Motala, David Malkin. Assessing the utility of circulating tumor DNA as a surveillance tool for sarcomas and Li-Fraumeni syndrome using a pre-clinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2741. doi:10.1158/1538-7445.AM2017-2741