bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A32: Screening for synthetic lethal interactions using customized epigenetic CRISPR-Cas9 libraries
Authors: Zhou Wenrong , Long Min , Li Xi , Peng Zhengang , Ji Qunsheng , Cang Yong 
Published: December 2017

Abstract
Identification of synthetic lethal (SNL) interactions provides a framework for exploring novel treatment options to cancer based on biomarker analysis. Recent research in this field has been powered up by the latest CRISPR-Cas9 gene editing technology, which allows for single gene manipulation or genome-scale knockout/activation screens. Typically, any non-essential gene can be inactivated in a cell line to generate an isogenic mutant cell line, and single-guide RNA (sgRNA) sequences against any list of genes of interest can be constructed to lentiviral Cas9 vectors to interrogate the isogenic cell lines for SNL interactions. Here we demonstrated two alternative types of SNL screens using customized epigenetic CRISPR-Cas9 libraries. In one screen, we built two sgRNA libraries targeting the N terminus or functional domains of 710 human epigenetic regulators. The libraries were infected to a pomalidomide-resistant multiple myeloma (MM) cell line, which was then followed by pomalidomide treatment. Deep sequencing of the sgRNAs from these cells identified potential targets which when inactivated would re-sensitize the cells to pomalidomide. In the other screen, we built a sgRNA library targeting the functional domains of 116 mouse methyltransferases and demethylases, which was infected to a mouse melanoma cell line Cloudman S91. Syngeneic mouse tumor model derived from the infected cells was treated with anti-mPD-1 monoclonal antibody. Deep sequencing of the tumors would identify potential druggable targets to sensitize or antagonize the tumors to anti-PD-1 immunotherapy. In summary, SNL screens combining CRISPR-Cas9 library with targeted therapeutics or with single gene editing in isogenic cell lines can enable discovery of novel targets for precision cancer treatment.
Citation Format: Wenrong Zhou, Min Long, Xi Li, Zhengang Peng, Qunsheng Ji, Yong Cang. Screening for synthetic lethal interactions using customized epigenetic CRISPR-Cas9 libraries [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A32.
Abstract B03: Functional Stratification of Cancer Variants via Network Perturbations
Authors: Sahni Nidhi , Yi Song 
Published: December 2017

Abstract
In the past decade, genome and exome sequencing projects have identified thousands of genetic variants in patients across a large number of cancer types. However, the explosion of genomic information has left many fundamental questions regarding genotype-phenotype relationships unresolved. One critical challenge is to distinguish causal disease mutations from non-pathogenic polymorphisms. Even when causal mutations are identified, the functional consequence of such mutations is often elusive. Classical one gene, one function, one disease models can not reconcile with the complexity that different mutations of the same gene often lead to different phenotypes. The extent to which network perturbations are involved in disease malfunction and how distinct interaction perturbation patterns can distinguish cancer mutations are largely unknown. Here we report a systematic approach to investigate genetic variant-specific effects on molecular interactions at large scale across diverse human cancers. Remarkably, in comparison to non-disease polymorphisms, disease mutations are more likely to associate with interaction perturbations. A large fraction of missense disease mutations are found to cause protein interaction alterations. While half result in loss of all their interactions, the other half exhibit selective elimination of specific interactions (edgetic). Different mutations of the same gene give rise to different interaction profiles, accounting for distinct disease outcomes. Edgetic mutations perturb interactions through disrupting specific interaction interfaces, and the perturbed partners are more likely expressed in relevant disease tissue. Together, our approach is insightful in prioritizing disease-causing variants, and uncovering patient mutation-specific disease mechanisms at a base-pair resolution, a critical step towards personalized precision medicine. Furthermore, our results suggest distinct interaction perturbations as a widespread mechanism underlying genetic heterogeneity, providing a fundamental link between genotype and phenotype in cancer.
Citation Format: Nidhi Sahni, Song Yi. Functional Stratification of Cancer Variants via Network Perturbations [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B03.
Abstract B05: Discovery, validation and targeting of novel synthetic lethal interactions in academic drug discovery
Authors: March H. Nikki , Chapman Phil , Blaikley Elizabeth , Eberlein Catherine A. , Cockerill Mark , Hitchin Samantha , Waddell Ian D. , Ogilvie Donald 
Published: December 2017

