bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-C24: Resistance to ALK inhibition is associated with enhanced BRD4 dependence in ALK-mutated MYCN-amplified neuroblastoma
Authors: Debruyne David , Sharma Bandana , Gray Nathanael , George Rani 
Published: May 2016

Abstract
Despite substantial therapeutic advances, the long-term survival rate of patients with high-risk neuroblastoma (NB), a tumor of the peripheral sympathetic nervous system is still dismal. Activating mutations in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase represent promising therapeutic targets in this disease and have prompted clinical trials of ALK inhibitors. But as with all molecularly targeted therapies, resistance is inevitable and will limit the ultimate utility of this therapeutic strategy. To elucidate the mechanisms of resistance to ALK inhibitors, we have generated isogenic NB cells, expressing the tumorigenic ALKF1174L mutation and amplified MYCN, with acquired resistance to the ALK inhibitor TAE684, through continuous exposure of increasing concentrations of the compound over time. We found that resistance was associated with downregulation of ALK activity, thus ruling out secondary mutations as a mechanism of resistance, and interestingly the other major oncogenic driver in neuroblastoma, MYCN, was downregulated as well. A comparative genome-wide expression analysis revealed global transcriptional downregulation in the resistant cells, as compared with their parental sensitive counterparts, in accordance with the aforementioned MYCN downregulation, as MYCN is known to act as a transcriptional amplifier in MYCN-amplified NB cells. Additionally, these resistant cells exhibited a 10-fold increased sensitivity to the BRD4 inhibitor JQ1, compared to sensitive cells, and MYCN as well as global gene expression were rescued after treatment. These results strongly suggest that resistance to ALK inhibition in ALKF1174L MYCN-amplified NB cells leads to a MYCN-independent enhanced BRD4 dependence, therefore providing a rationale for the use of BET inhibitors to overcome such resistance. Studies are currently underway to characterize the unique epigenetic landscape driving the resistant cells' survival and therefore identify novel targets that could be taken advantage of in future therapeutic strategies.
Citation Format: David Debruyne, Bandana Sharma, Nathanael Gray, Rani George. Resistance to ALK inhibition is associated with enhanced BRD4 dependence in ALK-mutated MYCN-amplified neuroblastoma. [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-C24.
Abstract PL03-05: Drugging RAS into oblivion
Authors: Verdine Gregory L. 
Published: May 2016

Abstract
The two major oncogenic drivers of human cancer, RAS and MYC, have thus far proven recalcitrant toward therapeutic targeting by any small-molecule agent. WarpDrive Bio has pioneered a potentially transformational solution toward drugging such recalcitrant oncogenic drivers using multiple independently acting agents. The company's proprietary new targeting technology, the Small Molecule-Assisted Receptor Targeting modality (SMART modalityTM), has enabled WarpDrive Bio to make significant progress toward the development of multiple agents that independently target RAS in the GTP and GDP states, respectively, and that are either selective for particular mutations or engage the effector surface and are expected to function as pan-RAS antagonists. Our strategy of targeting RAS using multiple agents, each of which engages the protein in a unique way, is ultimately intended to increase the durability of patient responses to anti-RAS therapy by decreasing the probability of mutational escape. Progress toward our ultimate goal of drugging RAS-driven cancers into oblivion via RAS-directed polypharmacy will be reviewed in this talk.
Citation Format: Gregory L. Verdine. Drugging RAS into oblivion. [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 PL03-05.
Abstract PL05-04: PARP trapping versus PARP catalytic inhibition and coupling with TDP1
Authors: Pommier Yves G. , Murai Junko 
Published: May 2016

