bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-B20: Characterization and Enumeration of Multiple Circulating Tumor Cell Phenotypes Using Two Distinct Platforms Establishes Presence of Epithelial-Mesenchymal Transition CTCs in Patients
Authors: Wang Lihua , Owusu Francis , Khin Sonny , Parchment Ralph , Chen Alice , Kummar Shivaani , Doroshow James H. , Kinders Robert J. 
Published: May 2016

Abstract
We are employing a “liquid biopsy” approach for monitoring drug responses to new anti-cancer agents in early stage clinical trials by measuring drug effects in circulating tumor cells (CTCs), which requires the capability to capture and characterize CTCs from patients with diverse diseases including sarcomas, lymphomas and carcinomas. We have been applying the Apostream platform (DEP-FFF separation) with fluorescence imaging and have recently added the 5-channel CellSearch system (MAb coated ferrofluid) for specimen analysis. Use of both CD146 and EpCam capture per specimen, with addition of vimentin and the tumor markers, significantly increased the number of CTCs captured with the 5 channel CellSearch®. A “homebrew” CTC kit was developed that captures circulating cells that are either EpCAM or CD146 marker positive, and it was capable of identifying high numbers of EMT+ tumor marker+ double positive cells in patient specimens. There was statistical equivalency of events flagged as CTCs (CD45-/EpCam+/CK+) in patient specimens analyzed using Apostream or 5-Color CellSearch versus 4-channel CellSearch and 100% concordance between the CellSearch platforms. Reproducibility, as assessed by image re-analysis using Definiens software, was also high (&gt;90%). Tumor marker specificity was established by analyzing normal donor blood, which varied from zero to 2 cells per ml blood depending on the marker set employed (only CD45 negative cells assessed). This approach solves a major limitation of using CTCs to monitor pharmacodynamic response by enumerating statistically significant cell numbers from patients with solid tumors of diverse histologies.
Strikingly, both platforms demonstrated the presence of high numbers of CTCs with the Epithelial-Mesenchymal Transition (EMT) phenotype (10-100 cells per ml in Phase 1 trial populations), and widely used tumor markers such as MUC1, CEA, TLE1, or proteins generated by recombination events such as ASPL-TFE3. The presence of large numbers of CTCs expressing the EMT phenotype may be related to the intensive prior treatment (&gt;3 prior therapies, median) of our phase 1 population.
Funded by NCI contract # HHSN261200800001E.
Citation Format: Lihua Wang, Francis Owusu, Sonny Khin, Ralph Parchment, Alice Chen, Shivaani Kummar, James H. Doroshow, Robert J. Kinders. Characterization and Enumeration of Multiple Circulating Tumor Cell Phenotypes Using Two Distinct Platforms Establishes Presence of Epithelial-Mesenchymal Transition CTCs in Patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B20.
Abstract LB-C04: Modeling the impact of somatic alterations across human cancers
Authors: Osmanbeyoglu Hatice U. , Leslie Christina 
Published: May 2016

Abstract
Modeling the impact of somatic alterations across human cancers
Hatice U. Osmanbeyoglu1, Christina S. Leslie1,*
1Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY
Abstract
Large-scale cancer genomics projects like The Cancer Genome Atlas have generated a comprehensive catalog of somatic mutations and copy number aberrations across many tumor types, but the role of some frequently altered genes remains obscure. To better model the impact of these alterations, we developed a computational strategy for exploiting parallel phosphoproteomics and mRNA sequencing data for large tumor sets to link dysregulation of upstream signaling pathways with altered transcriptional response through the transcriptional circuitry. Our modeling allows us to interpret the impact of mutations and copy number events in terms of altered signaling and transcription factor (TF) activity. We used a novel machine learning strategy to train phosphoprotein-TF interaction models across 10 human cancers for which large reverse-phase protein array and RNA-seq data sets are available through TCGA. We then applied a novel algorithmic approach to extract networks of signaling proteins and TFs whose inferred activities are correlated across tumors and whose dysregulation is associated with specific somatically altered genes. Our analysis revealed both known and novel interactions of frequently altered genes with signaling pathways and transcriptional programs in a pan-cancer context. Moreover, our algorithmic approach provides a general strategy for modeling the impact of recurrent mutations and copy number alterations on signaling pathways and transcriptional programs through pan-cancer analysis.
Citation Format: Hatice U. Osmanbeyoglu, Christina Leslie. Modeling the impact of somatic alterations across human cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C04.
Abstract LB-C08: Exploring glycan markers for immunotyping and precision-targeting of breast circulating tumor cells (CTCs)
Authors: Sambucetti Lidia C. , Liu Xiaohe , Hsieh Ben , Bruce Richard , Somlo George , Huang Jiaoti , Wang Denong 
Published: May 2016

