bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1669: Identification of mutant KRas-Raf-1 binding disruptors
Authors: Vangipurapu Rajanikanth , Chen Liwei , Kennedy Perry , Morrison Karen C. , Hergenrother Paul J. , Sebti Said M. 
Published: August 2018

Abstract
Mutant KRas is a major driver of human cancer, yet currently no clinically approved therapies that directly target mutant KRas are available. In order to identify novel drugs that bind either mutant KRas or its effector Raf-1, we used alpha-screen and GST-pull down assays to identify disruptors of KRas G12D binding to the Ras-binding domain of Raf-1. From a novel, natural product-inspired chemical library called Complexity To Diversity (CTD), we have identified a series of 5 hits that belong to a family of gibberellic acid-derived compounds and 2 hits from a family of pleuromutilin-derived compounds. At present we are using Differential Scanning Fluorimeter (DSF) and Isothermal calorimetry (ITC) assays to determine whether these hits bind to KRas G12D or Raf-1 RBD. These studies may lead to identifying chemical probes that can be developed to target mutant KRas-driven cancers.
Citation Format: Rajanikanth Vangipurapu, Liwei Chen, Perry Kennedy, Karen C. Morrison, Paul J. Hergenrother, Said M. Sebti. Identification of mutant KRas-Raf-1 binding disruptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1669.
Abstract 1672: Preclinical evaluation of WXFL1024H251, a potent second-generation HSP90 inhibitor
Authors: yan Xiaobing , Ding Charles Z. , Hu Lihong , Huang Wei , Chen Shuhui , Wu Dongdong , Wu Jiahu , Ma Guoqiang , Zhang Qiyao , Gao Rui , Zhu Yusong , Dong Tiantian , Zhu Yizhong , Yan Caixia , Yan Yan 
Published: August 2018

Abstract
Objective: Heat Shock Protein 90 (Hsp90) is a molecular chaperone that mediates the post-translational stability of its protein substrates, many of which are onco-proteins. Hsp90 is emerging as an important target for cancer therapy because its inactivation may abrogate multiple signaling pathways simultaneously, irrespective of the mutational status of proteins involved. We disclose here our clinical candidate WXFL1024H251, a novel second-generation small-molecule Hsp90 inhibitor with a chemical structure unrelated to the first generation, the ansamycin family of Hsp90 inhibitors.
Method: The anti-proliferative activity of WXFL1024H251 was evaluated in a variety of cancer cell lines in a 96-hour viability assay. QW, Q2W or TIW intravenous administration of at doses of 5~50 mg/kg was used to evaluate the in vivo anti-tumor activity of WXFL1024H251 in BT474 cell line-derived xenograft (CDX) breast cancer model. Effects of WXFL1024H251 on HSP90 function were assessed by western blot analysis of PD markers HSP70, Her2 and p-Her2 in the BT474 tumors.
Result: A panel of 20 cancer cell lines were screened for sensitivity to WXFL1024H251. Proliferation of 2 cancer cell lines A549 and BT474 were potently inhibited by WXFL1024H251, with IC50 of 0.007 μM and 0.009 μM, respectively. A549 cell line has KRAS mutation and medium to high EGFR expression. BT474 is an ER+ and ERBB2+ breast cancer cell line. In the BT474 tumor model, 3 week treatment with WXFL1024H251 showed good antitumor efficacy with T/C values of 36% at 7.5 mg/kg Q2W and 45% at 10 mg/kg QW; toxicity were acceptable with both dosing regiments.
Conclusion: These preclinical studies showed good antitumor efficacy of WXFL1024H251, which was associated with client protein maturation and HSP70 up-regulation in the tumor tissue. WXFL1024H251 may represent a novel promising clinical antitumor agent for treating breast cancer and other cancer types with high expression of HSP90.
Citation Format: Xiaobing yan, Charles Z. Ding, Lihong Hu, Wei Huang, Shuhui Chen, Dongdong Wu, Jiahu Wu, Guoqiang Ma, Qiyao Zhang, Rui Gao, Yusong Zhu, Tiantian Dong, Yizhong Zhu, Caixia Yan, Yan Yan. Preclinical evaluation of WXFL1024H251, a potent second-generation HSP90 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1672.
Abstract 1679: Interference of PD-1 and PD-L1 interaction with small-molecule inhibitors enhances the efficacy of tumor-specific CTLs
Authors: Redd Priscilla S. , Lu Chunwan , Ostrov David , Lebedyeva Iryna , Liu Kebin 
Published: August 2018