Abstract
The identification of novel oncology targets for small molecule drug discovery is becoming increasingly challenging despite 10-15% of the human genome estimated to be druggable. The literature is an important source of novel targets; however, several recent reports by pharma and academia have indicated that approximately 11-55% of published studies are irreproducible. Moreover, oncology drug attrition rates are extremely poor, with 66% of candidates in Phase III clinical trials not achieving approval. This is reflected by increasing failure rates of drug development projects in Phase II, from 72% in 2006-2007 to 82% in 2008-2009. These failures have been attributed to lack of efficacy, thus highlighting the critical requirement for new novel drug targets that demonstrate clear promise of clinical efficacy through predictive in vitro and in vivo models. Furthermore, it is important to prioritize and pursue targets that are most likely to bind a small molecule inhibitor with high infinity. We sought to utilize the wealth of unvalidated genomic data now available in the public domain by developing a bioinformatic pipeline founded on the collateral vulnerability hypothesis, which is based on the concept of synthetic lethality and exploits the co-occurrence of deletions of genes flanking tumor suppressors that are lost during the course of tumor evolution. We can then target the paralogs of these genes if together they belong to gene families with essential predicted function, thereby exploiting a vulnerability of the cancer cells with these losses. Here, we describe our industry-standard approaches to the target validation of the output generated from lung adenocarcinoma data, and present the validation and de-validation of several novel targets predicted by the collateral vulnerability pipeline, including SMARCA2, KMT2C, and SETD1B.
Citation Format: H. Nikki March, Phil Chapman, Elizabeth Blaikley, Catherine A. Eberlein, Mark Cockerill, Samantha Hitchin, Ian D. Waddell, Donald Ogilvie. Discovery, validation and targeting of novel synthetic lethal interactions in academic drug discovery [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B05.
Abstract B06: HTSvis: An user-friendly application for analysis of arrayed high-throughput experiments by interactive data representations
Authors: Scheeder Christian , Heigwer Florian , Boutros Michael 
Published: December 2017

Abstract
The presented application HTSvis provides an user-interface tool for interactive analysis of arrayed high-throughput screening experiments. Arrayed formats are broadly used for cell-based screens which help to reveal mechanisms of complex diseases such as cancer. Technological advances allow to screen tens of thousands experimental conditions in a single experiments resulting in large datasets with complicated annotation files. Software packages for standardized analysis with a minimized programming effort have been developed accordingly. Even though such pipelines provide comprehensive analysis options, interpretation of the results remains a challenge as the user has to manually compare files and possibly re-run the analysis to prosecute certain hypotheses. Here we present HTSvis, a web application that visualizes data from arrayed screens. The data can be read-in as result files of the established R package CellHTS2 or as any spreadsheet table. This enables the user to feed in data which has been statistically analyzed whilst preserving flexibility to analyze data independent of the CellHTS2 package. The application provides several informative data representations like heatmaps, scatter plots and tables. Within the application, the data can be browsed in an ad hoc manner via the implemented user interface. This allows the user to assess data quality, compare experiments, identify measurements of interest and to verify generated hypotheses in an exploratory manner. The direct allocation of data points to experimental conditions is preserved in all representations facilitating an intuitive interpretation. HTSvis is easy to install, data input is straight forward and no programming skills are required for the usage. The application is compatible with common web browsers and can be set up on local computers as well as on server clusters which allows parallel access for multiple users. Summarized, HTSvis provides a helpful tool for interactive data analysis and interpretation for both, users with and without programming skills. Thereby, the application also promotes the cooperation and exchange of ideas between bioinformaticians and experimental biologists or between collaborators.
Citation Format: Christian Scheeder, Florian Heigwer, Michael Boutros. HTSvis: An user-friendly application for analysis of arrayed high-throughput experiments by interactive data representations [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B06.
Abstract B16: Epistatic mapping of signaling and chromatin regulators
Authors: Henkel Luisa , Heigwer Florian , Winter Jan , Rauscher Benedikt , Boutros Michael 
Published: December 2017