Abstract
The five clinical PARP inhibitors (veliparib, olaparib, niraparib, rucaparib and talazoparib) are potent submicromolar competitive NAD+ inhibitors for PARP1 and PARP2, thereby blocking PARylation reactions [i.e. formation of poly(ADPribose) polymers]. In addition, PARP trapping, which determines the anticancer activity of PARP inhibitor as single agents, is drug-specific, and PARP inhibitors can be ranked according to their PARP trapping potency: talazoparib &gt;&gt; niraparib ≈ olaparib ≈ rucaparib &gt; veliparib. We will review evidence that PARP trapping is the primary cytotoxic mechanism of PARP inhibitors as single agents and that cancer-specific DNA repair alterations as well as SLFN11 expression determine the cytotoxicity of trapped PARP-DNA complexes in cancers beyond BRCA inactivation. Used in combination in cellular models, PARP inhibitors are highly synergistic with alkylating agent (temozolomide or methyl methanesulfonate) and topoisomerase I (Top1) inhibitors (camptothecin and its clinical derivatives (topotecan and irinotecan) and the non-camptothecin indenoisoquinoline Top1 inhibitors in clinical development (LMP400, LMP776 and LMP744). Both alkylating agents and Top1 inhibitors induce DNA single-strand breaks sensed by PARP. Yet, the molecular mechanisms of synergy are different. For alkylating agents (temozolomide and MMS), both PARP trapping and PARylation inhibition account for the synergy, whereas for Top1 inhibitors, there is no involvement of PARP trapping and it is PARylation inhibition that deters the coupling of PARP with the repair enzyme, tyrosyl-DNA phosphodiesterase, TDP1. We will review the molecular pharmacology differences between PARP inhibitors as single agents and the rationale for choosing among different PARP inhibitors in combination with alkylating agents or Top1 inhibitors based on trapping vs. catalytic inhibition.
Citation Format: Yves G. Pommier, Junko Murai. PARP trapping versus PARP catalytic inhibition and coupling with TDP1. [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 PL05-04.
Abstract PR04: Comprehensive analyses of tumor immunity with implications to cancer immunotherapies
Authors: Li Bo 
Published: May 2016

Abstract
Recent breakthrough in checkpoint blockade drugs achieved remarkable success in treating late stage tumors, although a substantial fraction of patients failed to respond. Despite growing efforts, the clinical and molecular prognostic predictors of immunotherapy response remain elusive. We developed a novel computational method to deconvolute six tumor-infiltrating immune cells from the molecular profiles of over 10,000 samples across 23 cancer types, and validated the estimates using simulations, orthogonal estimates, and pathology. Correlating the computationally-inferred immune infiltrates with patient clinical features, viral infection status, and cancer genetic alterations, we discovered associations not only extensively supported by previous studies, but also novel ones such as B cell infiltration with better outcome in glioblastoma. Analysis of cancer/testis antigen expression and CD8 T-cell abundance suggested that MAGEA3 is potentially effective in melanoma but not in NSCLC, and implicated CALR3 and SPAG5 as alternative cancer vaccine targets. We also observed PD-1 and CTLA4 expression to be associated with CD8 T-cell abundance in most cancers, supporting combined use of checkpoint blockade drugs. Finally, we found that melanomas expressing high levels of CTLA4 showed two distinct levels of CD8 T-cell infiltration, which may influence clinical responses to anti-CTLA4 agents. Taken together, our systematic analyses of tumor immunity have the potential to inform effective cancer vaccines and checkpoint blockade therapies.
Citation Format: Bo Li. Comprehensive analyses of tumor immunity with implications to cancer immunotherapies. [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 PR04.
Abstract A03: A brain cancer cell migration simulator based on a motor-clutch model
Authors: Bangasser Benjamin L. , Rosenfeld Steven R. , Odde David J. 
Published: May 2016

