bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-95: Construction and application of elastin-like polypeptide containing IL-4 receptor targeting peptide.
Authors: Devi Sarangthem Vijaya , Park Rang-Woon 
Published: August 2014

Abstract
Cancer cells express a number of cell surface and matrix proteins that mediate tumor growth, migration, invasion, and metastasis. Screening for ligands that specifically target these molecules represents an excellent cancer therapy strategy. AP1 is a recently discovered peptide, homing onto atherosclerotic plaques and breast tumor tissues through selective binding to the interleukin 4 receptor (IL-4R). IL-4Rs are highly expressed in a variety of human tumors and it has been reported that IL-4/IL-4R interactions amplify the expression of some anti-apoptotic proteins thereby preventing drug-induced cancer cell death. Thus, targeting the IL-4R could possibly increase the therapeutic efficacy of anticancer drugs. Even though AP1 peptide possesses high target specificity and efficient tumor-homing, it has limitation due to easy elimination from the circulation and short half-life. To improve the binding affinity of AP1 and its avidity towards the IL-4R as well as its half-life, we incorporated multiple AP1 peptides into the elastin-like polypeptides (ELPs). Tandem repeats of ELP polymers containing AP1 peptide (AP1-ELPs) were prepared by using recursive directional ligation (RDL) method. The fluorescence-labeled A6V72, an AP1-ELP containing six AP1 units displayed superior binding ability to the IL-4R expressing cancer cell lines, H226 and MDA-MB-231. Surface plasmon resonance analysis showed that multivalent presentation of the targeting ligand AP1 in the ELP polymer backbone increased binding affinity to IL-4R approximately ~10, 000-fold compared to the free AP1 peptide, which is important for tumor targeting approach. The binding of AP1-ELPs was remarkably reduced when IL-4Rs were blocked with antibody against IL-4 receptor. Confocal microscopic imaging revealed the increased accumulation and uptake of A6V72 than V84 control ELP by H226 cells. Furthermore, the Cy5.5-labeled AP1-ELP showed excellent homing and longer retention in xenografted tumor tissues in mouse model. Immunohistological analysis of excised tumor tissues further verified the targeting of AP1-ELP to tumor. The present results imply that the AP1-ELPs can serve as novel carriers for effective delivery of therapeutic drugs to tumors.
Citation Format: Sarangthem Vijaya Devi, Rang-Woon Park. Construction and application of elastin-like polypeptide containing IL-4 receptor targeting peptide. [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 LB-95. doi:10.1158/1538-7445.AM2013-LB-95
Abstract SY03-01: Genotypic and phenotypic features of de novo and acquired resistance to cancer therapies.
Authors: Dancey Janet E. 
Published: August 2014

Abstract
Drug resistance is the single cause of cancer treatment failure resulting in cancer related death. Despite its paramount importance, our mechanistic understanding and means of circumventing cancer drug resistance is limited. In the current era, the evolutionary processes in cancer development and progression have been elucidated and provide insights into the biology of cancer and in particular cancer heterogeneity. However, our understanding of the contribution of evolutionary processes and tumor heterogeneity to the development of drug resistance is limited. As a result, our ability to translate knowledge into effective clinical strategies is similarly limited and remains largely on the use combination chemotherapy based on Goldie and Coldman's principles first described in 1984. Pragmatically, resistance may be de novo (i.e. treatment has no effect) or acquired (i.e. treatment had initial effect but tumors eventually progress due to repopulation by resistant cells). De novo resistance is thus equivalent to primary refractoriness and acquired resistance is emergent in the presence and presumably as a direct response to the selective pressures imposed by therapy. Mechanisms of resistance may be divided into various categories; however, a simple construct is to consider resistance as a manifestation of failure of one or more of the following: drug delivery, drug uptake, drug-target interaction and cellular response and cellular adaptation. Genetic, epigenetic, physiochemical and spatial properties of cancers may contribute to drug resistance and it is likely that different mechanisms of drug resistance develop concomitantly. The most important challenge is how to tackle the interrelated problems of tumor genetic and epigenetic heterogeneity and drug resistance in cancer using rational drug selections. The identification of tumor dependencies driven by dominant oncogenes, hormones, or metabolites may prove vulnerable to regimens designed to intercept them assuming dependencies are identifiable, targets or target pathways are “druggable” and such agents and combinations are tolerable and effective for cancer patients. Although the issues are complex, they can and should be addressed. Serial and comprehensive sampling to identify genetic and epigenetic changes of tumor to guide drug therapy will be required as will identifying susceptibilities such as oncogene addiction, synthetic lethality and genomic instability. Rational selection of drug dose, schedule and combination partners can follow. Treatment advances will occur to the extent that mechanisms of resistance can be identified or predicted and circumvented.
Citation Format: Janet E. Dancey. Genotypic and phenotypic features of de novo and acquired resistance to cancer therapies. [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 SY03-01. doi:10.1158/1538-7445.AM2013-SY03-01
Abstract SY06-01: Targeting IAP proteins for the treatment of cancer.
Authors: Vucic Domagoj 
Published: August 2014

