bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2733: Developing novel anti-OX40 antibodies on Biocytogen's in vivo drug screening platform
Authors: Guo Chaoshe , Guo Yanan , Shen Yuelei , Yang Benny 
Published: August 2018

Abstract
OX40, also known as CD134 or TNFRSF4, is a member of the TNFR superfamily of receptors. OX40 is a co-stimulatory receptor, and it interacts with its ligand to providepositive signal for T cell activation. OX40 is not expressed on resting naïve T cells, however its expression goes up after 24 to 72 hours following activation. Disruption of OX40 pathway led to defective T cell responses and overexpression of OX40 caused massive immune activation. Due to its importance in keeping immune homeostasis, strategies modulating the OX40 pathway hold great promise in fighting against cancer and autoimmune diseases. We have interests in developing novel OX40 antibodies for boosting cancer patients' own immunityinlight of other successful immune checkpoint modulators. We developed a cohort of OX40 specific antibodies using the classic hybridoma technology. In order to screen their efficacy to stimulate anti-tumor activity in live animals, we managed to rank these antibodies using Biocytogen'shumanized mouse platform of immune checkpoints. Specifically, we utilized humanized OX40 mice (h-OX40) and implanted syngeneic tumors subcutaneously, followed by treating mice with purified testing antibodies. Via this approach, we are able to discern several lead antibodies that effectively inhibited tumor growth without prior knowledge of their in vitro activities. Furthermore, we identified that one clone works in concert with Keytruda in the dual humanized model of h-OX40 and h-PD1. We are currently investigating the mechanisms of action underlying these potentially useful antibodies.
Citation Format: Chaoshe Guo, Yanan Guo, Yuelei Shen, Benny Yang. Developing novel anti-OX40 antibodies on Biocytogen's in vivo drug screening platform [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 2733.
Abstract 2745: EpCAM targeted immunotoxin prolongs survival of metastatic colorectal cancer patients by a previously unknown immunostimulatory mechanism
Authors: Fodstad Øystein , Dueland Svein , Flatmark Kjersti , Inderberg Else Marit , Kvalheim Gunnar , Andersson Yvonne 
Published: August 2018

Abstract
A first-in-man study of the anti-EpCAM immunotoxin MOC31PE with and without parallel immunosuppression with Cyclosporin A (CsA) was performed in metastatic colorectal cancer (CRC) patients. The safety and maximum tolerable doses in patients with EpCAM-positive tumors were determined, and only mild and reversible dose-limiting liver toxicity was seen, with no subjective side effects to the patients. Although no complete or partial responses were observed on CT scans at eight weeks, upon evaluation of the overall survival (OS) of the patients we surprisingly found that CRC patients treated with immunotoxin alone (n=15) had a median OS of 16.3 months (95% CI=5.6-27.0) compared to 6.0 months (CI=5.8-6.2) (p&lt;0.001) for the combination group (n=18) (hazard ratio (HR): 0.248, 95% credible interval (CrI): 0.109-0.564). The 6.0 months OS for the patients treated with CsA in addition to the immunotoxin is comparable to OS of patients with progressive disease on last line of standard chemotherapy. The Th1 cytokine profile in sera from patients treated with MOC31PE alone indicated that the immuntoxin induces an immunogenic cell death resulting in T-cell activation, and that this effect disappeared in the patients who had received simultaneous treatment with CsA. Further, we demonstrate in in vitro experiments that the immunogenic cell death factors ATP and HMGB1 were secreted from CRC cell lines treated with MOC31PE alone. Finally, conditioned media from MOC31PE treated CRC cells induced maturation of dendritic cells and promoted activation of killer (CD8+) and helper (CD4+) T cells, showing that MOC31PE treatment induces release of immune stimulating factors. The present results demonstrate the novel and exciting finding that MOC31PE induces an immunogenic effect resulting in prolonged overall survival of patients with metastatic CRC, an effect obliterated by the parallel immunosuppression of CsA.
Citation Format: Øystein Fodstad, Svein Dueland, Kjersti Flatmark, Else Marit Inderberg, Gunnar Kvalheim, Yvonne Andersson. EpCAM targeted immunotoxin prolongs survival of metastatic colorectal cancer patients by a previously unknown immunostimulatory mechanism [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 2745.
Abstract 2752: EGFR tyrosine kinase inhibitor limits tumor relapse through enhancing anti-tumor T cell responses
Authors: Liu Zhida , Han Chuanhui , Shen Aijun , Dong Chunbo , Qiao Jian , Fu Yang-Xin 
Published: August 2018