Abstract
Programmed cell death-1 (PD-1) is an immunosuppressive receptor expressed on T cells upon activation. Once interacting with its ligands, programmed death ligand-1 (PD-L1), the PD-1:PD-L pathway curbs T cell activation and thereby serves as a natural protection mechanism against autoimmunity. However, this pathway has been hijacked by cancer cells in order to evade the immune system. In fact, PD-L1 is commonly overexpressed on the surface of tumor cells as well as other cells in the tumor microenvironment, such as myeloid-derived suppressor cells. This interface has already been recognized as an effective target for cancer therapy. Blocking the PD-1:PD-L axis would unleash T cells from suppression to maintain their effector function against tumor cells. At least two anti-PD-1 and three anti-PD-L1 blocking antibodies have been approved for human cancer immunotherapy. However, these drugs are only successful in a small number of cancers. Therefore, developing inhibitors that block this axis more effectively and have a wider scale of impact is necessary. We used a molecular docking model and performed virtual chemical library screening to identify small molecule inhibitors of PD-1 and PD-L1 interactions. To this end, we have identified 175 PD-L1 small molecule inhibitors. Functional assays were established with the 4T1 murine breast cancer cell line and a tumor-specific murine T cell line in the presence or absence of the PD-L1 small molecule inhibitors to test if these small molecule PD-L1 inhibitors can increase T cell killing of tumor cells. Cell viability assays were also done to test the toxicity of these inhibitors on tumor cells in the absence of T cells. From these studies, we have identified ten novel PD-L1 small molecule inhibitors that can significantly increase the lytic activity of the tumor-specific cytotoxic T lymphocytes (CTLs) to kill 4T1 tumor cells. These ten PD-L1 small molecule inhibitors show little to no cytotoxicity to 4T1 tumor cells in the absence of the antigen-specific T cells, suggesting that these small molecule inhibitors themselves are not cytotoxic, and therefore are potentially safe as therapeutic agents. These proof of concept studies indicate that these small molecule inhibitors are potentially potent agents for blocking PD-1 and PD-L1 interaction in cancer immunotherapy.
Citation Format: Priscilla S. Redd, Chunwan Lu, David Ostrov, Iryna Lebedyeva, Kebin Liu. Interference of PD-1 and PD-L1 interaction with small-molecule inhibitors enhances the efficacy of tumor-specific CTLs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1679.
Abstract 1709: Enhanced proliferation and effector functions of human immune cells in response to immune checkpoint therapy of MDA-MB-231 tumor bearing huNOG mice engrafted with human CD34+ cells
Authors: Bui Thi , Shinn Karyn McArtan , O'Koren Emily G. , Derrick Ashleigh , Godfrey Beverly , Belle Ian , Davis Jason , Synnott Aidan , Avrutskaya Anya , Marval Paula L. Miliani De 
Published: August 2018

