bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5568: Towards decoding the interplay between glycolysis and oxidative phosphorylation in cancer
Authors: Jia Dongya , Yu Linglin , Lu Mingyang , Ben-Jacob Eshel , Ma Jianpeng , Levine Herbert , Kaipparettu Benny A. , Onuchic Jose 
Published: July 2017

Abstract
Abnormal metabolism is a hallmark of cancer, yet its regulatory mechanism is poorly understood. Cancer cells were considered to mostly utilize glycolysis, referred to as the Warburg effect. However recent evidence suggests that oxidative phosphorylation also plays a crucial role during cancer progression. Here we utilized a systems biology approach to decipher the regulatory principle of glycolysis and oxidative phosphorylation. Integrating information from literature, we constructed a regulatory network of genes and metabolites, from which we extracted a core circuit containing HIF-1, AMPK and ROS. Our circuit analysis showed that while normal cells have an oxidative state and a glycolytic state, cancer cells can access an additional hybrid state with both metabolic modes coexisting, due to higher ROS production and/or oncogenic activation, such as RAS, MYC and c-SRC. The anti-correlation between AMPK and HIF-1 and the association of metabolic states with oncogenes were further confirmed using TCGA patient transcriptomics data of multiple cancer types and single-cell RNA-seq data of lung adenocarcinoma. We propose that the hybrid phenotype contributes to metabolic plasticity, allowing cancer cells to adapt to various microenvironments. Using model simulations, we predicted the efficacies of several metabolic cancer therapies based on their effectiveness in reducing metabolic plasticity. Our theoretical framework of metabolism can serve as a platform to decode cancer metabolic plasticity and design cancer therapies targeting metabolism.
Citation Format: Dongya Jia, Linglin Yu, Mingyang Lu, Eshel Ben-Jacob, Jianpeng Ma, Herbert Levine, Benny A. Kaipparettu, Jose Onuchic. Towards decoding the interplay between glycolysis and oxidative phosphorylation in cancer [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 5568. doi:10.1158/1538-7445.AM2017-5568
Abstract 5586: PPMX-T003, a fully human anti-TfR1 antibody with potent efficacy against hematologic malignancies
Authors: Zhang Lilin , Nomura Fumiko , Aikawa Yoichi , Kurosawa Yoshikazu , Morishita Kazuhiro , Sudo Yukio 
Published: July 2017

Abstract
Transferrin receptor1 (TfR1) is a type II transmembrane glycoprotein that involves intracellular uptake of iron. TfR1 is ubiquitously expressed at low levels in normal cells except erythroblasts and placental trophoblasts, which express high levels of TfR1 due to the need of up taking a large amount of iron. Accumulating studies have shown elevated levels of TfR1 in both solid tumor cells, as well as hematologic malignant cells when compared to their normal counterparts. Since TfR1 is implicated in growth and survival in various cancer cells, targeting TfR1 could be attractive strategy for cancer therapeutics. To this end, we have developed a fully human antibody against TfR1, PPMX-T003, which displayed potent anti-tumor activity in vitro and in vivo. PPMX-T003 induced apoptosis or cell cycle arrest with EC50s of 3~200ng/ml in various tumor cell lines. Mechanistically, PPMX-T003 triggers apoptosis or cell growth arrest by inhibiting binding of TfR1 to its ligand transferrin and blocking iron uptake. In addition, PPMX-T003 elicits antibody dependent cellular cytotoxicity (ADCC) activity in cancer cells. Importantly, PPMX-T003 showed potent efficacy against several blood cancer xenograft models. PPMX-T003 completely eradicated established subcutaneous tumors in two acute myeloid leukemia (AML) models generated by Kasumi-1 and HL-60, at a dose of 10 mg/kg when administrated (I.V.) once a week for 4 weeks. Moreover, PPMX-T003 completely eradicated established tumors in a lymphoma xenograft model (SU-DHL-2) at a dose of 3 mg/kg. Furthermore, PPMX-T003 greatly prolonged mice survival in a disseminated leukemia model (CCRF-CEM: acute lymphoblastic leukemia cell line). The control mice engrafted with CCRF-CEM cells (n=10) developed leukemia and died within 42 days, whereas 8 of the 10 mice treated with PPMX-T003 survived 179 days until the experiment was terminated. A preliminary toxicology study in Cynomolgus monkeys with multiple doses was also carried out. Although moderate anemia was observed at the dose of 30 mg/kg, no other abnormalities were observed, indicating a tolerable safety profile. Taken together, these results indicate that PPMX-T003 could be a potent therapeutic antibody for the treatment of hematologic malignancies.
Citation Format: Lilin Zhang, Fumiko Nomura, Yoichi Aikawa, Yoshikazu Kurosawa, Kazuhiro Morishita, Yukio Sudo. PPMX-T003, a fully human anti-TfR1 antibody with potent efficacy against hematologic malignancies [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 5586. doi:10.1158/1538-7445.AM2017-5586
Abstract 5604: Novel biomarkers Ly6E/K play important role in drug resistance and tumor immune escape
Authors: Hossiny Midar A. , Frazier William R. , Steiner Noriko , Kallakury Bhaskar , Kumar Rakesh , Upadhyay Geeta 
Published: July 2017