Abstract
WHO Grade IV astrocytoma, also known as glioblastoma, is an invasive disease where cell migration drives dispersion of tumor cells throughout the brain. To predict cell migration speeds in complex mechanochemical environments, we developed a cell migration simulator based on our published motor-clutch framework [1-3]. One of the key predictions of our previous modeling is that cell traction force is biphasic with respect to environmental stiffness, i.e. there is an optimal stiffness at which cell traction force is maximal. To test whether such optimality exists within a whole cell migration simulator, we extended our model to allow for multiple cellular protrusions in 1D, 2D, or 3D environments. The cell migration simulator imposes that forces balance and that masses of key elements- actin, adhesions, and myosin motors- are conserved. Using the Gillespie stochastic simulation algorithm implemented in matlab, we simulated cell traction force, F-actin retrograde flow, cell aspect ratio, and cell migration as a function of cell stiffness. We found that all four variables depends biphasically on simulated environmental stiffness with approximately overlapping optima. In addition, the model predicts that the optimal stiffness can be shifted by coordinate shifting of motor and adhesive clutch numbers, a prediction that we are now testing experimentally in vitro. Overall, our modeling results predict that effective anti-migratory treatment of patients will require knowledge of the cell migration speed landscape within parameter space. In particular, we predict that simultaneously inhibiting motors and clutches will be beneficial for patients whose tumors operate near the optimum, largely ineffective for those below the optimum, and potentially detrimental to those above the optimum. Thus, our cell migration simulator provides dynamic physical biomarkers that can potentially be used to classify glioblastoma patients for more precise treatment.
References:
1. Bangasser, B.L. and D.J. Odde, Master Equation-Based Analysis of a Motor-Clutch Model for Cell Traction Force. Cellular and Molecular Bioengineering, 2013. 6: p. 449-459.
2. Bangasser, B.L., S.S. Rosenfeld, and D.J. Odde, Determinants of maximal force transmission in a motor-clutch model of cell traction in a compliant microenvironment. Biophys J, 2013. 105(3): p. 581-92.
3. Chan, C.E. and D.J. Odde, Traction dynamics of filopodia on compliant substrates. Science, 2008. 322(5908): p. 1687-91.
Citation Format: Benjamin L. Bangasser, Steven R. Rosenfeld, David J. Odde. A brain cancer cell migration simulator based on a motor-clutch model. [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 A03.
Abstract A09: Effects of Podocalyxin on neural stem/progenitor cells
Authors: San Isabelle V. Leefa Chong , Prost Gaelle , Nuber Ulrike 
Published: May 2016

Abstract
Podocalyxin (PODXL) is a highly glycosylated and sialylated protein found mainly on podocytes and up-regulated in various types of tumors. Known to be a marker of hematopoietic progenitors and pluripotent stem cells, PODXL is also increasingly considered a marker of malignancy in several aggressive tumor types. Though the exact role of PODXL in tumors is not yet established, it has increasingly been shown in vitro to be involved in cell migration and invasion.
We found Podxl to be highly expressed in murine tumorigenic neural stem/progenitor cells. To investigate effects of elevated Podxl levels in neural stem/progenitor cells (NSPs), Podxl or an empty control construct were over-expressed in these cells. Podxl-overexpressing NSPs did not form brain tumors upon intracranial transplantations, indicating that high levels of this gene alone are not sufficient for tumorigenesis. In vitro studies however revealed how Podxl might contribute to the development and /or maintenance of tumors. Podxl overexpression had a positive effect on cell number, sphere formation and cell viability.
To find out how Podxl exerts its pro-survival effects, the proteome of Podxl-overexpressing and empty control NSPs was analysed by mass spectrometry. These experiments revealed an up-regulation of Annexin A2, a calcium-regulated phospholipid binding protein interacting with the cytoskeleton and extracellular matrix. In addition to elevated Annexin A2 protein levels, we also found increased transcript levels indicating that PODXL stimulates expression of the Annexin A2 gene. NSPs lacking Annexin A2 and overexpressing Podxl are less viable than wild type Podxl-overexpressing NSPs, suggesting that PODXL-mediated pro-survival effects can at least in part be explained by increased Annexin A2 levels. We are now investigating how Podxl and Annexin A2 mechanistically interact to enhance cell viability
Citation Format: Isabelle V. Leefa Chong San, Gaelle Prost, Ulrike Nuber. Effects of Podocalyxin on neural stem/progenitor cells. [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 A09.
Abstract A12: Genomically unstable glioblastoma are sensitive to Parp inhibition
Authors: McDonald Kerrie L. , Khasraw Mustafa , Jue Toni Rose , Joshi Swapna , Yin Julia 
Published: May 2016