Abstract
Given the recent success of cancer immunotherapies, well characterized pre-clinical models are needed to enable drug discovery efforts. The recently developed humanized mouse models composed of various types of immune cells offer a unique tool to evaluate aspects of the human immune system in response to immunotherapy. MDA-MB231 cells express high levels of the T-inhibitory molecule PD-L1 making this breast cancer line an ideal candidate for testing the efficacy of the immune-checkpoint inhibitors pembrolizumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in the CD34+ huNOG humanized mouse strain. We analyzed the distribution of CD4 and CD8 T lymphocytes, Treg cells, NK cells and B cells in blood, spleen and tumor samples from MDA-MB231 tumor bearing huNOG humanized treated-mice via flow cytometry. We found that combination therapy enhanced the effector functions of CD4+ and CD8+ T cells associated with increased expression of IFN-gamma and Granzyme B. Supporting this data, we observed an increase in Ki-67+ cells which correlates with a decrease in PD-1 expression in response to pembrolizumab therapy associated with activation of T lymphocytes. In summary, these results demonstrate the potential of humanized mouse models to evaluate the anti-tumor activity of human immune cells in a preclinical setting in response to human specific immune checkpoint targeted therapies.
Citation Format: Thi Bui, Karyn McArtan Shinn, Emily G. O'Koren, Ashleigh Derrick, Beverly Godfrey, Ian Belle, Jason Davis, Aidan Synnott, Anya Avrutskaya, Paula L. Miliani De Marval. Enhanced proliferation and effector functions of human immune cells in response to immune checkpoint therapy of MDA-MB-231 tumor bearing huNOG mice engrafted with human CD34+ cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1709.
Abstract 1720: Analysis of multiplexed immunotherapy targets and secreted ligands using computational tumor microenvironment profiling
Authors: Caldara Jenifer , Hirsch Brooke , Krueger Joseph , Bunker Chris , Kim Jeff , Laeremans Annelies , Qutaish Mohammed , Harney Allison 
Published: August 2018

Abstract
As the number and diversity of cellular and signaling pathway therapeutic targets in immuno-oncology increases, more therapy combinations are aimed at multiple cell types in the tumor microenvironment (TME). To develop rational combinations of therapies that will be effective in any individual patient, multivariate biomarker assays will be required to understand each patient's specific tumor and immune profile. Understanding the mechanistic effects of immunotherapy includes the tissue context of direct immunotherapy targets and downstream effector molecules such as secreted cytokines. Although the content of tumor-infiltrating immune cells and gene expression of the total tumor can be ascertained through several methods, spatial arrangements and proximity of cells and co-localization of biomarkers can only be achieved with tissue-based assays. Duplex chromogenic in situ hybridization assays using the RNAscope platform allows for the visualization of gene expression of mRNA targets directly in tissue for multiple cell types or biomarkers. Computational Tissue Analysis (cTA™) was used to quantify cellular spatial distributions including regional density maps, proximity measurements, and colocalization of biomarkers in both the tumor nests and the surrounding stroma that would be challenging by visual inspection of duplex RNAscope assays in non-small cell lung cancer (NSCLC) tissue microarrays (TMAs). Often, neither immune effector cells nor the therapeutic target is sufficient in isolation to understand blocked anti-tumor immune responses and therefore the potential efficacy of a single or combination therapeutic strategy. Multiplex RNAscope assays and cTA™ in combination allow the assessment of end points that measure spatial relationships between cell types expressing certain biomarkers. As these are performed in the context of the tissue microarchitecture within and across multiple tissue sections, they are a significant advancement over traditional tissue-based manual end points.
Citation Format: Jenifer Caldara, Brooke Hirsch, Joseph Krueger, Chris Bunker, Jeff Kim, Annelies Laeremans, Mohammed Qutaish, Allison Harney. Analysis of multiplexed immunotherapy targets and secreted ligands using computational tumor microenvironment profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1720.
Abstract 173: Adipocytes-derived collagen reorganization in microenvironment promotes breast cancer progression
Authors: Xiaohui Wei , Jinyong He , Sijing Li , Shengtao Yuan , Li Sun 
Published: August 2018