Abstract
Stem cell antigen Sca-1 is implicated in murine cancer stem cell biology and breast cancer models, but the role of its human homologs Ly6K and Ly6E in breast cancer are not established. Here we report increased expression of Ly6K/E in human breast cancer specimens correlates with poor overall survival, with an additional specific role for Ly6E in poor therapeutic outcomes. Increased expression of Ly6K/E also correlated with increased expression of the immune checkpoint molecules PDL1 and CTLA4, increased tumor-infiltrating T regulatory cells, and decreased natural killer (NK) cell activation. Mechanistically, Ly6K/E was required for TGFβ signaling and proliferation in breast cancer cells, where they contributed to phosphorylation of Smad1/5 and Smad2/3. Furthermore, Ly6K/E promoted cytokine-induced PDL1 expression and activation and binding of NK cells to cancer cells. Finally, we found that Ly6K/E promoted drug resistance and facilitated immune escape in this setting. Overall, our results establish a pivotal role for a Ly6K/E signaling axis involving TGFβ in breast cancer pathophysiology and drug response, and highlight this signaling axis as a compelling realm for therapeutic invention.
Citation Format: Midar A. Hossiny, William R. Frazier, Noriko Steiner, Bhaskar Kallakury, Rakesh Kumar, Geeta Upadhyay. Novel biomarkers Ly6E/K play important role in drug resistance and tumor immune escape [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 5604. doi:10.1158/1538-7445.AM2017-5604
Abstract 5610: Quantitative cell-based bioassays to advance individual or combination immune checkpoint immunotherapy
Authors: Grailer Jamison , Stecha Pete , Garvin Denise , Hartnett Jim , Fan Frank , Cong Mei , Cheng Zhi-jie Jey 
Published: July 2017

