bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-B16: In vitro monitoring of the efficacy of cancer immunotherapy designs trough an impedance-based platform
Authors: Cerignoli Fabio , Zhu Jenny , Xi Biao , Zhao Leyna , Irelan Jeff , Abassi Yama 
Published: May 2016

Abstract
Immunotherapy is emerging as one of the most promising approaches in cancer treatment, allowing specific targeting of cancer cells from CD8+ T Lymphocytes based on surface marker expression. In vitro characterization of the efficacy and potency of BiTEs or CAR T-Cell constructs is a necessary step before moving to animal models and Phase I and II clinical studies. In this study we present the optimization of several protocols to analyze cancer immunotherapy reagents using an impedance-based platform. The platform allows detection of cell adhesion and cell death trough monitoring the change in conductance of microelectrodes embedded on the bottom of the culture dish. Because cell adhesion over the electrodes alters the conductivity of the surface, any change in cell morphology, adhesion or number is detected as alteration of an impedance-related parameter called Cell index (Ci). Furthermore, because the platform avoid the use of any chemical label or sample processing, it allows continuous monitoring of cell activity. Dose-responses curves of BiTEs antibodies against epithelial tumor cell lines with a range of expression of the EpCAM antigen show correlation between surface expression level and efficacy of the constructs. Decreasing ratios between effector and target cells, in combination with longer time of monitoring reveal the efficacy of such constructs also at equivalent stoichiometric ratio. Taken together our results demonstrate higher sensitivity of the impedance-based approach over established methodologies like Chromium-51 release assay and live-cell imaging, improving and speeding up the workflow for therapy optimization.
Citation Format: Fabio Cerignoli, Jenny Zhu, Biao Xi, Leyna Zhao, Jeff Irelan, Yama Abassi. In vitro monitoring of the efficacy of cancer immunotherapy designs trough an impedance-based platform. [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-B16.
Abstract LB-C20: Lead generation and optimisation of a series of novel glutaminase (GLS) inhibitors
Authors: Charles Mark D. , Cairnduff Ceri , Brookfield Joanna , Sabin Verity , Ekwuru Tennyson , Jones Neil , Ting Attilla , Smith James , Nissink Willem , Finlay Ray , Powell Steve , Critchlow Susan , Ward Richard , Wood Matthew , Ruston Linette , Winter Jon , Hollingsworth Ian 
Published: May 2016

Abstract
Glutamine is an essential nutrient for cancer cells and is used to support cancer cell growth. Glutamine is converted to glutamate by the enzyme glutaminase, which is then converted into alpha-ketoglutarate, a metabolic intermediate within the TCA cycle which serves as a precursor for the biosynthesis of ATP, NADPH, fatty acids, glutathione, nucleic acids and amino acids. As such, we regarded glutaminolysis as a key pathway for therapeutic intervention.
At the outset of the project there were several reported inhibitors of glutaminase known in the literature; however, they possess undesirable drug like properties. We describe here our efforts to discover novel inhibitors of glutaminase with a promising development profile. From a high throughput screen of approximately 900,000 compounds in the AstraZeneca collection, we were able to identify three series of glutaminase inhibitors. One of these series has been optimised to deliver cell potent, selective and orally bioavailable inhibitors of glutaminase 1.
Citation Format: Mark D. Charles, Ceri Cairnduff, Joanna Brookfield, Verity Sabin, Tennyson Ekwuru, Neil Jones, Attilla Ting, James Smith, Willem Nissink, Ray Finlay, Steve Powell, Susan Critchlow, Richard Ward, Matthew Wood, Linette Ruston, Jon Winter, Ian Hollingsworth. Lead generation and optimisation of a series of novel glutaminase (GLS) inhibitors. [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-C20.
Abstract PL03-03: K-RAS dependency in pancreatic cancer
Authors: Tuveson David A. 
Published: May 2016