Abstract
Purposes
Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to reorganize collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, whether cancer-associated adipocytes (CAAs) involve in the collagen reorganization and ultimately promoting metastasis of breast cancer is still unknown. In this study, we seek to understand whether adipocytes involve in the extracellular matrix collagen reorganization in breast cancer and its underline mechanism.
Methodology
In vitro mature adipocytes and breast cancer transwell co-culture model and orthotopic xenograft mouse model of human breast tumor formation in vivo were used to study the crosstalk between adipocytes and breast cancer cells, and then using a combination of proteomics, database analysis and clinical breast cancer samples analysis to study the mechanism mediated adipocytes-derived collagen reorganization.
Results
Here, we found that CAAs co-cultured with breast cancer cells increased the linearly aligned type I collagen fibers deposition in vitro and in vivo, which accompanied with increasing collagen lysyl hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression. Breast cancer cells migrated orderly along the CAAs-derived collagen, while randomly migrated through the mature adipocyte-derived collagen. Simultaneously, clinical breast cancer samples analysis showed LH2 was high expression in the areas where cancer cells infiltrated into fatty tissue, which accompanied with poor prognosis. It is well-known that interaction between adipocytes and cancer altered the secretion of cytokines. In the present study, proteomics analysis showed that IL-6, MIF-1, TECK, MCP-1, PAI-1, IGFBP-1, TIMP1 and TIMP2 are highly secreted in adipocytes-breast cancer system. And using agonist or antagonist of these cytokines showed that these cytokines might involve in the reorganization of adipocyte-derived collagen. Mechanistic investigations demonstrated PI3K/AKT pathway and JAK/STAT3 signaling pathway involved in the rearrangement of adipocyte-derived collagen, which mediated by promoting forkhead-box(FOX) and phosphorylation STAT3(p-STAT3) translocate to the nucleus, respectively. Moreover, FOX and STAT3-dependent induction of LH2 expression further potentiated the adipocytes-derived collagen reorganization, which thus promoting breast cancer metastasis.
Conclusion
Collectively, our findings reveal new insights underlying increased breast cancer progression and offer new opportunities for stromal-targeted therapies in breast cancer.
Citation Format: Wei Xiaohui, He Jinyong, Li Sijing, Yuan Shengtao, Sun Li. Adipocytes-derived collagen reorganization in microenvironment promotes breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 173.
Abstract 1739: Tumor extracellular vesicles are required for tumor-associated macrophage programming
Authors: Rabe Daniel C. , Lee Jiyoung , Rustandy Felicia , Rosner Marsha R. 
Published: August 2018

Abstract
Triple-negative breast cancers (TNBC) are highly infiltrated by tumor-associated macrophages (TAMs) that promote tumor growth, survival, metastasis and therapeutic resistance. Although cytokines such as CCL5 have been implicated in TAM recruitment to TNBC tumors, the mechanism by which tumor cells educate TAMs is not understood. Here we show that tumor extracellular vesicles (EVs) are both necessary and sufficient for programming TAMs toward a pro-metastatic phenotype. The mechanism involves CCL5 regulation of tumor EVs, which activate TLR2 and TLR3, leading to secretion of a common set of cytokines that further stimulate tumor cell invasion and metastasis as well as alter the tumor microenvironment. Cytokine expression is significantly correlated to CCL5 expression and up-regulated in TNBC patient tumors. These results demonstrate for the first time that tumor EVs are key mediators of TAM education, phenocopy the pro-metastatic and drug resistant state of the tumors to TAMs, and illustrate the potential clinical relevance of these findings to TNBC patients.
Citation Format: Daniel C. Rabe, Jiyoung Lee, Felicia Rustandy, Marsha R. Rosner. Tumor extracellular vesicles are required for tumor-associated macrophage programming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1739.
Abstract 1755: PEGylated adenosine deaminase (ADA2) prevents adenosine-mediated increase in tumor growth and improves antitumor immune responses
Authors: Londoño-R Luz Marina , Cowell Jessica , Wang Lin , Zhao Qiping , Huang Lei , Thanos Chris , LaBarre Michael J. , Li Xiaoming , Cekic Caglar 
Published: August 2018

