bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4317: PTEN-null tumors cohabiting the same lung display differential Akt activation and sensitivity to dietary restriction.
Authors: Curry Natasha L. , Mino-Kenudson Mari , Oliver Trudy G. , Yilmaz Omer H. , Yilmaz Vedat O. , Moon Jade , Jacks Tyler , Sabatini David M. , Kalaany Nada Y. 
Published: August 2014

Abstract
PTEN loss is considered a biomarker for activated PI3K/Akt, a pathway frequently mutated in cancer, and recently shown to confer resistance to dietary restriction (DR). Here we demonstrate that PTEN loss is not sufficient to drive Akt activation and resistance to DR in tumors with low growth factor receptor levels. We describe a murine PTEN-null Kras-driven lung cancer model that harbors both DR-resistant, higher-grade, bronchiolar tumors with high-Akt-activity, and DR-sensitive, lower-grade, alveolar tumors with low-Akt-activity. We find that this phenotype is cell-autonomous and that normal bronchiolar cells express higher levels of IGF1R and ENTPD5, an endoplasmic reticulum (ER) enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF1R levels and sensitize bronchiolar tumor cells to serum in vitro and to DR in vivo. Furthermore, we find that a significant percentage of human non-small cell lung cancer (NSCLC) have low Akt activity despite PTEN loss. Our studies point to a heterogeneity of Akt activation in the same murine PTEN-null lung tissue, as well as in human NSCLC, underscoring the challenges facing personalized cancer therapy based solely on cancer genotype. They further indicate that the tumor response to anti-cancer therapies, including DR, needs to be based upon PI3K/Akt activity per se, rather than genetic alterations in the PTEN/Akt pathway.
Citation Format: Natasha L. Curry, Mari Mino-Kenudson, Trudy G. Oliver, Omer H. Yilmaz, Vedat O. Yilmaz, Jade Moon, Tyler Jacks, David M. Sabatini, Nada Y. Kalaany. PTEN-null tumors cohabiting the same lung display differential Akt activation and sensitivity to dietary restriction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4317. doi:10.1158/1538-7445.AM2013-4317
Abstract 4325: Monoclonal antibodies to transmembrane proteins.
Authors: Brown Michael C. , Chambers Ross , Onisk Dale V. , Joaquim Tony R. , Stafford Lewis J. , Lindpaintner Klaus , Keter Daniel , Stave James W. 
Published: August 2014

Abstract
Transmembrane proteins, including multipass transmembrane proteins like GPCRs and ion channels, are important targets for therapeutic monoclonal antibody (mab) discovery. Therapeutic antibodies to this class of proteins are generally targeted to extracellular domains displayed on the surfaces of living cells. Challenges associated with developing antibodies to this class of targets are small numbers of extracellular amino acids, membrane-dependent protein conformation, difficulty in expression at high levels, high amino acid sequence homology of human and mouse proteins, and post-translational modifications. DNA immunization strategies with full-length constructs and high throughput flow cytometry screening of mab binding to transfected and control cells was used to generate and identify large numbers of mabs to CXCR4 and ADORA2A (GPCRs) and CD20 (a tetraspan membrane protein). Panels of mabs were generated for all 3 targets with low numbers of hybridoma fusions. For each target the mab gene sequences were shown to be unique and contain levels of somatic hypermutation comparable to existing benchmark therapeutic antibodies. Epitope mapping with mutant proteins identified diverse patterns of reactivity including known and novel specificities. Functional assays including apoptosis and receptor modulation (calcium flux and cAMP modulation) further demonstrated that the technical approach generated diverse panels of antibodies that exhibit functional activity as good or better than existing benchmark therapeutic antibodies
Citation Format: Michael C. Brown, Ross Chambers, Dale V. Onisk, Tony R. Joaquim, Lewis J. Stafford, Klaus Lindpaintner, Daniel Keter, James W. Stave. Monoclonal antibodies to transmembrane proteins. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4325. doi:10.1158/1538-7445.AM2013-4325
Abstract 4331: Advantages of polyacetal polymer-based antibody drug conjugates employing cysteine bioconjugation.
