bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B34: Quantitative systems pharmacology and immunotherapy: accelerating lead generation and optimization of a PD-1 x TIM-3 biotherapeutic in immuno-oncology
Authors: Apgar Joshua F. , Wong Jamie , Phennicie Ryan , Briskin Mike , Burke John M. 
Published: May 2016

Abstract
The goal of this collaboration was to provide early quantitative decision making guidance for the project team by developing and interrogating a quantitative systems pharmacology (QSP) model of the co-modulation inhibitory receptors PD-1 and TIM-3 in immuno-oncology. The QSP model was to: (1) provide predictions of the best-in-class profile for a PD-1 and TIM-3 dual antagonist biologic(s), (2) accelerate project timelines, (3) provide biological insights, and (4) reduce experimental costs.
The QSP model was based on first principles as a system of elementary mass-action, mechanistic PKPD, ordinary differential equations. The model parameters and reactions were based on biophysics, and are interpretable. The model reactions include protein synthesis and elimination, ligand-receptor and drug-target formation and turnover, and drug administration and first order clearance. There were four versions of the model: PD-1 monospecific, TIM-3 monospecific, PD-1 x TIM-3 bispecific and fixed dose combination (FDC) targeting PD-1 and TIM-3. The monospecific models were then benchmarked against published data such that model parameter values were set to known values and unknown parameters were estimated. Once benchmarked, the FDC and bispecific models were analyzed by systematically investigating how tuning the model parameters (e.g., affinity, avidity, dose, half-life, target expression, etc.) impacted target inhibition, and to simulate patient variability.
The model was in good agreement with published clinical data from nivolumab and pembrolizumab, and data from RMT3-23 in the TIM-3 driven mouse model. QSP model analysis predicted: (1) there would be diminishing returns on very tight binding biologics due to Target Mediated Drug Disposition (TMDD) that offsets potency, and (2) there is no advantage between FDC, 2-2 bispecific, and 2-1 bispecific formats, which are predicted to be roughly equivalent. As a result of these analyses, there was a significant reduction in the number of experiments, and acceleration of project timelines by (1) eliminating rounds of affinity maturation, as drug leads were in predicted optimal drug parameter ranges, and (2) eliminating the need to construct and evaluate bi-specific constructs and proceed with FDCs.
Citation Format: Joshua F. Apgar, Jamie Wong, Ryan Phennicie, Mike Briskin, John M. Burke. Quantitative systems pharmacology and immunotherapy: accelerating lead generation and optimization of a PD-1 x TIM-3 biotherapeutic in immuno-oncology. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B34.
Abstract IA15: Functional diversity of the pancreas tumor stroma
Authors: LeBleu Valerie S. , Özdemir Berna C. , Pentcheva-Hoang Tsvetelina , Carstens Julienne L. , Zheng Xiaofeng , Wu Chin-Chia , Simpson Tyler , Laklai Hanane , Sugimoto Hikaru , Kahlert Christoph , Novitskiy Sergey V. , Acosta Ana DeJesus , Sharma Padmanee , Heidari Pedram , Mahmood Umar , Chin Lynda , Moses Harold , Weaver Valerie , Maitra Anirban , Allison James P. , Kalluri Raghu 
Published: May 2016