Abstract
Evasion of cell death is a characteristic feature of human cancers and represents a key cause of resistance to current treatment approaches. Therefore, reactivation of cell death programs in cancer cells is a promising strategy to overcome treatment resistance, one of the major unsolved problems in clinical oncology. Inhibitor of apoptosis (IAP) protein family members block cell death in response to diverse stimuli and are expressed at elevated levels in the majority of human malignancies, which makes them attractive targets for developing a novel class of cancer therapeutics. We have designed small-molecule IAP antagonists (smac mimetics) that bind with high affinities to select baculovirus IAP repeat (BIR) domains of IAPs resulting in a dramatic induction of c IAP auto-ubiquitination activity and rapid proteasomal degradation. IAP antagonists inhibit tumor growth in vivo as single agents and in combination with a number of anti-tumor agents. Using several different proteomic approaches we have discovered novel binding partners for IAP proteins and determined the spatial and temporal pattern of endogenous IAP-mediated ubiquitination during proliferative, apoptotic and necrotic signaling. The differential expression levels and posttranslational modifications of identified proteins will be used to build diagnostic profiles for the treatment with IAP antagonists. These compounds can be used in the treatment of malignancies in which IAP expression contributes to tumor progression and resistance to conventional chemotherapeutic agents.
Citation Format: Domagoj Vucic. Targeting IAP proteins for the treatment of cancer. [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 SY06-01. doi:10.1158/1538-7445.AM2013-SY06-01
Abstract SY28-02: Tumor targeting with antimitotic monoclonal antibody drug conjugates.
Authors: Senter Peter 
Published: August 2014

Abstract
Monoclonal antibodies (mAbs) have played a major role in cancer medicine, with active drugs such as trastuzumab, cetuximab, bevacizumab and rituximab in a wide range of therapeutic applications. The mechanism of activity of these agents involves cell signaling, effector functions through interactions with Fcγ receptor positive cells, and complement fixation. The activity of mAbs can be enhanced through the generation of antibody drug conjugates (ADCs) that are capable of delivering cytotoxic agents with some degree of selectivity to tumor cells. Early work in this field involved the use of clinically approved anticancer drugs that generally were low in potency. Consequently, the resulting ADCs had suboptimal activities. Because of this, significant attention was directed towards the identification of appropriate drugs for targeted delivery, the most successful being antimitotic drugs such as monomethyl auristatin E (MMAE), and maytansinoids. These drugs inhibit tubulin polymerization and arrest cell growth in a cell-cycle dependent manner. Successful delivery of these agents requires drug, linker, and conjugation optimization, in addition to judicious selection of an antigen target on tumor cell surfaces. Brentuximab vedotin, a conjugate comprised of the anti-CD30 mAb cAC10 conjugated with MMAE through a highly stable peptide linker, is an example of how addressing these considerations can lead to ADCs with pronounced clinical efficacy. In August 2011, brentuximab vedotin received accelerated approval by the US Food and Drug Administration for use in relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, two diseases with significant unmet medical needs. An overview of how this targeted antimitotic drug was developed and how we are extending the technology will be provided.
Citation Format: Peter Senter. Tumor targeting with antimitotic monoclonal antibody drug conjugates. [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 SY28-02. doi:10.1158/1538-7445.AM2013-SY28-02
Abstract SY36-03: Hijacking homeostatsis: How heterogeneity drives tumor progression and treatment failure.
Authors: Anderson Alexander RA 
Published: August 2014