Authors: Yurkovetskiy Alex , Bodyak Natalya , Yin Mao , Thomas Joshua , Conlon Patrick , Stevenson Cheri , Uttard Alex , Qin Liu , Gumerov Dmitry , Ter-Ovaneysan Elena , DeVit Michael , Lowinger Timothy B. 
Published: August 2014

Abstract
The application of polymers to antibody drug conjugate (ADC) design and preparation can provide numerous advantages, including 1) significantly higher capacity for drug payload; 2) utilization of alternative payloads not suitable for direct conjugation approaches; 3) improvement of physicochemical properties of resulting ADCs; 4) utilization of protein recognition scaffolds beyond the commonly used IgGs; and 5) improvements in PK and biodistribution. Herein we present results of a novel, biodegradable polyacetal polymer-based conjugation system to create next-generation ADCs. The basis of this new conjugation system is a hydrophilic, fully biodegradable polyacetal carrier (PHF or poly(1-hydroxymethylethylene hydroxymethylformal) modified with chemically orthogonal linkers. One linker is used to covalently attach a targeting moiety (mAb or alternative) via cysteine conjugation, while a second, chemically distinct linker is used to attach a drug payload and to control the mechanism and rate of drug release.
Previously we have reported highly efficacious polyacetal ADCs prepared by utilizing random lysine modification. In this report we present an alternative cysteine-based bioconjugation strategy. Conventional, direct drug-cysteine linked ADCs are destabilized due to loss of inter-chain disulfide bridges. In contrast, the polyacetal polymer conjugated via cysteines in the antibody hinge region stabilizes the resulting ADCs through the formation of inter-chain bridge structures.
To demonstrate the benefits of this approach, we prepared Her-2 targeted ADCs with protein recognition scaffolds ranging in size from 15 kDa to 150 kDa, all targeting the Her-2 antigen, and bearing an anti-tubulin agent as the drug payload. ADCs were highly active and selective in vitro in Her-2 expressing cell lines. These polyacetal cysteine-based ADCs exhibited prolonged plasma and tumor exposure in the Her-2 expressing BT474 mouse xenograft model and tumor-specific accumulation. The ADCs were well-tolerated, and resulted in 100% tumor-free survivors.
Citation Format: Alex Yurkovetskiy, Natalya Bodyak, Mao Yin, Joshua Thomas, Patrick Conlon, Cheri Stevenson, Alex Uttard, Liu Qin, Dmitry Gumerov, Elena Ter-Ovaneysan, Michael DeVit, Timothy B. Lowinger. Advantages of polyacetal polymer-based antibody drug conjugates employing cysteine bioconjugation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4331. doi:10.1158/1538-7445.AM2013-4331
Abstract 4333: Self-stabilizing ADCs: antibody-drug conjugates prepared with maleimido drug-linkers that catalyze their own thiosuccinimide ring hydrolysis.
Authors: Lyon Robert P. , Setter Jocelyn R. , Bovee Tim D. , Doronina Svetlana O. , Anderson Martha E. , Leiske Chris L. , Senter Peter D. 
Published: August 2014

Abstract
Many antibody-drug conjugates (ADCs) currently in clinical trials employ maleimide-containing drug-linkers which are conjugated to antibody cysteine residues to form thiosuccinimide linkages. It is now known that these thiosuccinimide linkages can undergo two competing reactions while in plasma: elimination of the maleimide resulting in undesirable loss of drug from the ADC, and hydrolysis of the thiosuccinimide ring resulting in a succinic acid derivative which cannot undergo elimination. Thus, thiosuccinimide ring hydrolysis is a reaction which stabilizes the chemical linkage of the drug to the antibody. We have engineered a new class of drug-linkers which incorporate a basic amino group adjacent to the maleimide, providing intramolecular base catalysis of the ring hydrolysis. This basic group induces the thiosuccinimide to undergo rapid self-catalyzed hydrolysis at neutral pH and room temperature, with complete hydrolysis achieved in less than 2 hours. Once hydrolyzed, the drug-linker is no longer subject to maleimide elimination reactions, preventing loss of drug from the antibody by this mechanism and forming a highly stable ADC. To compare these new drug-linkers to traditional maleimido drug-linkers, a number of in vitro and in vivo studies have been conducted. Results of these studies will be presented to demonstrate a robust improvement in drug-linker stability compared to traditional drug-linker formats.