Abstract
Background: The development of effective targeted drugs for the treatment of glioblastoma (GBM) represents a major unmet need. Veliparib (ABT-888; Abbvie) inhibits both PARP1 and PARP2 (poly[ADP-ribose] polymerase). The successful clinical application of veliparib and other PARP inhibitors (PARPi) will be assisted by the identification of predictive biomarkers.
Materials and Methods: We performed whole genome sequencing (WGS) on ten GBM specimens with matched normal DNA. Mutations were detected using qSNP and GATK and indels called with Pindel and GATK. Somatic structural variants were identified using the qSV package. For all ten specimens we developed patient derived cell lines (PDCLs). We tested the efficacy of the combination of veliparib and temozolomide (TMZ) on all of the PDCLs.
Results: Strikingly, in 2 patient samples denoted as G89 and G54, the mutation rate was at least 16-fold higher compared to the other 8 participants. G89 and G54 exhibited a large number of single nucleotide variants (SNVs), insertions, deletions and structural variant (SV) events (&gt;2 million) when compared to the other 8 patient samples. The scale of genomic instability suggested defects in DNA maintenance, which could potentially define sensitivity to DNA damaging agents. Upon closer examination of the mutational profile of G89 and G54, mutations were found in at least one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2. We also detected mutations in other genes involved in DNA maintenance such as XRCC4, FANCA, FANCD2, ATR, RPA1, REV3L and PARP1. We designated these patients' GBM as U-GBM class. We found the U-GBM class of tumors, G89 and G54 to be hypersensitive to the combination of TMZ/veliparib.
Conclusion: Mutations in DNA maintenance pathways may be a method for selecting patients for therapies involving the combination of DNA damaging agents such as radiotherapy, and PARP inhibitors. Additionally, the signature associated with genomically unstable GBM may be a method of identifying potential responders to PARP inhibitor therapy.
Citation Format: Kerrie L. McDonald, Mustafa Khasraw, Toni Rose Jue, Swapna Joshi, Julia Yin. Genomically unstable glioblastoma are sensitive to Parp inhibition. [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 A12.
Abstract A31: Cyclic NGR peptide functionalized PEG-PLGA nanoparticles as dual-targeting carrier for site specific antitumor drug delivery
Authors: Gupta Dr. Madhu , Sharma Dr. Vikas , Agrawal Prof. G.P. , Vyas Prof. S.P. 
Published: May 2016

Abstract
CD13 receptors are abundantly overexpressed in tumor cells as well as in neovasculature. The polymeric nanoparticles (NPs) as the nanomodules for anticancer drug carriers are well known. Nowadays, targeted delivery options are becoming a fascinating approach, so CD13 receptors was selected as a targeted site and NPs as a delivery system. By combining all the issue, a cyclic NGR (cNGR) peptide as a ligand was coupled on the terminal end of polyethylene glycol-b-poly(lactic-co-glycolic acid) (PEG-b-PLGA) and prepared the dual targeted polymeric NPs (cNGR-PEG-PTX-NPs) in order to enhance the intracellular delivery of anticancer drug to the tumor cells and tumor endothelial cells via ligand-receptor interaction. In-vitro cytotoxicity studies confirmed that the presence of cNGR enhanced the cytotoxic efficiency by 2.8 folds in human umbilical vein endothelial (HUVEC) cells, while cytotoxicity was improved by 2.6 folds in human fibrosarcoma (HT-1080) cells as compared to non-specific stealth NPs. Compared with other tested NPs, cNGR-PEG-PTX-NPs revealed more cytotoxicity by inducing more apoptosis, higher cell uptake and more G2/M phase arrest. The tumor volume inhibition rate was 59.7% in case of cNGR-PEG-PTX-NPs that was comparatively more with other formulations, indicating that cNGR-PEG-PTX-NPs could more effectively inhibit tumor growth. As a consequence, the cNGR-PEG-PTX-NPs play a key role in enhancing tumor therapeutic efficiency for treatment of CD13 receptor specific solid tumor.
Citation Format: Dr. Madhu Gupta, Sr., Dr. Vikas Sharma, Prof. G.P. Agrawal, Prof. S.P. Vyas. Cyclic NGR peptide functionalized PEG-PLGA nanoparticles as dual-targeting carrier for site specific antitumor drug delivery. [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 A31.
Abstract A32: Cell autonomous and cell non-autonomous roles of p75 neurotrophin receptor (p75NTR) in glioma invasion
Authors: Alshehri Mana , Ahn Bo Young , Wang Xiuling , Tanveer Shiekh , Chan Jennifer , Senger Donna L , Robbins Stephen M 
Published: May 2016