Abstract
2015 AACR-NCI-EORTC
K-RAS dependency in Pancreatic Cancer
David Tuveson, M.D., Ph.D., Cold Spring Harbor Laboratory
Efforts to inhibit the KRAS oncogene in pancreatic cancer have focused on classical downstream pathways and empirically identified dependencies. We have developed organoid models of mouse and human pancreatic cancer to expedite such translational approaches for this disease. We find that organoid models of PDA demonstrate ERBB pathway activation in response to dual MEK/AKT inhibition, and that this feature is absent in non-neoplastic organoids. Furthermore, organoid models predict the limited activity of EGFR specific inhibitors in PDA patients that are also receiving MEK or AKT inhibitors. These models have also been an invaluable resource for probing new dependencies in PDA, and will be discussed.
Citation Format: David A. Tuveson. K-RAS dependency in pancreatic cancer. [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 PL03-03.
Abstract PL07-02: Tumor hypoxia and radiation resistance: Anything new on the horizon?
Authors: Deutsch Eric , Chargari CYrus 
Published: May 2016

Abstract
Hypoxia is one of the key factors influencing clinical outcome after radiotherapy responsible for reduced local control that will influence overall survival, as may the hypoxic conditions by increasing malignant progression. In sharp contrast with the progresses and the rapid diffusion of functional imaging to characterize hypoxic tumors and the fact that experimental correction of tumor tumor hypoxia reverses tumor resistance to irradiation, there is no approved concomitant therapy in order to maximize response to radiotherapy for the treatment of hypoxic tumors. For decades, hypoxia was thought to act primarily on intrinsic tumor cells resistance, namely the number of clonogenic cancer stem cells surviving after radiation treatment. In the meantime, improvements into the understanding of the mechanisms triggered by hypoxia have unveiled novel molecular targets for potential combination to radiation therapy such as the interplay between STAT3 signaling and adaptation to hypoxia while the impact of tumor hypoxia on tumor microenvironment changes have expand to the immune network. Increased cellular turnover and hypoxia promote the production and release of large amounts of immunosupressive adenosine into the local microenvironment. Hypoxia can induce HIF-1a-dependent expression of arginase-1 and M2 polarization of macrophages. The spectrum of candidate therapies to target hypoxic tumors has moved from bioreductive cytotoxic agents to HIF-1, STAT3 inhibitors while growing number of immunological tools are becoming available for targeting the immune component. The ongoing EORTC 1219-ROG-HNCG/DAHANCA project 29 has gained form the past clinical attempts to target hypoxic tumors and will provide the methodology way for future clinical development of such novel combos based on optimal patients selection using biological and/or imaging criteria.
Citation Format: Eric Deutsch, CYrus Chargari. Tumor hypoxia and radiation resistance: Anything new on the horizon? [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 PL07-02.
Abstract PR08: ARV-330: An androgen receptor PROTAC degrader for prostate cancer
Authors: Winkler James D. , Jin Meizhong , Crew Andy P. , Rossi AnnMarie K. , Willard Ryan R. , Dong Hanqing , Siu Kam , Wang Jing , Gordon Deborah A. , Chen Xin , Ferraro Caterina , Crews Craig M. , Coleman Kevin , Neklesa Taavi K. 
Published: May 2016