Citation Format: Robert P. Lyon, Jocelyn R. Setter, Tim D. Bovee, Svetlana O. Doronina, Martha E. Anderson, Chris L. Leiske, Peter D. Senter. Self-stabilizing ADCs: antibody-drug conjugates prepared with maleimido drug-linkers that catalyze their own thiosuccinimide ring hydrolysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4333. doi:10.1158/1538-7445.AM2013-4333
Abstract 434: Radiation-induced matrix metalloprotease-9 promotes mesenchymal transition of Daoy cells and initiates activation of pro-matrix metalloprotease-2.
Authors: Nalla Arun Kumar , Asuthkar Swapna , Dasari Venkata Ramesh , Rao Jasti S. 
Published: August 2014

Abstract
Ionizing radiation is an efficient therapeutic modality against cancer and a potent carcinogenic agent with the ability to alter cellular genotype. Earlier, we reported that medulloblastoma cells exposed to ionizing radiation showed enhanced invasive and adhesive characteristics. Invasion is the cumulative effort of cells to degrade the extracellular matrix (ECM) and to modulate cellular phenotype to invade the ECM. Therefore, we examined the modulation gained by irradiated medulloblastoma cells leading to enhanced invasiveness. Radiation-induced invasion increased with the increase in the recovery time after radiation treatment and was identified to be associated with MMP-9/MMP-2 activity. Radiation enhanced the expression of MMP-9 and induced the cleavage of pro-MMP-2 into active form, and the latter was associated with MT-MMP-1 expression. A significant time lag observed between the radiation exposure time and MMP-2 activation was identified as a period required for the irradiated cells to acquire cellular alteration, such as mesenchymal characteristics. Recombinant protein(s) and inhibitor(s) studies demonstrated that radiation-induced MT-MMP-1 expression and MMP-2 activation are in harmony with JNK activation. MMP-9 gene silencing and protein supplementation studies confirmed that MMP-9 activates JNK signaling and potent inducers of mesenchymal markers such as Snai1 and N-Cadherin. Further, gene-specific silencing of either MMP-9 or N-Cadherin showed significant reduction of MMP-2 activation in irradiated Daoy cells. Collectively, our results provide an insight on the role of MMP-9 in radiation-induced invasion and in initiating signaling cascades that modulate Daoy cells to acquire mesenchymal characteristics and activate MMP-2.
Citation Format: Arun Kumar Nalla, Swapna Asuthkar, Venkata Ramesh Dasari, Jasti S. Rao. Radiation-induced matrix metalloprotease-9 promotes mesenchymal transition of Daoy cells and initiates activation of pro-matrix metalloprotease-2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 434. doi:10.1158/1538-7445.AM2013-434
Abstract 4346: Formulation and characterization of a nanoparticulate drug delivery system for cancer therapy.
Authors: Desai Kunal P. , Patel Jay V. , Do Duc P. 