Abstract
Heterogeneity in cancer is an observed fact, both genotypically and phenotypically. Cell-cell variation is seen in almost all aspects of cancer from early development all the way through to invasion and subsequent metastasis. Our current understanding of this heterogeneity has mainly focused at the genetic scale with little information on how this variation translates to actual changes in cell phenotypic behavior. Given that many genotypes can lead to the same cellular phenotype, it is important that we quantify the range and scope of this heterogeneity at the phenotypic scale as ultimately this variability will dictate the aggressiveness of the tumor and its treatability. Central to our understanding of this heterogeneity is how the tumor cells interact with each other and with their microenvironment. Since it is these very interactions that drive selection and that ultimately define the ecology of the tissue in which the tumor is developing. Considering an organ as an ecological system, means that we should view normal tissue homeostasis as an equilibrium that cancer cells must disrupt if they are to be successful. Disruption of this equilibrium is often one of the first events in cancer development, as the normal control mechanisms of the tissue are damaged or ignored. We will discuss the interplay between homeostasis, heterogeneity, evolution and ecology in cancer progression and treatment failure with an emphasis on the metabolism of breast cancer.
Citation Format: Alexander RA Anderson. Hijacking homeostatsis: How heterogeneity drives tumor progression and treatment failure. [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 SY36-03. doi:10.1158/1538-7445.AM2013-SY36-03
Abstract A26: Role of Dermcidin in Tumorigenesis of Skin Cancers
Authors: Sangiuliano Beatriz A. , Perez Marcela Nancy , Cadurin Aline , Aguiar Andrew , Moreira Dayson F. , Belizario Jose E. 
Published: August 2014

Abstract
Dermcidin (DCD) is a candidate oncogene localized at 12q13.1. It is produced by benign melanocytic naevi and dark cells of eccrine sweat glands and proteolytic processed and transported via sweat to the epidermal surface to act as peptide antibotic, but it is not induced under inflammation. We have established the role of DCD in melanoma growth and survival by silencing DCD expression in human melanoma G361 cell line and overexpression in murine melanoma B16 cell line. Downregulation of DCD in G-361 cell line significantly reduced cellular resistance to cytotoxic agents. Balb/c Nude mice inoculated with 1x106 G-361 cells underwent a progressive increase in the tumor size and body weight loss, whereas animals inoculated with G-361-IBC I melanoma cells expressing DCD shRNA, we observed a significant difference in tumor volumes. Moreover, administration of rabbit polyclonal antibody against DCD in mice bearing G361 xenografts for four weeks delayed tumor growth. To examine tumor heterogeneity we isolated by FACS cell sorting specific cancer-stem cell populations based on cell size and enhanced tumorigenic capacity in Nude mice. In parallel, we are employing the microarray and exome methodologies to define genes that are up- and downregulated, patterns of genetic modifications and gene mutation in specific oncogenic pathways to evaluate the hypothesis that DCD control multiple oncogenic stimuli (EGFR/HER2, C-MYC, PI3K/AKT/mTOR, VEGF, BRAF/RAS, etc.). We will summarize these results and highlight genetic and biological mechanisms suggesting that DCD functions as tumor growth and cell survival factor.
Citation Format: Beatriz A. Sangiuliano, Marcela Nancy Perez, Aline Cadurin, Andrew Aguiar, Dayson F. Moreira, Jose E. Belizario. Role of Dermcidin in Tumorigenesis of Skin Cancers [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A26.
Abstract A35: Discovery of driver-type therapeutic targets to reverse glucocorticoid resistance in T-ALL
Authors: Yu Jiyang , Piovan Ericah , Flaherty Maria Sol , Silva Jose , Ferrando Adolfo , Califano Andrea 
Published: August 2014

Abstract
Glucocorticoid (GC) resistance is a major driver of therapeutic failure in T-cell acute lymphoblastic leukemia (T-ALL). Here we developed a systems biology framework, Network-based Bayesian Inference of Disease Drivers (NetBID2), using transcriptomic data, to predict signaling or regulatory factors driving GC-resistance in T-ALL. With this algorithm, we identified the AKT1 kinase as a signaling modulator of GC-resistance. Mechanistically, AKT1 directly phosphorylates the glucocorticoid receptor (GCR) NR3C1 protein at position S134 and blocks glucocorticoid-induced NR3C1 translocation to the nucleus. Consistently, pharmacologic inhibition of AKT1 increases the response of T-ALL cells to glucocorticoid therapy and effectively reverses glucocorticoid resistance in vitro and in vivo. These results warrant the clinical testing of ATK1 inhibitors and glucocorticoids in combination for the treatment of T-ALL.
Genome-wide RNA interference screening emerges as a powerful tool for loss-of-function studies and searching for new therapeutic targets of diseases. We integrated this technology with our computational framework and identified 16 master regulators of GC-resistance in T-ALL, when repressed, sensitizing resistant cells. Out of 16 candidates, 13 were validated in vitro, and 10 outperformed positive controls. Moreover, 75% of only predicted drivers demonstrated significant effects on changing GC-sensitivity. Network analysis of validated drivers indicated that they might work cooperatively to induce resistance, suggesting potential combinatorial therapies to reverse GC-resistance in T-ALL.
Citation Format: Jiyang Yu, Ericah Piovan, Maria Sol Flaherty, Jose Silva, Adolfo Ferrando, Andrea Califano. Discovery of driver-type therapeutic targets to reverse glucocorticoid resistance in T-ALL [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A35.
Abstract A4: Two dimensional chemical interrogation of oncogenic systems and multi-omics integration of signatures reveals novel signaling pathways involved in the pathophysiology of cancer
Authors: Vishnudas Vivek K. , Du Min , Akmaev Viatscheslav , Sarangarajan Rangaprasad , Narain Niven R. 
Published: August 2014