Abstract
The desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC) is composed of functionally diverse cellular components embedded in a complex and dynamic fibrotic matrix. In this context, the marked accumulation of stromal myofibroblasts has long been associated with pro-tumorigenic functions, by enhancing tumor cell growth, and limiting immune infiltration and chemotherapeutic drug delivery. Testing of some of these concepts in the clinical care of PDAC patients was however met with paradoxical results. Precise functional auditing of the stromal fibroblasts using genetic targeting in genetically engineered mouse models of PDAC depicted a more complex picture, wherein myofibroblast emerged in this context as tumor-limiting stromal cells. Depletion of the stromal fibroblasts in the early and late stages of PDAC in mice led to more invasive tumors with a negative impact on overall survival, and failed to improve response to Gemcitabine therapy. While our result indicated that suppression of the desmoplastic reaction was associated with decreased tumor angiogenesis, increased intratumoral hypoxia, and epithelial-to-mesenchymal transition of cancer cells with heightened tumorigenicity, our study also informed on the immunomodulatory functions of myofibroblasts in murine PDAC. Depletion of myofibroblasts supported an enhanced response to anti-CTLA4 checkpoint blockade therapy with prolonged survival of mice.
Citation Format: Valerie S. LeBleu, Berna C. Özdemir, Tsvetelina Pentcheva-Hoang, Julienne L. Carstens, Xiaofeng Zheng, Chin-Chia Wu, Tyler Simpson, Hanane Laklai, Hikaru Sugimoto, Christoph Kahlert, Sergey V. Novitskiy, Ana DeJesus Acosta, Padmanee Sharma, Pedram Heidari, Umar Mahmood, Lynda Chin, Harold Moses, Valerie Weaver, Anirban Maitra, James P. Allison and Raghu Kalluri. Functional diversity of the pancreas tumor stroma. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA15.
Abstract IA20: Chromatin looping factors and breast cancer
Authors: Treloar Aislinn , Wu Xue , Penrod Nadia , Bailey Swneke D. , Zhang Xiaoyang , Desai Kinjal , Gyorffy Balazs , Lupien Mathieu 
Published: May 2016

Abstract
Estrogen signaling in breast cancer cells relies on chromatin interactions connecting distal regulatory elements bound by the estrogen receptor alpha (ER) to target gene promoters. This ensures stimulus and subtype-specific transcriptional responses. Chromatin looping factors, including CTCF, ZNF143 and RAD21, are genetically altered in breast cancer. However, the impact of these alterations on breast cancer development is ill defined. Here we demonstrate that ZNF143 directly regulates the formation of chromatin interactions by marking promoters connecting with distal regulatory elements. ZNF143 occupies the promoter of most early-response estrogen target genes in ER-positive breast cancer cells. Its chromatin occupancy is unaffected by estrogen stimulation suggesting that chromatin interactions are stable as opposed to modulated by stimulus. ZNF143 overexpression within ER-positive breast cancer patients associates with a worse outcome. Its loss abrogates the estrogen response in breast cancer cells. Overall, these results suggest that ZNF143 is a critical effector of the estrogen response and highlights the contribution of the chromatin looping machinery to ER-positive breast cancer development.
Citation Format: Aislinn Treloar, Xue Wu, Nadia Penrod, Swneke D. Bailey, Xiaoyang Zhang, Kinjal Desai, Balazs Gyorffy, Mathieu Lupien. Chromatin looping factors and breast cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA20.
Abstract IA27: Retooling CRISPR to turn genes on and off
Authors: Gilbert Luke A. , Horlbeck Max A. , Villalta Jacqueline , Hao Shao , Gestwicki Jason E. , Weissman Jonathan S. 
Published: May 2016