Abstract
Patients with prostate cancer who progress on therapy often have enhanced Androgen Receptor (AR) signaling due to several mechanisms: increased androgen production, increased AR expression, and/or specific AR mutations that render current therapies ineffective. A novel approach to block AR signaling is to specifically target AR for degradation. To do this, we have created AR PROTACs (PROtein-TArgeting Chimeras), bi-functional molecules that have an AR binding moiety on one end and an E3 ligase-recruiting element on the other end, which leads to AR ubiquitination and degradation. We have applied this technology to determine whether it could address mechanisms of resistance to current therapy in prostate cancer models.
Our lead AR PROTAC, ARV-330, degrades AR in LNCaP and VCaP cells with 50% degradation concentrations (DC50s) &lt; 1nM. AR degradation had functional consequences in cells, suppressing the AR target gene PSA, inhibiting proliferation, and potently inducing apoptosis in VCaP cells, with maximal apoptosis observed around 20 nM, versus 1 uM for enzalutamide. While both ARV-330 and enzalutamide block proliferation of VCaP cells in response to 0.1 nM of the AR agonist R1881, enzalutamide lost antiproliferative potency with increasing R1881 concentrations, whereas ARV-330 maintained antiproliferative effects. In cells containing the ARF876L mutation, enzalutamide was ineffective; however, ARV-330 maintained complete effectiveness. In mice, ARV-330 exhibited good pharmacokinetic properties, with t1/2 values of several hours and bioavailability of &gt;80% after sc injection. Treatment of mice with ARV-330, at doses ranging from 0.3 to 10 mg/kg, resulted in reduction of AR protein levels and prostate involution in normal mice and, in mice implanted with VCaP tumors, reduction in plasma PSA and blockade of tumor growth.
In summary, the AR PROTAC ARV-330 removes AR from prostate cancer cells in a potent manner and produces therapeutic effects as a result. This cellular efficacy has translated into biomarker activity and efficacy in animal models, and ARV-330 is now in preclinical development. Thus, targeted degradation of AR may provide a novel mechanism for providing efficacious therapy for patients with prostate cancer for whom current therapies have failed.
Citation Format: James D. Winkler, Meizhong Jin, Andy P. Crew, AnnMarie K. Rossi, Ryan R. Willard, Hanqing Dong, Kam Siu, Jing Wang, Deborah A. Gordon, Xin Chen, Caterina Ferraro, Craig M. Crews, Kevin Coleman, Taavi K. Neklesa. ARV-330: An androgen receptor PROTAC degrader for prostate cancer. [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 PR08.
Abstract A14: Loss of LKB1 gene alone causes malignant transformation of astrocytes
Authors: Braun David , Feinstein Douglas , Engelhard Herbert 
Published: May 2016

Abstract
Liver Kinase B1 (LKB1) is a master kinase regulating activation of multiple downstream kinases, and plays roles in cell polarity, metabolism, proliferation, and inflammatory activation. The role LKB1 plays in the malignant transformation of normal astrocytes has not previously been reported. We hypothesized that LKB1 deficiency would influence the growth and differentiation of astrocytes. To test this, we prepared primary cortical astrocytes from homozygous LKB1 f/f mice. When the cells reached confluency, they were infected with AAV-CMV-Cre-GFP virus (knocking out the LKB1 gene), or with AAV-CMV-GFP as control. After 7 additional days, the control cells continued to have the typical appearance of astrocytes, while the LKB1 knockout cells began to form spheroids, with a 5-fold increase in proliferation by MTS assay. The LKB1 knockout astrocytes also showed loss of contact inhibition, increased migrative capability (by scratch assay), and loss of GFAP staining. Our data show that LKB1 deficiency alone induces a transformed phenotype in astrocytes, providing a new model for glioma and indicating its pathogenesis.
Citation Format: David Braun, Douglas Feinstein, Herbert Engelhard. Loss of LKB1 gene alone causes malignant transformation of astrocytes. [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 A14.
Abstract A24: Brain tumor induction after somatic inactivation of rb1 in zebrafish
Authors: Solin Staci L. , Shive Heather R. , Essner Jeffrey J. , McGrail Maura 
Published: May 2016

Abstract
Purpose: We found that targeted somatic inactivation of rb1 leads to solid tumor formation in the central nervous system of adult zebrafish. The purpose of our study was to characterize the histological and genetic features of the tumors.
Methods: Zebrafish rb1 tumor suppressor was inactivated in somatic tissue by injection of transcription activator-like effector nucleases (TALENs) targeting exon 2 and exon 3 at the one-cell stage. Histopathology and immunohistochemistry with s100 and pH3 was performed on tumor tissue.
To confirm TALEN-mediated editing of the targeted rb1 loci and characterize the frequency and type of indel alleles in tumor and somatic tissues we sequenced cloned amplicons from each locus.
Results: Zebrafish injected with TALENs targeting exon 2 or exon 3 of rb1 presented with cranial tumors beginning at six months of age. By one year the frequency of adults with tumors was 33-50% and 11%, respectively. Histopathological analyses of tumors from eight exon 2-targeted and six exon 3-targeted fish revealed a range of undifferentiated and differentiated tumor phenotypes. Seven tumors exhibited features suggestive of primitive neuroectodermal tumors (PNET). The remainder exhibited more differentiated tumor phenotypes resembling glioma. S100 was detected in a subset of the tumors. pH3 labeled regions of high mitotic activity in each of the tumors. In 4 out of 4 tumors the frequency of rb1 mutant alleles (61%-87% of cloned amplicons) was consistently higher than wild type. However, only one or two specific rb1 alleles were present in 3 out of 4 tumors. In contrast, the mutation frequency in retinal, muscle, and germline tissues was highly variable (3%-100%), and represented by up to seven different mutant rb1 alleles.
Conclusion: Somatic inactivation of rb1 resulted in brain tumors showing varying degrees of differentiation suggesting the possibility that transformed neural progenitors give rise to tumors. rb1 allele frequency is consistent with clonal expansion contributing to tumor growth. Predisposing zebrafish to brain tumors by somatic inactivation of rb1 with site-specific nucleases suggests a simple method for investigating pathways cooperating in tumor progression.
Citation Format: Staci L. Solin, Heather R. Shive, Jeffrey J. Essner, Maura McGrail. Brain tumor induction after somatic inactivation of rb1 in zebrafish. [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 A24.
Abstract B14: Targeting a network of cancer control nodes through rescue of c-Cbl: A novel therapeutic approach in GBM
Authors: Stripay Jennifer L. , Stevens Brett M. , Bardin Addie L. , Noble Mark D. 
Published: May 2016