Abstract
Oncogenic events involve activation of kinases either in case of direct mutation or as a secondary event as recipients and mediators of oncogenic signals. Kinases transduce signals that lead to cell proliferation or inhibition of programmed cell death by activating transcription factors and inhibiting pro apoptotic molecules. Despite the knowledge and huge market for the kinases as targets, small molecule modulators have failed repeatedly to deliver as cancer therapeutics. Primarily, the failure is thought to stem from the lack of kinase discovery platforms that enable a mechanistic understanding of signaling pathways involving transmembrane and cytoplasmic kinases. The Berg Interrogative Biology® Kinase Discovery Platform offers novel technology driven solutions for understanding of kinases in oncogenesis. The approach is powered by “two-dimensional chemical interrogation” where in vitro cancer and control models were interrogated by a kinase inhibitor (sorafenib) in the first dimension. Overall changes in kinase activity were captured by a second dimension of chemical interrogation employing activity-based kinase enrichment probes. Kinases were identified by LC-MS based mass spectrometry. In addition, changes in phospho proteome in response to kinase inhibitor were captured using a phosphoprotein enrichment method followed by LC-MS for identification of proteins. Finally quantitative changes in total protein expression were obtained. Multi-omics data collated from the above mentioned approach was integrated using an AI-based informatics tool leading to generation of data-driven inference of causal networks representing differential kinase activity driving phosphorylation of proteins that are operational in cancer and not in normal models. The technology platform led to discovery of novel kinases that are mechanistically relevant to pathophysiology of cancer.
Citation Format: Vivek K. Vishnudas, Min Du, Viatscheslav Akmaev, Rangaprasad Sarangarajan, Niven R. Narain. Two dimensional chemical interrogation of oncogenic systems and multi-omics integration of signatures reveals novel signaling pathways involved in the pathophysiology of cancer [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A4.
Abstract IA20: General methods to conditionally regulate protein stability
Authors: Wandless Thomas J. 
Published: August 2014

Abstract
There is an increasing need for experimental perturbation methods that provide scientists with a high degree of control over the proteins they study. In order to provide scientists with general techniques to conditionally regulate protein function, we have developed experimental methods to regulate protein stability rapidly and reversibly through the administration of cell-permeable small molecules to cultured cells or living animals. These perturbation strategies depend upon engineered protein domains called “destabilizing domains” that bind tightly to small molecule ligands. When a destabilizing domain is fused to a targeted protein-of-interest, investigators can tunably regulate the expression levels of the targeted fusion protein through the administration of the appropriate ligand. We have developed several experimental systems in which the addition of a ligand can be used to either stabilize or destabilize a destabilizing domain, thereby restoring or eliminating the function of the protein-of-interest.
Citation Format: Thomas J. Wandless. General methods to conditionally regulate protein stability [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA20.
Abstract IA21: Changing chasses and inventing elements: Developing a combined systems biology and engineering approach to designing complex function in cells
Authors: Arkin Adam P. 
Published: August 2014

Abstract
To meet the goal of creating reliable, predictable, efficient, and transparent methods to harness cellular capabilities for human benefit, it is necessary both to have standard libraries of elements from which useful pathways can be constructed and an understanding of the how host physiology and the environment impacts the functioning of these heterologous circuits. We show how variations in cellular and environmental context affect the operation of the basic central dogma functions underlying gene expression. Then we describe progress on creating a complete, scalable, and relatively homogeneous and designable sets of part families that can control central dogma function predictably in the face of varying configurations, genetic contexts, and environments. We show the challenges that arise in attempting this in applications such as a tumor destroying bacteria.
Citation Format: Adam P. Arkin. Changing chasses and inventing elements: Developing a combined systems biology and engineering approach to designing complex function in cells [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA21.