Abstract
CRISPR (clustered regularly interspaced short palindromic repeats) is an adaptive genome defense system in bacteria and archaea. CRISPR has been widely repurposed as an RNA-guided genome editing method. We have shown that the endonuclease domains of the Cas9 protein can be mutated to create a programmable RNA-guided DNA-binding protein. In human cells, we have shown we can control transcription of endogenous coding and non-coding genes over a wide range (up to 1000 fold) by using dCas9 chimeras to deliver protein domains that either repress (CRISPRi) or activate (CRISPRa) transcription. These experiments provide proof of principle that we can use dCas9 as an RNA-guided DNA binding platform to deliver in theory any protein to a specific genomic location, which may be useful for studying transcription, epigenetic regulation, DNA replication and DNA repair.
We have developed a genome-scale CRISPRi/a functional genomics platform for loss- and gain-of-function screening in human cells. We have demonstrated that our CRISPRi/a screening platform can robustly identify pathways and proteins required for cancer cell growth and survival. Gain-of-function CRISPRa screens promise to reveal a layer of genetic information missing from previous efforts. We have shown in a cell growth screen that CRISPRa reveals latent tumor suppressors and transcription factors that regulate cancer cell state in chronic myeloid leukemia cells. In proof of principle, we have also used CRISPRi/a screens to determine the mechanism of cellular uptake, trafficking, retro-translocation, and toxicity for a chimeric bacterial toxin. These experiments establish CRISPRi and CRISPRa as powerful tools that provide rich and complementary information for mapping complex pathways.
Recently, we have used our CRISPRi/a functional genomics platform to determine the genetics of cellular response to HSP70 inhibitors, which are a new class of anti-cancer drugs targeting a non-oncogene addiction. Together, our experiments demonstrate the utility of our CRISPRi/a functional genomics approach for studying principles of oncogene and non-oncogene addiction in cancer biology and cancer therapy.
Citation Format: Luke A. Gilbert, Max A. Horlbeck, Jacqueline Villalta, Shao Hao, Jason E. Gestwicki, Jonathan S. Weissman. Retooling CRISPR to turn genes on and off. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA27.
Abstract IA34: Clinical proof of concept for the first-in-class BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199)
Authors: Leverson Joel D. 
Published: May 2016

Abstract
Many cancer cells maintain survival through over-expression of anti-apoptotic BCL-2 family proteins, which sequester high levels of their pro-apoptotic counterparts. While this makes BCL-2 proteins compelling targets for the development of cancer therapeutics, synthesizing small molecules capable of disrupting these protein-protein interactions has been a major challenge for the field. Structure-based drug design led to the discovery of navitoclax (ABT-263), a dual inhibitor of BCL-2 and BCL-XL. Navitoclax has shown promising activity in the clinic but its efficacy has been limited by thrombocytopenia caused by BCL-XL inhibition. To avoid this toxicity, we designed a BCL-2-selective inhibitor, venetoclax (ABT-199/GDC-0199), that maintains efficacy in hematologic malignancies while sparing platelets. In this presentation, I will review the preclinical work that led to the discovery of venetoclax, the translational studies that have pointed to utility for venetoclax in a variety of cancers, and the results from ongoing clinical studies, in which venetoclax has demonstrated clear signs of activity. I will discuss what we have learned from multiple iterations of translational work between the bench and the bedside, and how we are using a toolkit of highly selective BCL-2 family inhibitors to parse the roles of BCL-2 family proteins in cancer cell survival.
JDL is an AbbVie employee. The design, study conduct and financial support was provided by AbbVie and Genentech. AbbVie and Genentech participated in the data generation, interpretation of data, review and approval of this publication (A5107572).
Citation Format: Joel D. Leverson. Clinical proof of concept for the first-in-class BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199). [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA34.
Abstract A09: The long noncoding RNA SPRIGHTLY regulates cell proliferation in primary human melanocytes
Authors: Zhao Wei , Mazar Joseph , Lee Bongyong , Sawada Junko , Li Jian-Liang , Shelley John , Govindarajan Subramaniam , Towler Dwight , Mattick John S. , Komatsu Masanobu , Dinger Marcel E. , Perera Ranjan J. 
Published: May 2016