Abstract
Adenosine deaminase 2 (ADA2) is a human serum protein that catalyzes the reaction of deamination of adenosine to inosine. Besides catalytic activity, ADA2 has a heparin-binding domain and a growth factor-like domain. Adenosine accumulates in the tumor microenvironment and suppresses anti-tumor immune responses, while promoting tumor cell metastasis. Previously, we showed that treatment of mice with PEGylated forms of ADA2 (PEG ADA2) can decrease the accumulation of tumor-associated adenosine. Here, we analyzed the TCGA RNA-seq database using OncoLnc tool and observed that high expression of the ADA2 gene (CECR1) in certain immunotherapy responsive tumors correlated with increased survival of patients. We then tested different engineered ADA2 variants, using the inactive enzyme variant as a control, for the reversal of adenosine-mediated responses in human T cells, mouse peritoneal macrophages, and mouse and human tumor cell lines. ADA2 variants with higher catalytic activity were able to reverse adenosine-mediated suppression of human T-cell proliferation, cAMP accumulation in tumors and human T cells, and polarization of macrophages into an immunosuppressive, pro-tumor phenotype, whereas the inactive ADA2 variant failed to cause any of these effects. In addition, the variant that lacks the ability to bind to heparin but has improved catalytic activity (PEG NME8058) showed similar responses to those with the catalytically improved variant with intact heparin-binding domain (PEG NME8062). These results suggest that the improved immune cell activity with ADA2 in the presence of adenosine requires the enzyme activity of this molecule. Next, we assessed PEG NME8062 in MC38 and CT26 colon carcinoma syngeneic tumors in C57BL/6 and Balb/c mice, and observed delayed growth in both tumors. Using the inactive enzyme variant, we have shown that anti-tumor effect of PEG NME8062 depends on enzyme activity. Delayed tumor growth was also associated with increased density of key anti-tumor immune cell populations in both tumor models. These data suggest that PEG ADA2 can reduce tumor growth in an enzyme-activity-dependent manner and promote anti-tumor immune responses in vitro and in vivo. These findings have important implications for targeting purinergic signaling for cancer therapy.
Citation Format: Luz Marina Londoño-R, Jessica Cowell, Lin Wang, Qiping Zhao, Lei Huang, Chris Thanos, Michael J. LaBarre, Xiaoming Li, Caglar Cekic. PEGylated adenosine deaminase (ADA2) prevents adenosine-mediated increase in tumor growth and improves antitumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1755.
Abstract 1764: Neurovascular-targeting antibodies discovered using yeast biopanning enhance drug delivery and improve survival for glioblastoma
Authors: Clark Paul A. , Umlauf Benjamin J. , Shusta Eric V. , Kuo John S. 
Published: August 2018

Abstract
INTRODUCTION: Median survival for newly diagnosed glioblastoma (GBM) patients remains less than two years despite aggressive clinical interventions. Antibody-based GBM-targeting could improve brain delivery and accumulation of therapies, but it has been challenging to identify universal tumor cell antigens due to intra-tumor and inter-patient GBM heterogeneity. We hypothesized that antigens of the neurovascular extracellular matrix (nvECM) within GBM-disrupted blood-brain barrier (BBB) may localize and enhance efficacy of therapeutic agents.
METHODS: Yeast surface display biopanning and high throughput screening identified Variable Lymphocyte Receptors (VLR, i.e. jawless vertebrate lamprey antibodies) that preferentially accumulate at nvECM. Lead VLR candidates were tested for tumor targeting via combination with chemotherapeutic doxorubicin (DOX) liposomes and assessed for anti-GBM effects in vitro and against orthotopic mouse xenografts in vivo.
RESULTS: VLR clones were enriched for binding to mouse brain endothelial cell (bEnd.3 line) ECM with two rounds of biopanning, then screened for preferential binding to brain-derived ECM. Lead VLR clone P1C10 was chosen for further testing for nvECM specificity vs. fibroblast (3T3 line) ECM in a high throughput screen, high affinity (Kd=48±6.1 nM), and immunolabeling of normal mouse and human brain, and GBM samples. Clone P1C10 demonstrated tumor-specific targeting in orthotopic U87 GBM xenografts, with 50% more DOX fluorescence detected at GBM after intravenous injection of P1C10-DOX liposomes compared to control, non-specific VLR-DOX. Finally, administration of P1C10-DOX liposomes (15 mg/kg, i.p., 1/week) significantly improved survival of mice bearing U87 xenografts, compared to non-targeted VLR-DOX (Kaplan-Meier, p&lt;0.01).
CONCLUSIONS: We report combining yeast surface display biopanning and screening to identify VLRs that preferentially accumulate at disrupted nvECM of GBM-disrupted BBB, and demonstrate GBM-targeting specificity in vitro and in vivo with significant survival benefit. These results support the nvECM immune-targeting strategy to improve anti-GBM therapeutic efficacy, potentially improving survival and quality-of-life in brain cancer patients.
Citation Format: Paul A. Clark, Benjamin J. Umlauf, Eric V. Shusta, John S. Kuo. Neurovascular-targeting antibodies discovered using yeast biopanning enhance drug delivery and improve survival for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1764.