Abstract
Immune checkpoint receptors play a critical role in maintaining immune homeostasis and are genetically and functionally associated with autoimmune disease, cancer and persistent viral infections. Blockade of immune checkpoints (e.g., PD-1 and CTLA-4) has emerged as a promising new approach to enhance anti-tumor immune responses. While immunotherapies directed against PD-1 and CTLA-4 are showing unprecedented efficacy in the treatment of cancer, many patients and tumor types remain refractory to these therapies. This has resulted in a broadening of immunotherapy research and development to include additional immune checkpoint receptors (e.g., LAG-3, TIGIT, CD112R) targeted individually or in combination with other immunotherapy strategies.
A major challenge in the development of biologics that target immune checkpoints is access to quantitative and reproducible functional bioassays. Existing methods rely on primary cells and measurement of complex functional endpoints. These assays are cumbersome, highly variable, and fail to yield the quality of data that is required for drug development in a quality-controlled environment. To address this need, we have developed a suite of immune cell line-based bioluminescent reporter bioassays for individual and combination immune checkpoint immunotherapy targets including PD-1 (PD-L1 or PD-L2), CTLA-4, LAG-3, TIGIT, PD-1+TIGIT and more. These assays consist of stable cell lines that express luciferase reporters driven by specific response elements under the precise control of intracellular signals mediated by the T cell receptor and immune checkpoint target(s). These mechanism of action-based bioassays are available in “thaw-and-use” format and demonstrate high specificity, sensitivity and reproducibility. The bioassays are pre-qualified according to ICH guidelines and demonstrate the performance required for use in antibody screening, potency testing and stability studies.
Citation Format: Jamison Grailer, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative cell-based bioassays to advance individual or combination immune checkpoint immunotherapy [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 5610. doi:10.1158/1538-7445.AM2017-5610
Abstract 5615: Genomic differential expression analysis of fusion proteins incorporating the pro-apoptotic molecule Granzyme B reveals new potential targets for treatment of breast cancer
Authors: Mohamedali Khalid A. , Cheung Lawrence H. , Alvarez-Cienfuegos Ana , Rosenblum Michael G. 
Published: July 2017

Abstract
Granzyme B (GrB) is a member of the serine protease family of enzymes that play a critical role in the body’s defense against viral infection and tumor development. Cytotoxic T lymphocyctes (CTL) and natural killer (NK) cells directly deliver granzymes to target cells, which induces apoptosis through both caspase-dependent and caspase-independent multiple-cascade mechanisms. Anti-tumor efficacy studies have suggested that the targeted delivery of human Granzyme B to tumor cells has a significant potential for cancer treatment. We had previously developed a novel fusion construct composed of the VEGF121 growth factor and human GrB. The GrB/VEGF121 construct was found to be highly cytotoxic to vascular endothelial cells expressing the R2 (KDR) receptor for VEGF. In this study, we examined the mechanism of GrB/VEGF121-induced cytotoxicity against cells in culture at the genomic level. The TNBC cell line MDA-MB-231 was treated with an IC50 dose of GrB/VEGF121 for 24 hours; the cells were then harvested and the effect of GrB/VEGF121 on intracellular events was examined by extraction of mRNA followed by microarray analysis. Gene-level differential expression analysis revealed that a total of twenty genes were upregulated by over 3-fold, while 25 were downregulated 3-fold or more. These included genes involved in signal transduction, stress response, cell cycle control, hypoxia and metastasis. Particularly impacted were the Nuclear Receptors Meta pathway, NRF2 pathway, nuclear receptors in lipid metabolism and toxicity, matrix metalloproteinases, and the notch signaling pathway. Validated data will be reported following complete analysis of gene level differential expression and alternative splicing. Our data suggests that GrB/VEGF121 induces expression of genes known to be induced by VEGF alone, as well as molecules previously not associated with either Granzyme B or VEGF.This data suggests a previously unsuspected impact of the serine protease GrB on various molecular pathways within the cell and may lead to a new understanding of how these agents operate at the molecular level. Research conducted, in part, by the Clayton Foundation for Research.
Citation Format: Khalid A. Mohamedali, Lawrence H. Cheung, Ana Alvarez-Cienfuegos, Michael G. Rosenblum. Genomic differential expression analysis of fusion proteins incorporating the pro-apoptotic molecule Granzyme B reveals new potential targets for treatment of breast cancer [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 5615. doi:10.1158/1538-7445.AM2017-5615
Abstract 5616: Activation of CD137/CD137L results in reduced tumor cell proliferation in human colon cancer
Authors: Grimmig Tanja , Callies Simone , Naegele Hannes , Wagner Martin , Moench Romana , Polat Buelent , Germer Christoph-Thomas , Gasser Martin , Waaga-Gasser Ana Maria 
Published: July 2017