Abstract
EGFR tyrosine kinase inhibitors (TKIs) have been clinically considered as the first line therapy for EGFR-driven tumor patients. Although the initial outcome of patients has significantly improved, almost all patients eventually relapse. Fully understanding the mechanisms of the anti-tumor effect of EGFR TKIs will help promote the clinical development of more efficient therapeutic strategies. The traditional view of the main mechanism is that the inhibitors can directly inhibit EGFR downstream signaling pathways to induce tumor cell death. Whether and how EGFR TKIs affect the host immune system is largely unknown. In current study, we have established syngeneic murine tumor models that are sensitive to EGFR TKIs treatment. To our surprise, we revealed that EGFR TKI treatment could control tumor growth and limit tumor relapse in T cells dependent manner. Mechanistically, EGFR TKI triggers type I IFN and its stimulation gene CXCL10 production through the Myd88 signaling pathway to enhance tumor specific T cells infiltration and activation. However, EGFR TKI cannot efficiently limit tumor relapse in advanced tumor models because of PD-L1 upregulation in the tumor microenvironment after treatment. We have observed that anti-PDL1 blockade can synergize with EGFR TKI to control advanced tumors. Our study will challenge the current regimen of EGFR TKI in clinic and provide new efficient therapeutic strategies for EGFR dependent cancer patients.
Citation Format: Zhida Liu, Chuanhui Han, Aijun Shen, Chunbo Dong, Jian Qiao, Yang-Xin Fu. EGFR tyrosine kinase inhibitor limits tumor relapse through enhancing anti-tumor T cell 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 2752.
Abstract 2799: New-generation glucose transporter inhibitors targeting non-small cell lung cancer and triple-negative breast cancer
Authors: Shriwas Pratik , Qian Yanrong , Wang Xuan , Roberts Dennis , Bergmeier Stephen , Chen Xiaozhuo 
Published: August 2018

Abstract
Cancer is a top killer second only to cardiovascular diseases. Cellular metabolic reprogramming and altered energetics are key features of cancer. Opportunistic uptake of extracellular nutrients has recently been named as an emerging hallmark of cancer metabolism. Glucose is a key nutrient taken in by cancer cells to meet their high energy and biosynthesis needs. Drastic upregulation of glucose uptake and glycolytic activity, a phenomenon called the Warburg effect, is prevalent in most cancers, including non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). Cancer cells overexpress specific glucose transporters (GLUTs), particularly GLUT1, on their membranes to transport glucose via facilitated diffusion. Considering the addiction of cancer cells for glucose and their sensitivity and vulnerability to changes in glucose supply, GLUTs, especially GLUT1, have been recognized as an attractive anticancer target. We previously reported the identification of first-generation lead GLUT1 inhibitor WZB117. WZB117 treatment of human NSCLC A549 cells resulted in inhibition of glucose uptake, glycolysis and induction of apoptosis and necrosis (1). In addition, WZB-117 reduced tumor growth by more than 70% in an A549 tumor mouse model (1). Through a structure activity relationship (SAR) study of WZB117, a second-generation lead, DRB18, has been identified. DRB-18 is much more stable and 5 to 10 times more potent than WZB117 in inhibiting growth and proliferation in more than 90% of the 60 different cancer cell lines in 9 major cancer types as revealed by NCI-60 screenings. The compound shows particularly higher potency against cell lines with more metastatic potential such as HOP92 (NSCLC) and MDA-MB-231 (TNBC) with IC50 values in high nM range. DRB-18 also demonstrates a favorable liver microsomal metabolic profile and a maximal tolerance dose (MTD). All these indicate that DRB-18 is a potential therapeutic candidate for treating NSCLC and TNBC.
Reference: 1. Liu Y, Cao Y, Zhang W, et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther 2012;11(8):1672-82.
Citation Format: Pratik Shriwas, Yanrong Qian, Xuan Wang, Dennis Roberts, Stephen Bergmeier, Xiaozhuo Chen. New-generation glucose transporter inhibitors targeting non-small cell lung cancer and triple-negative breast cancer [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 2799.
Abstract 281: Identifying genetic variation and cellular heterogeneity with a comprehensive cancer analysis toolkit
Authors: Garcia Sarah , Bharadwaj Rajiv , Boutet Stéphane , Catalanotti Claudia , Giangerra Valeria , Lee Josephine , Terry Jessica , Williams Stephen , Zheng Grace X. , Mikkelsen Tarjei , Schnall-Levin Michael , Hindson Ben , Church Deanna M. 
Published: August 2018