Abstract
The long non-coding RNA (lncRNA) SPRIGHTLY (formerly SPRY4-IT1), which lies within the intronic region of the SPRY4 gene is upregulated in human melanoma cells compared to melanocytes. SPRIGHTLY regulates a number of cancer hallmarks including proliferation, motility, and apoptosis. To better understand its oncogenic role, SPRIGHTLY was stably transfected into human melanocytes, which resulted in increased cellular proliferation, invasion, and development of a multinucleated dendritic-like phenotype. RNA sequencing and mass spectrometric analysis of SPRIGHTLY-expressing cells revealed changes in the expression of genes involved in cell proliferation, apoptosis, chromosome organization, regulation of DNA damage responses, and cell cycle. The proliferation marker Ki67, minichromosome maintenance genes (MCM2-5), and the anti-apoptotic genes X-linked inhibitor of apoptosis (XIAP) and baculoviral IAP repeat-containing 7 (livin) were upregulated in SPRIGHTLY-expressing melanocytes, while the pro-apoptotic tumor suppressor gene DPPIV/CD26 was downregulated. Since downregulation of DPPIV is known to be associated with malignant transformation in melanocytes, SPRIGHTLY-mediated DPPIV downregulation may play an important role in melanoma pathobiology. These findings provide novel insights into how SPRIGHTLY regulates proliferation, and apoptosis in primary human melanocytes.
Citation Format: Wei Zhao, Joseph Mazar, Bongyong Lee, Junko Sawada, Jian-Liang Li, John Shelley, Subramaniam Govindarajan, Dwight Towler, John S. Mattick, Masanobu Komatsu, Marcel E. Dinger, Ranjan J. Perera. The long noncoding RNA SPRIGHTLY regulates cell proliferation in primary human melanocytes. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A09.
Abstract B12: Rapamycin-induced miR-21 promotes the survival of mTORC1 hyperactivated cells in tuberous sclerosis complex models
Authors: Lam Hilaire C. , Filippakis Harilaos , Cottrill Katherine A. , Lope Alicia Llorente , Khabibullin Damir , Priolo Carmen , Ogorek Barbara , Chan Stephen Y. , Pereira Ana , Henske Elizabeth P. 
Published: May 2016

Abstract
Background: Tuberous sclerosis complex (TSC) is a multisystem, hamartomatous disease associated with tumors of the brain, skin and kidney, as well as progressive cystic lung destruction characteristic of lymphangioleiomyomatosis (LAM). TSC is caused by mutations in TSC1 or TSC2, resulting in hyperactive mechanistic Target of Rapamycin (mTOR) 1 signaling. Rapamycin and related rapalogs inhibit mTORC1 activity and stabilize tumors in TSC patients, but tumor progression proceeds at pretreatment rates following cessation of therapy. MicroRNA repress target gene expression and are commonly dysregulated in cancers. In previously published work, we identified a group of rapamycin responsive miRNA, rapa-miRs. Surprisingly the most upregulated rapa-miRs, miR-21 in particular, are known pro-survival oncogenic miRNA (oncomiRs). We hypothesize that inhibiting miR-21 and downstream targets may lead to more complete and durable responses to mTORC1 inhibitors.
Methods: We utilized qRT-PCR to determine the kinetics of miR-21 induction with rapamycin in various cell types and in mouse xenografts. Mimics and inhibitors were used to determine the functional consequences of miR-21 in TSC2-null cells. Expression profiling was used to identify miRNA target genes. Bioinformatics and network analysis approaches were implemented to identify biological relationships between the miR-21 targets.
Results: Our initial screens identified miR-29b, -21, -24, -221, -106a and -199a as candidate rapa-miRs. Rapamycin induced miR-21 greater than 1.5 fold in diverse cell lines and in mouse xenografts. We have identified pro-cell death targets, PPIF, TP53BP2 and PDCD4, which are negatively regulated by miR-21 upon rapamycin treatment. Network analysis using the Consolidated Interactome (CI) revealed that rapa-miRs inhibit multiple key pro-apoptotic targets. These data suggest that rapa-miRs regulate proteins critical for cell fate determination and survival in response to rapamycin treatment.
Conclusions: Rapamycin induces pro-survival oncomiR, miR-21, which may be a valuable target for therapeutic intervention in TSC.
Citation Format: Hilaire C. Lam, Harilaos Filippakis, Katherine A. Cottrill, Alicia Llorente Lope, Damir Khabibullin, Carmen Priolo, Barbara Ogorek, Stephen Y. Chan, Ana Pereira, Elizabeth P. Henske. Rapamycin-induced miR-21 promotes the survival of mTORC1 hyperactivated cells in tuberous sclerosis complex models. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr B12.
Abstract B24: Identification of immunosuppressive networks in colon cancer
Authors: Sarver Anne E. , Sarver Aaron L. , Subramanian Subbaya 
Published: May 2016