Published: August 2014

Abstract
Most anticancer agents are not targeted to neoplastic cells. As a result, the development of dosage forms and drug delivery systems containing anticancer drugs capable of targeting cancer cells is highly desired. Our research investigated an albumin-based nanoparticulate delivery system as a platform technology for the delivery of anticancer agents. Doxorubicin hydrochloride was used as the model drug. Drug-encapsulated nanoparticles were prepared by microencapsulation through spray-drying and were characterized for their physicochemical properties. Raman spectroscopy was used to investigate the stability of the encapsulated drug. Additionally, Zeta potential measurements were used to assess the colloidal stability and surface properties of the nanoparticles. Dissolution studies were carried out to examine the release profile of the drug from the nanoparticles. The in vitro efficacy of the drug-loaded nanoparticulate drug delivery system was analyzed in MCF-7 breast cancer cell line. Raman spectroscopy data suggested that the drug is stable in the nanoparticulate drug carrier. Nanoparticles have Zeta potential measurements of approximately -30 mV, suggesting that the system is stable in an aqueous environment. Dissolution studies showed that the drug was released from the nanoparticles at a sustained rate over a period of over 24 hours. In vitro data in MCF-7 cell line indicated that there was more than 10% more inhibition of cell viability when doxorubicin was used with the biodegradable polymeric carrier. Similar results were observed from clonogenic studies. Additionally, our in vitro data suggested that cell death induced by the drug-loaded nanoparticles was caused by apoptosis. Hence, the data suggest that biodegradable albumin nanoparticles are capable of targeting cancer cells.
Citation Format: Kunal P. Desai, Jay V. Patel, Duc P. Do. Formulation and characterization of a nanoparticulate drug delivery system for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4346. doi:10.1158/1538-7445.AM2013-4346
Abstract 437: ATM regulates glioma migration via MEK-ERK not AKT.
Authors: Allen Jasmine L. , Wagner Allison F. , Beckta Jason M. , Watson James , Golding Sarah E. , Valerie Kristoffer C. 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is a lethal brain cancer with a life expectancy of only 12-15 months. Current standard treatment for GBM is surgery and chemoradiation. However, there are many difficulties when it comes to treating this aggressive brain cancer due to the inherent radio- and chemo-resistance. Consequently, there is a critical need for new therapeutic approaches to make radiation/chemotherapy more effective. Ataxia telangiectasia (A-T) patients are extremely sensitive to ionizing radiation. The protein mutated in A-T, ATM (A-T mutated), controls the cells’ response to radiation, referred to as the DNA damage response (DDR). ATM is a master protein kinase that targets many proteins during the DDR including regulators of cell cycle checkpoints, DNA repair, and apoptosis. In addition, without any radiation, ATM might regulate glioma dispersal. Using a highly specific inhibitor of the ATM kinase (ATMi), we recently showed that ATM regulates both the ERK and AKT signaling pathways and controls glioma cell migration and invasion in vitro. To take these studies further we have now used a genetic approach and knocked down ATM in human glioma cells. We have recapitulated our previous finding with an ATMi and shown that ATM knockdown glioma cells have reduced ability to migrate in vitro. In order to determine whether MEK/ERK and/or AKT regulate migration, human glioma cells were exposed to a MEK (PD0325901) or an AKT (MK-2266) inhibitor in a ‘scratch-assay’. We found that only the former compound affected migration in vitro. Hence, we have shown that ATM regulates glioma migration in vitro, perhaps via MEK/ERK. On the other hand, ATM might regulate invasion via AKT. The signaling relationship in vitro between ATM, ERK, and AKT is currently being investigated. Furthermore, ongoing studies will establish whether ERK and AKT signaling affect migration and invasion in vivo.
Citation Format: Jasmine L. Allen, Allison F. Wagner, Jason M. Beckta, James Watson, Sarah E. Golding, Kristoffer C. Valerie. ATM regulates glioma migration via MEK-ERK not AKT. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 437. doi:10.1158/1538-7445.AM2013-437
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4370: Protein kinase inhibitor screening uncovers differential kinase dependencies in triple negative breast cancer (TNBC).
Authors: Fink Lauren S. , Beatty Alexander , Devarajan Karthik , Peri Suraj , Peterson Jeffrey R. 