Abstract
Understanding disease development, progression and response to treatment remains elusive for most types of cancer. This is due both to the genetic complexity seen in tumors as well as differences in how the surrounding cells and immune system respond to the developing tumor. To fully understand all aspects of disease progression and response to treatment, a systems level approach is needed. We have developed a platform that allows for high resolution multi-omics analysis of the tumor and its microenvironment. This platform is built upon a microfluidic system that enables the production of hundreds of thousands to millions of partitioned barcoded reactions. On this platform we generate Linked-Reads that allow for the detailed resolution of complex structural variant events. To obtain more detailed information about tumor heterogeneity and clonal structure, we also perform single cell DNA analysis that allows for the detection of sub-megabase copy number variants at the single cell level.The platform also provides detailed resolution of the cells occupying the microenvironment surrounding the tumor. Using a combination of single cell gene expression and enriched V(D)J B and T cell repertoire analysis, we identify cells constituting a tumor, as well as the immune and nonimmune cells surrounding the tumor. We also provide single cell profiling of the paired antigen receptor chains for both B and T cells. As a demonstration, we have performed this analysis on three types of tumor samples: metastatic melanoma (MM), primary colorectal cancer (CRC) and primary clear cell renal carcinoma (CCRC). We are able to identify a clonal expansion in the CCRC sample and determine there is no expansion in the CRC sample. The combination of these approaches allows for unparalleled characterization of disease development, progression and response.
Citation Format: Sarah Garcia, Rajiv Bharadwaj, Stéphane Boutet, Claudia Catalanotti, Valeria Giangerra, Josephine Lee, Jessica Terry, Stephen Williams, Grace X. Zheng, Tarjei Mikkelsen, Michael Schnall-Levin, Ben Hindson, Deanna M. Church. Identifying genetic variation and cellular heterogeneity with a comprehensive cancer analysis toolkit [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 281.
Abstract 2836: Spatially resolved single-cell analysis of cellular plasticity and mechanisms of drug resistance
Authors: Pitchiaya Sethuramasundaram , D'silva Jeremy , Lee Nicole , Narayanan Sathiyapandi , Jiang Xia , Dhanasekaran Saravana M. , Chinnaiyan Arul M. 
Published: August 2018

Abstract
Cellular heterogeneity adversely affects clinical stratification, treatment decisions, and development of therapeutic resistance in cancer. Heterogeneity manifests as variability in gene expression and scales with the number of unique cell types and/or the extent of phenotypic plasticity. Therefore, an incisive tool that effectively quantifies heterogeneity, robustly identifies rare cell populations, efficiently predicts cell state transitions, and preserves the associated phenotypic manifestations will provide key insights into the mechanisms of plasticity and development of drug resistance. To this end, we developed High-Throughput Single-cell analysis using single-molecule Fluorescence In Situ Hybridization (HITS-FISH) - a completely automated imaging-based tool that provides absolute quantification of gene expression (mature and immature transcripts that are coding or non-coding), while still preserving spatial and morphological information. Using a combination of HITS-FISH and single cell RNAseq, which provides a high-throughput readout of gene expression signatures, we find that multiple, potentially plastic cell states (genetic, epigenetic, and cell cycle) coexist within a seemingly homogeneous population of cancer cells from various tissues. HITS-FISH suggests that one of the major contributors of such heterogeneity is pervasive aneuploidy, which is accentuated during treatment of cancer cells with chemotherapeutic agents and subsequent development of resistance against such drugs. Currently, we are further characterizing these plastic cells via lineage tracing and single-cell analysis to identify pre-resistant cell states and drug-induced gene-expression reprogramming.
Citation Format: Sethuramasundaram Pitchiaya, Jeremy D'silva, Nicole Lee, Sathiyapandi Narayanan, Xia Jiang, Saravana M. Dhanasekaran, Arul M. Chinnaiyan. Spatially resolved single-cell analysis of cellular plasticity and mechanisms of drug resistance [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 2836.
Abstract 2839: Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC
Authors: Arasada Rajeswara Rao , Shilo Konstantin , Zhang Jianying , Ghanem Rashelle , Yamada Tadaaki , Yano Seiji , Carbone David 
Published: August 2018