Abstract
Phenotypes are often not only based on the effect of a single gene, but are rather influenced by multiple genetic (also termed epistatic) interactions. Prominent examples are synthetic lethal interactions, where the individual loss-of-function of two genes does not lead to phenotypic alterations, whereas their simultaneous perturbation results in reduced fitness or even cell death. Previously, we have established large-scale genetic interaction mapping experiments in Drosophila cells that discovered a high-number of functional interactions of conserved factors. Here, we aim to create a platform to investigate epistatic interactions of genes encoding chromatin remodeling and signaling factors in human cells.
As part of the transcriptional regulatory machinery, chromatin remodeling enzymes buffer various genetic perturbations via adaptations within the transcriptional program, e.g. via repression of mutant or activation of functional alleles. Furthermore, chromatin remodeling factors link epigenetic modifications to corresponding signaling pathway outputs. While some of these enzymes have been extensively studied, many remain largely uncharacterized. As epigenetic dysregulation constitutes a characteristic feature of many cancers, chromatin remodeling proteins are promising targets in anticancer therapies.
To map interaction networks of chromatin and signaling factors, we use pooled genome-scale CRISPR/Cas9 genetic interaction screens. To this end, CRISPR/Cas9 mapping will be performed in a human cell line to reveal unknown functions and interactions of chromatin remodeling enzymes. We will present our screening platform, including custom library design and analysis tools to identify screening hits that emerge to be promising for synthetic lethality targeting in anticancer therapy.
Citation Format: Luisa Henkel, Florian Heigwer, Jan Winter, Benedikt Rauscher, Michael Boutros. Epistatic mapping of signaling and chromatin regulators [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B16.
Abstract B18: Mechanisms of regulation and synthetic lethal strategies against PALB2 and APRIN, two DNA double-strand break repair proteins
Authors: Couturier Anthony M. , Buisson Rémi , Pauty Joris , Rodrigue Amélie , Caron Marie-Christine , Coulombe Yan , Joshi Niraj , Zou Lee , Masson Jean-Yves 
Published: December 2017

Abstract
One typical mechanism to promote genomic instability, a hallmark of cancer, is to inactivate tumor suppressors, such as PALB2. It has recently been reported that mutations in PALB2 increase the risk of breast cancer by 8-9 fold. PALB2 was identified BRCA2 interacting protein, essential for BRCA2 anchorage to nuclear structures and for its function in double-strand break repair. Inherited mutations in PALB2 are associated with a predisposition for ovarian, breast and pancreatic cancers. The basis of the tumorigenic potential of PALB2 is thought to be related to functions in homologous recombination. Therefore, the regulation of PALB2 during the DNA damage response and the effect of cancer-causing mutation is of high interest. Two mechanisms of regulation of PALB2 will be presented. The first mechanism regulates PALB2 localization to DNA damage sites in S-phase. To date, predicting the functional consequences of PALB2 mutations has been challenging as they lead to different aggressive phenotypes. Here, we performed a structure-function analysis of PALB2 using PALB2 truncated mutants (R170fs, L531fs, Q775X and W1038X), and uncovered a second PALB2 regulation mechanism by which cancer cells could drive genomic instability. We will present these regulatory mechanisms and synthetic lethal strategies to kill PALB2 deficient cells harbouring such mutations using PARP inhibitors. These strategies also apply to APRIN, A BRCA2 interactor, which also promote double-strand break repair by homologous recombination.
Citation Format: Anthony M. Couturier, Rémi Buisson, Joris Pauty, Amélie Rodrigue, Marie-Christine Caron, Yan Coulombe, Niraj Joshi, Lee Zou, Jean-Yves Masson. Mechanisms of regulation and synthetic lethal strategies against PALB2 and APRIN, two DNA double-strand break repair proteins [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B18.
Abstract B22: Mdig gene-environment interaction in human cancers
Authors: Thakur Chitra , Chen Fei 
Published: December 2017

Abstract
Mineral dust-induced gene, mdig has recently been identified and is known to be over expressed in a majority of human cancers and holds predictive power in the poor prognosis of the disease. Mdig is an environmentally expressed gene that is involved in cell proliferation, neoplastic transformation and immune regulation. With the advancement in deciphering the prognostic role of mdig in human cancers, our understanding on how mdig renders a normal cell to undergo malignant transformation is still very limited. This work displays the current knowledge of the mdig gene in context to human neoplasias and its relation to the clinico-pathologic factors predicting the outcome of the disease in patients. It also emphasizes on the promising role of mdig that can serve as a potential candidate for biomarker discovery and as a therapeutic target in inflammation and cancers. Considering the recent advances in understanding the underlying mechanisms of tumor formation, more preclinical and clinical research is required to validate the potential of using mdig as a novel biological target of therapeutic and diagnostic value.
Summary: Expression level of mdig influences the prognosis of several human cancers especially cancers of the breast and lung. Evaluation of mdig in cancers can offer novel biomarker with potential therapeutic interventions for the early assessment of cancer development in patients.
Citation Format: Chitra Thakur, Fei Chen. Mdig gene-environment interaction in human cancers [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B22.
Abstract B33: Tgif inactivation defines a synthetic lethal interaction among oncogenic Kras and Twist1 in pancreatic ductal adenocarcinoma
Authors: Parajuli Parash , Singh Purba , Wang Zhe , Kumar Santosh , Li Lena , Eragamreddi Sailaja , Nguyen Thien Ly , Younes Subhi Talal , Zhang Xu , Xu Keli , Razzaque Mohammed , Prunier Céline , Atfi Azeddine 
Published: December 2017