Abstract
Recognition of abnormal glycosylation in virtually every cancer type has raised great interest in exploration of the tumor glycome for biomarker discovery. Identifying glycan markers of circulating tumor cells (CTCs) represents a new development in tumor biomarker discovery. The aim of this study was to establish an experimental approach to enable rapid screening of CTCs for glycan marker identification and characterization. We applied carbohydrate microarrays and a high-speed fiber-optic array scanning technology (FASTcell) to explore potential glycan markers of breast CTCs (bCTCs) and targeting antibodies. An anti-tumor monoclonal antibody, HAE3-C1 (C1), was identified as a key immunological probe in this study. In our carbohydrate microarray analysis, C1 was found to be highly specific for an O-glycan cryptic epitope, gpC1. Using FASTcell technology, we established a procedure to quantify expression levels of gpC1 in tumor cells. In blood samples from five Stage IV metastatic breast cancer patients, the gpC1 positive CTCs were detected in all subjects; approximately 40% of bCTCs were strongly gpC1 positive. Interestingly, the CTCs from a triple-negative breast cancer patient with multiple sites of metastasis were predominantly gpC1 positive (92.5%, 37/40 CTCs). Taken together, we present here a practical approach to examine rare cell expression of glycan markers. Using this approach, we identified an O-core glyco-determinant gpC1 as a potential immunological target of bCTCs. Given its bCTC-expression profile, this target warrants an extended investigation in a larger cohort of breast cancer patients.
Citation Format: Lidia C. Sambucetti, Xiaohe Liu, Ben Hsieh, Richard Bruce, George Somlo, Jiaoti Huang, Denong Wang. Exploring glycan markers for immunotyping and precision-targeting of breast circulating tumor cells (CTCs). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C08.
Abstract LB-C11: HTLV-1 Tax-induced apoptosis to counteract tumor drug resistance
Authors: Ducas Vanessa C. , Kupfer Gary M. 
Published: May 2016

Abstract
p53 mutations have been identified in over 50% of human cancers. As p53-mutant tumor cells have an inherent resistance to therapy-induced apoptosis, such a mechanism of resistance is an important problem in cancer therapy. Interestingly, Tax, a protein expressed by the human T-cell lymphotropic virus type 1 (HTLV-1), increases the sensitivity of p53-mutant and p53-null cells to DNA-damaging drugs. Tax-induced chemosensitivity presents therefore a novel strategy that can be exploited to counteract p53-mutant tumor resistance. The objective of this work is to harness the chemosensitizing property of Tax and use it to develop a chemotherapeutic approach that can overcome the drug resistance observed in p53-mutant/p53-null cancers. We hypothesize that Tax initiates a proapoptotic response in cancer cells by modulating cyclin-dependent kinase 4 (CDK4) activity. We use a combination of in vitro and in silico analyses to determine the mechanism of Tax-induced chemosensitivity and to identify small molecules that can phenocopy the CDK4-activating and the proapoptotic effects of Tax. Immunoblot analyses and in vitro kinase assays reveal that Tax alters CDK4 expression and activity. In addition, flow cytometry and gene expression studies respectively indicate that Tax expression promotes G1-to-S phase transition and leads to increased expression of the TP73 gene, a known homolog of TP53. Moreover, our in silico analyses, using an N-terminal construct of Tax and a published structure of CDK4 (PDB 3G33), reveal that CDK4 interacts with the Tax construct via a C-terminal domain that is distinct from its nucleotide-binding and D-type cyclin-binding sites. Further analyses identify ten small molecule mimics of Tax and putative CDK4 activators, which we show have a proliferative effect on treated cells. Although the focus of ongoing studies in the field has been the development of kinase inhibitors, several tumors develop strategies allowing them to override the effect of those inhibitors. Our work adopts a different strategy that will maximize the cytotoxic effect of anticancer drugs to overcome acquired drug resistance.
Citation Format: Vanessa C. Ducas, Gary M. Kupfer. HTLV-1 Tax-induced apoptosis to counteract tumor drug resistance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C11.
Abstract LB-C19: The investigation of structural determinants that mediate selective inhibition of UBA5, the UFM1 activating enzyme
Authors: Paiva Stacey-Lynn , da Silva Sara , Bancerz Mathew , Geletu Mulu , Lewis Andrew M. , Chen Jijun , Cai Yafei , Lukkarila Julie L. , Li Honglin , Gunning Patrick T. 
Published: May 2016