Abstract
Despite important improvements over the past two decades in preventive screening and targeted therapies, colorectal cancer remains the third major cause of cancer-related deaths in the U.S. The majority (~85%) of colon cancer tumors are non-immunogenic, i.e. they lack a significant number of infiltrating cytotoxic T cells, and are typically unresponsive to the new immune-checkpoint inhibitor based therapies that have dramatically changed the way we treat many cancer patients. These non-immunogenic colon cancer tumors are also characterized by chromosome instability and are microsatellite stable (MSS). Microsatellite instable (MSI) tumors present a greater variety of antigens and are significantly more immunogenic. We analyzed the paired mRNA and microRNA RNA-Seq expression profiles contained in The Cancer Genome Atlas (TCGA), representing MSS colon cancer, MSI colon cancer, and normal colon tissues. These expression profiles reflect the heterogeneity of the tumor samples, with MSI samples showing distinct immune cell signatures. Integrative analysis of mRNA and microRNA expression patterns revealed signaling networks that may represent, in part, the molecular mechanisms by which cancer cells modulate the host response to create an immune privileged microenvironment. These findings could result in a novel therapeutic avenue, targeting a tumor's ability to suppress the immune response, addressing a critical barrier to treatment for non-immunogenic tumors.
Citation Format: Anne E. Sarver, Aaron L. Sarver, Subbaya Subramanian. Identification of immunosuppressive networks in colon cancer. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr B24.
Abstract B30: High-throughput, purification-free, multiplexed profiling of circulating miRNA for discovery, validation, and diagnostics
Authors: Stoner Isaac , Tackett Michael , Rafferty Conor , Windemuth Andreas , Atabakhsh Elnaz , Tytell Jessica , Pregibon Daniel 
Published: May 2016

Abstract
To address the needs for circulating miRNA biomarker validation, we developed the Multiplexed Circulating microRNA assay. This assay enables the detection of up to 68 microRNA targets per sample in 96-well format with readout on standard flow cytometers and analysis with an included bioinformatics software package. The Circulating microRNA assay combines particle¬-based multiplexing, using patented Firefly hydrogel particles, with single¬ step RT-PCR signal amplification using universal primers. Thus, the Circulating microRNA assay leverages PCR sensitivity while eliminating the need for separate reverse transcription reactions and mitigating amplification biases introduced by target¬-specific qPCR. Furthermore, the ability to multiplex targets in each well eliminates the need to split valuable samples into multiple reactions. Results from the Circulating microRNA assay are displayed and interpreted using our included Firefly Analysis Workbench, which allows visualization, normalization, and export of experimental data with only a few mouse clicks. To aid discovery and validation of biomarkers, we have generated fixed panels for Oncology, Cardiology, Neurology, Immunology, and Liver Toxicology. These carefully curated panels include hemolysis markers to assess sample quality, as well as critical normalization factors. Here we present the data from several studies investigating circulating and tumor microRNA profiles using the Firefly Circulating microRNA Assay Fixed Panels.
Together, this novel combination of bioinformatics tools and multiplexed, high¬-sensitivity assays enables rapid discovery and validation of microRNA biomarker signatures from fluid specimens.
Citation Format: Isaac Stoner, Michael Tackett, Conor Rafferty, Andreas Windemuth, Elnaz Atabakhsh, Jessica Tytell, Daniel Pregibon. High-throughput, purification-free, multiplexed profiling of circulating miRNA for discovery, validation, and diagnostics. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr B30.