Abstract
The homeodomain protein TGIF function as a potent inhibitor of transforming growth factor beta (TGF-β) cytostatic signaling, whose inactivation is deemed instrumental to the pathogenesis and progression of pancreatic ductal adenocarcinoma (PDAC) driven by oncogenic Kras. Surprisingly, we found that deletion of Tgif in the context of mutant Kras (KrasG12D) expression culminated in the development of highly metastatic PDAC, despite leading to hyperactivation of TGF-(β/Smad) signaling. Mechanically, we found that TGIF associated with and antagonized Twist1 by a process involving Smad4, a tumor suppressor that is frequently inactivated in human PDAC. Along these lines, Twist1 overexpression synergized with KrasG12D to induce PDAC progression, whereas its ablation completely blocked the malignant phenotype driven by the combined KrasG12D expression and TGIF ablation. Thus, by demonstrating that TGIF functions as a tumor suppressor in PDAC owing to its ability to antagonize the pro-malignant transcription factor Twist1, our studies provide key insights into the role of Twist1 that could be exploited to design synthetic lethal therapeutics against oncogenic Kras, which has proven so far to be intractable.
Citation Format: Parash Parajuli, Purba Singh, Zhe Wang, Santosh Kumar, Lena Li, Sailaja Eragamreddi, Thien Ly Nguyen, Subhi Talal Younes, Xu Zhang, Keli Xu, Mohammed Razzaque, Céline Prunier, Azeddine Atfi. Tgif inactivation defines a synthetic lethal interaction among oncogenic Kras and Twist1 in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B33.
Abstract IA06: Leveraging genome-wide CRISPR screens and synthetic lethal interactions for novel cancer therapeutics
Authors: Angers Stephane 
Published: December 2017

Abstract
Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43 mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation, and discovered a unique requirement for a Wnt signaling circuit engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context dependent specificity at the Wnt receptor level. We further derived a panel of recombinant antibodies that reports the expression of nine FZD proteins and confirm that FZD5 functional specificity cannot be explained by protein expression patterns. Antibodies that specifically bind FZD5 and FZD8 also robustly inhibited the growth of RNF43 mutant PDAC cells grown in vitro and as xenografts in vivo, providing strong orthogonal support for the functional specificity observed genetically. Proliferation of a patient-derived PDAC cell line harboring a RNF43 variant previously associated with PDAC was also selectively inhibited by the FZD5 antibodies, further demonstrating their use as a potential targeted therapy. Highlighting the potential generalizability of these findings, beyond PDAC, tumor organoid cultures from colorectal carcinoma patients that carried RNF43 mutations were also sensitive to the FZD5 antibodies. Our results provide the first example of how CRIPSR-based genetic screens can be leveraged to identify and validate cell surface targets for antibody development and cancer therapy.
Citation Format: Stephane Angers. Leveraging genome-wide CRISPR screens and synthetic lethal interactions for novel cancer therapeutics [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA06.
Abstract IA07: Defining, Optimizing, and Altering the Specificities of CRISPR-Cas Nucleases
Authors: Joung J. Keith 
Published: December 2017

Abstract
RNA-guided CRISPR-Cas nucleases are now widely used for research and are also being rapidly developed as novel therapeutics for various human diseases. In this talk, I will discuss methods developed by our group that enable unbiased, genome-wide assessment of off-target cleavage specificities of CRISPR-Cas nucleases in human cells. I will also summarize our efforts to use protein engineering to create CRISPR-Cas nuclease variants that robustly show substantially reduced off-target effects and/or altered DNA recognition specificities. Taken together, our results have yielded reagents, methods, and insights that will be important for research applications and potential clinical translation of these programmable nucleases.
Citation Format: J. Keith Joung. Defining, Optimizing, and Altering the Specificities of CRISPR-Cas Nucleases [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA07.