Abstract
Human glioblastoam is a heterogeneous tumor composed of tumor cells and a small population known as brain tumor initiating cells (BTICs) or glioblastoma stem-like cells. BTICs appear to drive tumor progression, underlie therapeutic resistance and have been highlighted as therapeutic targets for patients with malignant glioma. The ability of glioma cells to invade into the surrounding brain parenchyma is a major clinical issue rendering glioblastoma incurable by conventional therapies. In a previous study, we found that the p75 neurotrophin receptor (p75NTR) significantly enhanced invasion and migration of genetically distinct glioma by a cell autonomous mechanism. In addition, p75NTR was frequently observed in a highly invasive population of cells from freshly resected patient specimens. Importantly, p75NTR was found to mediate glioma invasion by neurotrophin-dependent regulated intramembrane proteolysis (RIP). Blocking of p75NTR proteolysis by the generation of cleavage-resistance mutants, or treatment of animals bearing p75NTR-postive intracranial tumors with γ-secretase inhibitors, significantly inhibited glioma invasion and prolonged survival. Using a large panel of patient-derived-BTICs we have investigated the role of p75NTR in the stem-like compartment. Here we investigate the biological effects of p75NTR down-regulation on glioma derived BTICs. Immunocytochemical studies western blot analysis reveal that p75NTR is variably expressed on BTICs and that treatment with γ-secretase inhibitors significantly decreases BTIC invasion in 3D cultures in vitro. Down-regulation of p75NTR using shRNA significantly decreases BTICs invasion, proliferation and self-renewal ability. Moreover, p75NTR was present on as a component of BTIC-derived extracellular vesicles (EVs) that are implicated in tumor cell invasion through a cell non-autonomous mechanism. We found that p75NTR containing EVs promote invasion of non-invasive glioma cells. The composition of p75NTR containing EVs and their roles in glioma invasion are currently been investigated.
Citation Format: Mana Alshehri, Bo Young Ahn, Xiuling Wang, Shiekh Tanveer, Jennifer Chan, Donna L Senger, Stephen M Robbins. Cell autonomous and cell non-autonomous roles of p75 neurotrophin receptor (p75NTR) in glioma invasion. [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 A32.
Abstract B12: GABP selectively binds and activates the mutant TERT promoter across multiple cancer types
Authors: Bell Robert J.A , Rube H. Tomas , Kreig Alex , Mancini Andrew , Fouse Shaun F. , Nagarajan Raman P. , Choi Serah , Hong Chibo , He Daniel , Pekmezci Melike , Wiencke John K. , Wrensch Margaret R. , Chang Susan M. , Walsh Kyle M. , Myong Sua , Song Jun S. , Costello Joseph F. 
Published: May 2016

Abstract
Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBM), harbor highly recurrent mutations in the TERT promoter specific to two nucleotide positions. The common mutation sites, G228A and G250A, may create de-novo ETS family transcription factor binding sites, but the precise mechanism of how these mutations confer increased TERT expression has been elusive. Here, we demonstrate the de-novo ETS motif to be critical for mutant TERT activation by site directed mutagenesis. A focused siRNA screen of the many ETS transcription factors expressed in GBM identifies GABPA as the single ETS factor to selectively regulate the mutant but not the wild type TERT promoter. Single molecule binding assays and ChIP-qPCR analysis reveal that GABPA is exclusively recruited to the mutant allele in vitro and in vivo respectively. Furthermore, this allelic recruitment is consistent across four tested cancer types, highlighting a shared mechanism underlying mutant TERT promoter activation. Tandem flanking native ETS motifs critically cooperate with these mutations to activate TERT, likely by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression and may provide a novel therapeutic target for multiple cancers.
Citation Format: Robert J.A Bell, H. Tomas Rube, Alex Kreig, Andrew Mancini, Shaun F. Fouse, Raman P. Nagarajan, Serah Choi, Chibo Hong, Daniel He, Melike Pekmezci, John K. Wiencke, Margaret R. Wrensch, Susan M. Chang, Kyle M. Walsh, Sua Myong, Jun S. Song, Joseph F. Costello. GABP selectively binds and activates the mutant TERT promoter across multiple cancer types. [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 B12.