Published: August 2014

Abstract
Triple-negative breast cancer (TNBC) constitutes approximately 20% of all breast cancer and disproportionately affects younger women and African-American women. These tumors, negative for estrogen receptor, progesterone receptor, and Her2 amplification, are resistant to standard targeted treatments, and the need for new therapeutic targets for this tumor type is urgent. Within the TNBC patient population, there is variability in response to treatment, and it is unclear what molecular features of the disease lead to this heterogeneity. Protein kinases are often amplified and/or mutated in human cancers, and they are attractive therapeutic targets due to their enzymatic activity and widespread expression. We have screened a library of small-molecule kinase inhibitors against a panel of 12 TNBC cell lines and 3 control cell lines in duplicate in cell viability assays. We generated dose-response curves and half maximal inhibitory concentration (IC50) values for each compound-cell line pair. The results support a heterogeneous dependence of different TNBC cell lines on specific kinases. Statistical analysis identifies significantly over-represented kinase targets and pathways in subsets of TNBC cell lines following inhibitor treatment. A number of compounds show selective toxicity for TNBC cell lines and suggest targetable kinase dependencies. Kinase inhibitor sensitivity in TNBC does not appear to correlate with gene expression patterns, suggesting alternative mechanisms for TNBC heterogeneity. Sequencing data and other biomarkers databases will be mined for correlations with sensitivity to kinase inhibition in TNBC. Thus this study will identify new potential therapeutic targets and biomarkers for TNBC.
Citation Format: Lauren S. Fink, Alexander Beatty, Karthik Devarajan, Suraj Peri, Jeffrey R. Peterson. Protein kinase inhibitor screening uncovers differential kinase dependencies in triple negative breast cancer (TNBC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4370. doi:10.1158/1538-7445.AM2013-4370
Abstract 4377: The Golgi protein GLG1 coordinates ARF3 activation in tumor cells.
Authors: Planche Anne 
Published: August 2014

Abstract
Increasing evidence suggests that endocytosis and membrane trafficking are deregulated in cancer cells. Because of their dependence on selected signaling pathways, tumor cells may need to rely on accelerated receptor recycling and increased secretion of a variety of molecules such as matrix components, adhesion molecules and growth factors. Mass spectrometry analysis of proteins associated with separase, recently shown to be an important regulator of membrane trafficking, identified the Golgi apparatus protein 1 (GLG1). GLG1 is primarily known as an E-selectin ligand that mediates the initial step of tethering and rolling of leukocytes on vascular endothelium. We therefore addressed the possibility that GLG1 could play a similar role in circulating tumor cells, facilitating arrest and extravasation into adjacent tissues. Consistent with this possibility, tail vein injection of stably GLG1-depleted tumor cells into NOD/SCID mice resulted in reduced numbers of metastatic nodules. Moreover, metastatic tumor growth was almost exclusively intravascular, indicating impaired extravasation of tumor cells. Further investigation, however, showed that, in tumor cells, GLG1 is almost exclusively localized to the Golgi apparatus, challenging the notion that it plays a direct role in mediating tumor cell adhesion to endothelium as in leukocytes.
To elucidate the molecular mechanisms by which GLG1 could affect tumor cell migration through interactions at the Golgi level, we conducted various experiments using GLG1-depleted human tumor cell lines. Transient silencing of GLG1 by siRNA was observed to modify cell shape (elongated morphology), to reduce migration of a range of tumor cell lines and to markedly alter Golgi architecture. Interestingly, subsequent experiments led to the identification of a new interactor of GLG1, the Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1), an ARF-GEF required to initiate membrane vesicle formation at the trans-Golgi compartment by promoting guanine-nucleotide exchange on ARF1 and ARF3. GLG1 was shown to participate in BIG1 and ARF3 recruitment to the Golgi membrane and subsequent ARF3 activation. Surprisingly, the observed morphological disruption of the Golgi apparatus and reduced ARF3 activation did not affect the secretory pathway in general, but rather seemed to impair secretion of selected molecules including MMP-9.
Taken together, our observations provide insight into a novel and specific role of GLG1 in tumor progression by affecting, thanks to its privileged position in the secretory pathway, trafficking of key molecules implicated in cell migration.
Citation Format: Anne Planche. The Golgi protein GLG1 coordinates ARF3 activation in tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4377. doi:10.1158/1538-7445.AM2013-4377