Abstract
Protein conjugation with the UFM1 small protein modifier promotes cellular survival in times of ER stress, which is a common occurrence within diseased cells. We have developed the first selective inhibitor of UBA5, the E1 activating enzyme responsible for initiating UFM1 conjugation. Based on the crystal structure of human UBA5, we identified acidic residues in close proximity to the ATP pocket that we chose to target using a zinc-coordinated polyazamacrocycle. This coordination complex was appended to adenosine through alkyl linkers of varying length in order to probe for optimal inhibition of UBA5 activity. Through this small structure-activity relationship (SAR), we identified our lead inhibitor 5C-Z that disrupts UBA5-mediated UFM1 conjugation in vitro through a non-competitive mode of action (IC50 = 4.1 μM, 95% Confidence Interval (C.I.) = 2.1-7.7 μM). Our compound demonstrates selectivity for UBA5 over other E1 enzymes in vitro, as well as over nearly 100 human kinases as evaluated using a kinome screen, despite containing adenosine within its structure. Currently, we are investigating the structural determinants that are indispensible for inhibitory activity. We are making iterative changes by varying each component of 5C-Z including the metal centre, the polyazamacrocycle, the linker, the ribose as well as the nitrogenous base. To date, we have shown that other transition metals are not as active as the zinc (II) centre, increasing the size of the macrocycle abolishes activity and reducing the linkage from the polyazamacrocycle to the linker also significantly abrogates activity. Investigating the role of each functional group on 5C-Z will help delineate the mechanism by which it selectively inhibits UBA5 activity and may shed light in progressing towards a more drug-like small molecule inhibitor.
Citation Format: Stacey-Lynn Paiva, Sara da Silva, Mathew Bancerz, Mulu Geletu, Andrew M. Lewis, Jijun Chen, Yafei Cai, Julie L. Lukkarila, Honglin Li, Patrick T. Gunning. The investigation of structural determinants that mediate selective inhibition of UBA5, the UFM1 activating enzyme. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C19.
Abstract PL07-03: The multifaceted role of Notch signaling in tumor/microenvironment interaction
Authors: Aster Jon C. 
Published: May 2016

Abstract
Notch receptors participate in a highly conserved signaling pathway with critical developmental roles in multicellular animals. Based on studies involving developing and adult organisms, it is evident that the outcome of Notch signaling is not fixed but varies widely with dose and context, allowing Notch to either drive or modulate a large number of different biologic processes. This complexity extends to cancer. The first mammalian Notch receptor to be identified, Notch1, was found due to its rearrangement in a rare subset of T cell acute lymphoblastic leukemia (T-ALL), immediately indicating a role for the pathway in oncogenesis. Since this time, mechanistic work in animal models and cancer genome sequencing studies have greatly expanded the scope of the proposed roles for Notch signaling in cancer to the point where it is now reasonable to think that Notch impacts all of the Weinberg/Hanahan “Hallmarks of Cancer”. Some of these roles stem from cell autonomous mutations that constitutively activate oncogenic Notch signaling in tumors such as T-ALL and triple negative breast cancer, or that inactivate Notch in tumors such as squamous cell carcinomas of the skin and head and neck, confirming that Notch can act as a context dependent oncogene or tumor suppressor. In addition, recent data suggest that certain classes of Notch mutations are selected for their ability to upregulate signaling in a microenvironment-dependent fashion, a type of gene-environment interaction that is highly specific for particular cancers, such as chronic lymphocytic leukemia and marginal zone B cell lymphoma. Additional roles for Notch involving the stromal compartment in cancers, particularly angiogenesis and host immunity, also are coming into focus. This talk will touch on a number of these emerging relationships, which have implications for ongoing attempts to effectively target the Notch pathway in patients with a broad spectrum of different cancers.
Citation Format: Jon C. Aster. The multifaceted role of Notch signaling in tumor/microenvironment interaction. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL07-03.
Abstract PR09: TAS3681, a new type androgen receptor antagonist, suppresses ligand-independent AR activation through its AR downregulation activity
Authors: Kajiwara Daisuke , Minamiguchi Kazuhisa , Seki Masanao , Mizutani Hiroya , Aoyagi Hiroki , Okajima Shigeo , Sasaki Eiji , Utsugi Teruhiro , Iwasawa Yoshikazu 
Published: May 2016