Abstract
Glioblastoma multiforme is the most common primary brain tumor in adults, the most malignant of all intracranial tumors, and is associated with inevitable recurrence and 15 month mean survival despite multimodal therapy. The majority of GBM tumors maintain heterogeneous amplifications (many in the absence of genetic mutation) in receptor tyrosine kinases (RTKs), which are mediators of growth factor signaling. Our lab has discovered that control over RTK levels in normal CNS progenitors is maintained by the Redox/Fyn/c-Cbl (RFC) pathway whereby increased oxidative state results in activation of the E3 ubiquitin ligase c-Cbl and the subsequent internalization and degradation of target RTKs. RFC signaling is disrupted in GBM due to a physical sequestration of c-Cbl, preventing pro-oxidative chemotherapeutics from reducing pro-survival signaling through Epidermal Growth Factor Receptor, Platelet-Derived Growth Factor Receptor, etc. Using a triangulating drug screen, we identified candidate FDA-approved small molecules capable of reducing signaling downstream of c-Cbl-targeted RTKs. We found that candidate URMC-06, an antidepressant with a good clinical safety profile, could rescue RFC signaling and significantly enhance the sensitivity of GBM cells to a pro-oxidative agent (Tamoxifen) in a c-Cbl-dependent manner. There is significant evidence to suggest that a tumor initiating cell population mediates the malignancy of GBM tumors. These cells express stem-cell associated markers and exhibit self-renewal capacity. We observed a c-Cbl-dependent inhibition of neurosphere formation (an in vitro measure of self-renewal) and a reduction in the expression of stem cell markers Sox2, beta-catenin, FoxM1 and Nestin in GBM cells treated with URMC-06. Our candidate also facilitated reduction in heat shock signaling and an inhibition of autophagy (both putative survival mechanisms) in GBM cells. URMC-06 was effective, in combination with clinically relevant agents (Temozolomide and Tamoxifen), at reducing tumor progression in an in vivo xenograft model of GBM. Our work supports the hypothesis that c-Cbl is a critical player in GBM that integrates multiple nodes of cancer control and that pharmacological rescue of c-Cbl represents a potentially powerful therapeutic approach.
Citation Format: Jennifer L. Stripay, Brett M. Stevens, Addie L. Bardin, Mark D. Noble. Targeting a network of cancer control nodes through rescue of c-Cbl: A novel therapeutic approach in GBM. [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 B14.
Abstract B18: Targeting histone deacetylase 6 (HDAC6) depresses proliferation and induces caspase-associated cell death in glioblastoma multiforme (GBM) cells and GBM stem cell-like spheroids
Authors: Saadatzadeh Mohammad Reza , Vishehsaraei Khadijeh Bijangi , Wang Haiyan , Cohen-Gadol Aaron , Pollok Karen E. , Safa Ahmad R. 
Published: May 2016