Abstract
EGFR tyrosine kinase inhibitors (EGFR-TKIs) usually cause dramatic responses in EGFR-mutant lung cancer, but different patients with identical drivers have widely different progression-free intervals, and resistance universally develops. In those cases without pre-existing resistant clones, even though every cell expresses the driver, some tumor clonogens survive in order to acquire target reactivation or bypass resistance mechanisms. The involvement of β-catenin in EGFR TKI resistance has been previously reported however the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Our transcriptome analysis identified that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We have previously reported that EGFR-TKI treatment rapidly activates Notch3, and here our co-immunoprecipitation studies identified a physical association of Notch3 with β-catenin, which in turn leads to increased stability and activation of β-catenin. In vitro pulmosphere formation assays and in vivo limiting dilution assays reveled that adaptive persisters display characteristics of stem-like cells. Furthermore, tumor xenograft studies using HCC827 and HCC4006 demonstrate that the combination of EGFR-TKI and the β-catenin inhibitor, ICG-001 inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival. Overall, Notch3 plays a pivotal role in the maintenance of lung cancer stem cells (CSCs) and the induction of EGFR TKI mediated drug persisters with cancer stem cell like characteristics, but is difficult to selectively target. Our study finds that this effect is driven by the Notch3-dependent activation of β-catenin signaling in a non-canonical fashion. A combination of EGFR TKI and β-catenin inhibitors decreases tumor take, delays tumor recurrence and increases overall survival in EGFR mutant models. Thus, our findings provide novel insights on role of drug persistence early after EGFR TKI therapy and presents a rationale for clinical testing of EGFR TKIs with β-catenin inhibitors for the treatment of EGFR mutant NSCLC.
Citation Format: Rajeswara Rao Arasada, Konstantin Shilo, Jianying Zhang, Rashelle Ghanem, Tadaaki Yamada, Seiji Yano, David Carbone. Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC [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 2839.
Abstract 2842: The biological effects and therapeutic potential of directly targeting K-Ras
Authors: Wolfe Andrew L. 
Published: August 2018

Abstract
K-Ras is a small GTPase that is among the most frequently mutated oncoproteins in cancer, with alterations common in lung adenocarcinoma, colorectal cancer, and up to 90% of pancreatic cancers. Tumors with mutant K-Ras often become addicted to its presence and in inducible genetic mouse models the sudden removal of mutant K-Ras can trigger cancer regressions. However, these cancers remain among the most refractory to therapy and pharmacological agents capable of inhibiting many common K-Ras mutants have remained elusive. Here, we set out to evaluate the efficacy of recently developed inhibitors that directly target K-Ras in cancer and understand potential mechanisms of resistance to K-Ras based therapies. Treatment of K-Ras mutant cells with K-Ras inhibitors led to mutant-specific halting of cell growth. Upon extended treatment a subpopulation of drug-resistant cells emerged that displayed adaptation patterns leading to reversible drug resistance. To identify cooperating factors that modulate sensitivity to K-Ras inhibition, screens were performed in wild-type and isogenic K-Ras mutant cells using a genome-wide CRISPRi library and a pharmacological compound library in the presence or absence of K-Ras inhibitors. These strategies identified synthetically lethal pathways and favorable combination therapies, moving toward the goals of identifying the optimal patient populations that can most benefit from K-Ras inhibitors and enabling a personalized medicine approach to cancer therapy.
Citation Format: Andrew L. Wolfe. The biological effects and therapeutic potential of directly targeting K-Ras [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 2842.
Abstract 2861: PUMA induction by p73 mediates response and resistance of colorectal cancer to anti-EGFR antibody therapy
Authors: Knickelbein Kyle , Tong Jingshan , Chen Dongshi , Wang Yi-Jun , Misale Sandra , Bardelli Alberto , Yu Jian , Zhang Lin 
Published: August 2018

Abstract
Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC), the second-leading cause of cancer-related death in the United States. However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we found that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. Inhibition of EGFR and downstream AKT by cetuximab and panitumumab promotes Tyr99 phosphorylation of p73, which then binds to PUMA promoter to activate its transcription, resulting in cell death via the mitochondrial pathway. PUMA induction and p73 phosphorylation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations and residual AKT activity. Upon screening a panel of anticancer drugs, we found that inhibition of aurora kinases preferentially kills mutant KRAS CRC cells. A combination with aurora kinase inhibitor overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction and eliminating the residual AKT activity. Collectively, our results suggest that p73-dependent PUMA induction plays a critical role in mediating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA induction and apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.
Citation Format: Kyle Knickelbein, Jingshan Tong, Dongshi Chen, Yi-Jun Wang, Sandra Misale, Alberto Bardelli, Jian Yu, Lin Zhang. PUMA induction by p73 mediates response and resistance of colorectal cancer to anti-EGFR antibody therapy [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 2861.