Abstract
Background: CD137L is expressed on antigen presenting cells and CD137/CD137L interaction co-stimulates activation and proliferation of CD137 expressing T cells. CD137L expression has also been detected on various cancer cells. While signaling in immune cells showed both inhibiting and activating effects the impact of CD137L induction on tumor cells is poorly understood. In this study, the expression of CD137 and CD137L and the effects of CD137L activation were analyzed in human colorectal cancer (CRC).
Methods: Expression of CD137 and CD137L was examined in human colon cancer cell lines HT29, SW480 and SW620 treated with or without hypoxia using RT-qPCR, Western blot and FACS analysis. Its differentiated expression was further analyzed in human CRCs by immunofluorescent double-staining. To dissect the effects of CD137L activation on cancer cells, MTS proliferation assays were additionally performed.
Results: All three human colon cancer cell lines demonstrated high cellular (FACS) and protein (Western Blot) CD137L expression. CD137 was found only in SW480 cells at weak expression. Additionally, both CD137 and CD137L were significantly upregulated in cells treated with hypoxia. In human CRCs both CD137 and CD137L expressing tumor cells were detected by immunofluorescent double-staining. Interestingly, activation of CD137L by immobilized CD137-Fc resulted in reduced cancer cell proliferation compared to IgG1-Fc controls.
Conclusion: Our results demonstrate tumor cell mediated expression of the costimulatory molecule CD137 and its ligand CD137L in both colon cancer cell lines and human colorectal cancer. Moreover, CD137L reverse signaling was found to reduce cancer cell proliferation in vitro. Based on these data, the CD137/CD137L signaling pathway seems to present a promising target for cancer therapy in CRC.
Note: This abstract was not presented at the meeting.
Citation Format: Tanja Grimmig, Simone Callies, Hannes Naegele, Martin Wagner, Romana Moench, Buelent Polat, Christoph-Thomas Germer, Martin Gasser, Ana Maria Waaga-Gasser. Activation of CD137/CD137L results in reduced tumor cell proliferation in human colon cancer [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 5616. doi:10.1158/1538-7445.AM2017-5616
Abstract 5625: Identification and validation of a PD-L1 specific peptide for determination of PD-L1 expression in tumors
Authors: Caldwell Charles , Johnson Cory , Hammer Richard , Kannan Raghuraman 
Published: July 2017

Abstract
In recent years, immunotherapy has seen a resurgence as a promising method of treating cancers. The interaction between Programmed Death Ligand 1 (PD-L1) and its receptor, Programmed Death 1 receptor (PD-1) has been of particular interest. Many different types of tumors have been shown to overexpress PD-L1, which causes host immune cells that express the PD-1 receptor and bind PD-L1 to cease killing the tumor. Patients who have tumors exhibiting high levels of PD-L1 show poor prognosis compared to those who do not. Inhibition of the PD-L1 PD-1 binding axis has been shown to restore host immunity to the tumor, and recently many new drugs such as atezolizumab and pembrolizumab have been developed to target this interaction. Current methods of PD-L1 diagnosis have shown to vary based on the antibody, detection kit brand, antigen retrieval method, and clinically strict defined methods for use by the FDA for assessment. To refine detection of PD-L1, we have identified a PD-L1 specific peptide which can be used to detect PD-L1 expressing tumors using either conventional immunohistochemistry or flow cytometry. Immunohistochemistry using this peptide was tested against the FDA-approved PD-L1 (SP263) Rabbit monoclonal primary antibody on biopsied patient tissues. Flow cytometry was performed on both cultured cell lines and patient tissues. We have shown that our PD-L1 peptide shows specific staining in the tumor regions of FFPE tissues where the SP263 kit does not stain, and we can also detect PD-L1 expression in both cell samples and patient tissues using flow cytometry.
Citation Format: Charles Caldwell, Cory Johnson, Richard Hammer, Raghuraman Kannan. Identification and validation of a PD-L1 specific peptide for determination of PD-L1 expression in 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 5625. doi:10.1158/1538-7445.AM2017-5625
Abstract 5626: Investigation of T cell activation by anti-human PD-1 antibodies Nivolumab, Pembrolizumab and BGB-A317 using tumor-infiltrating lymphocytes (TILs) from colorectal cancer and colorectal liver metastasis patients
Authors: Luo Lusong , Wu Xiaoran , Zhang Tong , Fu Chunyan , Zhang Yanjuan , Guo Amy , Zhou Dongping , Zhang Lianhai , Wang Kun , Xing Baocai , Ji Jiafu , Wang Lai , Li Kang 
Published: July 2017