Abstract
Glioblastoma multiforme (GBM) comprises the most common and very aggressive form of primary brain tumor with a dismal prognosis and very poor response to the current therapies. HDAC inhibitors (HDACi) are capable of inducing growth arrest and apoptosis in various tumor cell types. HDAC6 is a unique enzyme having two deacetylase domains, and a ubiquitin-binding domain. HDAC6 interacts with a number of proteins in the cytoplasm and is involved in tumorigenesis, cell motility, and metastasis. Significantly, it has been shown that HDAC6 knockout mice are viable. Therefore, in this study, we evaluated HDAC6 as a relevant target for GBM treatment by using a potent HDAC6 inhibitor, CAY 10603. Our data showed that CAY 10603 targets the established GBM cell line U86MG, M-HBT161 early primary cultures, and CD133- and SOX2-positive stem cell-like spheroids. CAY 10603 at 1-5 μM triggered significant inhibition of cell survival and induced apoptotic cell death in GBM cells and GBM spheroids. CAY 10603 reduced cell survival in these cells by 50% (IC50) at 1-3 μM treatment for 48 h. Similarly, CAY 10603 induced significant dose-dependent inhibition of spheroid survival in U87MG and M-HBT161 when the spheroids were grown in a defined GBM stem cell (GSC) growth medium on ultra-low attachment plates for four days. Interestingly, when grown in the same medium but on plates which promote attachment, the spheroids were 3-4 fold more sensitive to CAY 10603, indicating that growth conditions affect the sensitivity of GBM stem cell-like spheroids. Moreover, CAY 10603 triggered cell death in U87MG and M-HBT161 cells as well as CD133/SOX2-expressing spheroids was associated with activation of caspases-3, -6 and -9. Overall, our results show that CAY 10603 robustly inhibits the growth of GBM cells, and is effective in eliminating spheroids that contain GBM cancer stem cells which play a major role in drug resistance and disease recurrence. These results suggest that use of CAY 10603 alone or in combination with other agents may potentially improve the survival of brain tumor patients.
Citation Format: Mohammad Reza Saadatzadeh, Khadijeh Bijangi Vishehsaraei, Haiyan Wang, Aaron Cohen-Gadol, Karen E. Pollok, Ahmad R. Safa. Targeting histone deacetylase 6 (HDAC6) depresses proliferation and induces caspase-associated cell death in glioblastoma multiforme (GBM) cells and GBM stem cell-like spheroids. [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 B18.
Abstract B44: Acquisition of meiotic DNA repair regulators maintain genome stability in glioblastoma
Authors: Rivera Maricruz , Wu Qiulian , Hamerlik Petra , Hjelmeland Anita , Bao Shideng , Rich Jeremy 
Published: May 2016

Abstract
Glioblastoma (GBM), the most prevalent type of primary intrinsic brain cancer in adults, remains universally fatal despite maximal therapy, including radiotherapy and chemotherapy. Cytotoxic therapy generates double stranded DNA breaks (DSBs), most commonly repaired by homologous recombination (HR). We hypothesized that cancer cells coopt meiotic repair machinery as DSBs are generated during meiosis and repaired by molecular complexes distinct from genotoxic responses in somatic tissues. Indeed, we found that gliomas express meiotic repair genes and their expression informed poor prognosis. We interrogated the function of Disrupted Meiotic cDNA1 (DMC1), a homolog of RADiation sensitive51 (RAD51), the primary recombinase used in mitotic cells to search and recombine with the homologous DNA template. DMC1, whose only known function is as an HR recombinase, was expressed by GBM cells and induced by radiation. While targeting DMC1 in non-neoplastic cells minimally altered cell growth, DMC1 depletion in GBM cells decreased proliferation, induced activation of Checkpoint kinase 1 (CHK1) and expression of p21CIP1/WAF1, and increased replication protein A (RPA) foci, suggesting increased replication stress. Combining loss of DMC1 with ionizing radiation (IR) inhibited activation of DNA damage responses and increased radiosensitivity. Furthermore, loss of DMC1 reduced tumor growth and prolonged survival in vivo. Our results suggest that cancers coopt meiotic genes to augment survival under genotoxic stress, offering molecular targets with high therapeutic indices.
Citation Format: Maricruz Rivera, Qiulian Wu, Petra Hamerlik, Anita Hjelmeland, Shideng Bao, Jeremy Rich. Acquisition of meiotic DNA repair regulators maintain genome stability in glioblastoma. [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 B44.