Abstract
Background: Inhibitors of androgen receptor (AR) signaling axis, such as enzalutamide and abiraterone, represent important advances in the management of castration-resistant prostate cancer (CRPC). However, resistance to these drugs is still occurring. Recent reports suggest that there are several mechanisms of resistance. Ligand independent AR activation such as induction of AR splice variants or c-Myc expression is a major emerging mechanism of CRPC progression. There is an urgent need for developing a novel therapy to address these unresolved issues.
Methods: For assay of androgen-independent AR transactivation, prostate cancer cells were transiently transfected with androgen-responsive reporter gene construct. The transfected cells were treated with growth factor and cytokine in steroid-depleted media, and luciferase activity was measured. To evaluate the effect of TAS3681 on AR and c-Myc protein expression, prostate cancer cells were treated with TAS3681 in steroid-depleted media. AR and c-Myc protein levels were determined by Western blot. Real-time PCR was used to analyze the mRNA levels of c-Myc and c-Myc target gene. Chromatin immunoprecipitation was performed to determine the enrichment of AR at the element.
Results: TAS3681 dose-dependently reduced AR protein levels in prostate cancer cells. In contrast to enzalutamide, TAS3681 suppressed androgen-independent AR transactivation by growth factor and cytokine. In prostate cancer cells which express full-length AR and splice variant AR-v7, TAS3681 suppressed AR-v7 target gene expression through downregulation of AR-v7 occupancy at the enhancer. Moreover, TAS3681 reduced expression of c-Myc, critical driver of androgen-independent mechanisms of prostate cancer progression, via AR downregulation activity. In addition, real-time PCR assay showed the suppression of c-Myc and c-Myc target gene mRNA levels by TAS3681 but not by enzalutamide.
Conclusion: Our findings suggest that TAS3681, a new type AR antagonist with AR downregulation activity, has a potential to overcome ligand-independent AR activation and could be a candidate of breakthrough therapy for resistance to current AR pathway target drugs.
Citation Format: Daisuke Kajiwara, Kazuhisa Minamiguchi, Masanao Seki, Hiroya Mizutani, Hiroki Aoyagi, Shigeo Okajima, Eiji Sasaki, Teruhiro Utsugi, Yoshikazu Iwasawa. TAS3681, a new type androgen receptor antagonist, suppresses ligand-independent AR activation through its AR downregulation activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR09.
Abstract A33: Combinatorial targeting of tumor-associated macrophages/ microglia and radiotherapy in gliomas
Authors: Akkari Leila , Quail Daniela F. , Quick Marsha L. , Huse Jason T. , Sutton James C. , Joyce Johanna A. 
Published: May 2016

Abstract
Eighty percent of tumors that develop in the central nervous system are malignant gliomas, with over half being glioblastoma multiforme (GBM), the most aggressive form of this disease. Unfortunately, there have been minimal improvements in the survival of patients with GBM and these tumors remain essentially incurable. Even following treatment with standard of care therapy (surgery, radiation and temozolomide), the overall 5-year survival rate of patients diagnosed with GBM is less than 5%, highlighting the urgent need for novel and alternative therapeutic strategies to treat GBM.
In GBM patients and mouse models of the disease, the major non-cancerous cell type in the glioma microenvironment is tumor-associated macrophages/microglia (TAMMs). TAMMs can account for as much as 30% of the tumor mass in human GBM, and their accumulation is associated with poor patient prognosis. We previously used an inhibitor of colony stimulating factor 1 receptor (CSF-1R), BLZ945, to target macrophages in the RCAS-PDGF-B; nestin-TVA, Ink4a/Arf null mouse model of gliomagenesis, which faithfully recapitulates the hallmarks of human GBM. We found that CSF-1R inhibition dramatically improves survival in a long-term intervention trial and markedly regresses established high-grade lesions.
To determine the translational clinical potential for CSF-1R inhibition, we designed preclinical trials in combination with radiation, which is part of the standard treatment for GBM patients. We treated established GBMs with fractionated radiation concomitant with acute, short-term BLZ945 treatment and observed that the overall survival of animals was significantly extended compared to single treatment modalities. Moreover, incorporating long-term treatment with BLZ945 in tumors treated with fractionated radiation lead to a dramatic reduction in tumor recurrence, suggesting that reversing cancer-induced M2 macrophage programming has the potential to render gliomas more prone to response to radiotherapy. Interestingly, treatment of IR-resistant gliomas with BLZ945 de novo resulted in efficient regression of the disease, which may have important translational implications. We are currently examining the molecular mechanisms by which re-educating TAMMs increases radiation sensitivity. Together these results demonstrate critical roles for CSF1R-dependent TAMMs in promoting glioma malignancy, and highlight the clinical potential for CSF-1R inhibitors.
Citation Format: Leila Akkari, Daniela F. Quail, Marsha L. Quick, Jason T. Huse, James C. Sutton, Johanna A. Joyce. Combinatorial targeting of tumor-associated macrophages/ microglia and radiotherapy in gliomas. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A33.