Abstract
Blockade of the PD-1 pathway with anti-PD-1 antibody, such as nivolumab (nivo) and pembrolizumab (pembro), has led to remarkable clinical responses in patients with many different cancer types. In this study, we investigated the activation of tumor-infiltrating lymphocytes (TILs) from patients with colorectal cancer (CRC) and colorectal liver metastasis (CLM) by nivo, pembro and BGB-A317, a novel humanized IgG4 anti-PD-1 antibody under clinical development. BGB-A317 has a unique binding signature to PD-1 with high affinity. Additionally, it is engineered to remove Fc gamma receptor (FcγR) binding, including FcγRI, FcγRIIA, FcγRIIB and FcγRIIIA. In our studies, all three anti-PD-1 antibodies showed significant increases in IFN-γ and TILs proliferation in a 3D tumor spheroid model. In both CRC and CLM patients, BGB-A317 treatment at concentration levels of 0.1, 1 and 10 μg/mL led to higher IFN-γ production than that in nivo and pembro treated groups. The enhanced TILs function was associated with a high density of CD8+ T cells, but inversely correlated with the percentage of CD11b+ myeloid cells in CRC tumors. Of interest, BGB-A317 showed better activation of TILs in the liver metastasis tumor microenvironment (TME) where macrophages were more abundant. This observation is consistent with the hypothesis that removal of FcγR binding might offer advantage to PD-1 mAbs in tumor microenvironment enriched with macrophages.
Citation Format: Lusong Luo, Xiaoran Wu, Tong Zhang, Chunyan Fu, Yanjuan Zhang, Amy Guo, Dongping Zhou, Lianhai Zhang, Kun Wang, Baocai Xing, Jiafu Ji, Lai Wang, Kang Li. Investigation of T cell activation by anti-human PD-1 antibodies Nivolumab, Pembrolizumab and BGB-A317 using tumor-infiltrating lymphocytes (TILs) from colorectal cancer and colorectal liver metastasis patients [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 5626. doi:10.1158/1538-7445.AM2017-5626
Abstract 563: Quantitative EMT expression score for predicting survival outcome
Authors: George Jason T. , Jolly Mohit K. , Levine Herbert 
Published: July 2017

Abstract
Tumor aggressiveness and subsequent metastasis still remain as major limitations to curative treatments for cancer patients. The epithelial to mesenchymal transition (EMT) is a process that occurs naturally during embryogenesis and has been linked to metastasis in many cancer types. EMT is characterized by phenotypic changes that allow for tissue extravasation and migration of cancer cells into the bloodstream. These changes may be linked to specific patterns in the gene expression signature of cells undergoing EMT. Recent theoretical efforts have predicted the existence of a stable, hybrid (E/M) phenotype which has also been observed experimentally in single cells. However, the effects of this hybrid phenotype on cancer patient survival have not been well characterized. The ability to quantify a patient’s EMT status via a simple test involving a small collection of prognostic genes would provide an important tool for clinical risk stratification and treatment in the context of many cancer types. Here, we apply iterative statistical methods to generate an EMT score based on gene expression samples. We use this score to characterize the degree of the hybrid phenotype signature present in test samples. Predictions from our model are verified against cell lines with known EMT status. Lastly, we apply our model to clinical samples in order to assess survival differences in various EMT groups. We demonstrate that in many cases, EMT status successfully classifies patients into groups with statistically significant differences in survival, which is of immediate clinical relevance.
Citation Format: Jason T. George, Mohit K. Jolly, Herbert Levine. Quantitative EMT expression score for predicting survival outcome [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 563. doi:10.1158/1538-7445.AM2017-563