bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A23: Multi-parametric genetic interactions map dynamic genetic network rewiring upon anti-proliferative treatment
Authors: Heigwer Florian , Scheeder Christian , Miersch Thilo , Blass Claudia , Boutros Michael 
Published: December 2017

Abstract
Signaling pathways are often characterized as rather static networks whose outcome is the result of state changes of pathway components, e.g. by protein phosphorylation or other post-translational modifications. These state changes along signaling networks have been systematically studied using, for example proteomics methods. However it remained unknown how networks rewire under the influence of external stimuli, such as anti-cancer drug treatment. To analyze dynamic rewiring of a signaling network, we performed an arrayed high-throughput co-RNAi screen in a Drosophila melanogaster cell line (Dmel-2). Therin, we assessed statistic genetic interactions measured by 26 880 pairwise RNAi experiments under MEK1/2 inhibitor treatment over the time course of 96 hours. As phenotypic readout we conducted high-content imaging of DNA, cytoskeleton and microtubule markers and extracted &gt;150 cellular features from 4 423 680 images each representing a specific condition, and marker. Together these features precisely characterize ~100 000 alleviating and 160 000 aggravating synergistic effects resulting from combinatorial perturbations. While only 2 % of all interactions are explained by cell viability the vast majority of dynamic differential interactions is explained by other features. Correlation of genetic interaction profiles across those features allows us to precisely how genes change pathway affiliation under different conditions. Our results show that, among others, key signaling nodes e.g. ERK1/2 or the Mediator complex build different connections within genetic networks depending on the environmental conditions and reveal yet unknown synthetic interactions. Using the confidence we gain from time resolved measurements of different cellular features we could identify numerous interactions which could resolve mechanisms of resistance to MEK inhibitor driven treatments and reveal potential new therapeutic targets.
Citation Format: Florian Heigwer, Christian Scheeder, Thilo Miersch, Claudia Blass, Michael Boutros. Multi-parametric genetic interactions map dynamic genetic network rewiring upon anti-proliferative treatment [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 A23.
Abstract B07: Analysis of allele specific expression in esophageal squamous cell carcinoma with combination of exome sequencing and mRNA Sequencing
Authors: Takahashi Masahiko , Nakaoka Hirofumi , Akutsu Yasunori , Hanari Naoyuki , Murakami Kentaro , Kano Masayuki , Matsumoto Yasunori , Otsuka Ryota , Sekino Nobufumi , Yokoyama Masaya , Inoue Itsuro , Matsubara Hisahiro 
Published: December 2017

Abstract
In recent years, large-scale international studies have provide comprehensive catalogues of genomic alterations in cancers including Esophageal Squamous Cell Cancer(ESCC). They revealed that some gene associated with cell cycle/apoptosis pathway, NOTCH pathway, WNT pathway, such as TP53 and NOTCH1, harbored genetic abnormalities frequently. As the next step clinical sequencing studies are starting to evaluate efficacy of using targeted agents to patients with specific molecular aberrations.
We performed exome sequencing and RNA sequencing for 25 Japanese patients with esophageal squamous cell carcinoma (ESCC) to provide a comprehensive catalogue of genomic abnormalities in ESCC and found TP53 and ZNF750 significantly mutated genes. Additionally, we performed allele specific expression analysis of TP53, integrating mRNA sequencing data into the information of genomic abnormality. This analysis revealed that levels of expression changes depending on mutation types and nearly mono-allelic expression of TP53 was a common signature of ESCC patients with somatic mutations. And pattern of mono-allelic expression was dependent on mutation types. We expanded this analysis to all genes with somatic SNV mutations and revealed that mutant allele specific expression was observed in other genes including ZNF750, and many of them were belonged to cancer pathway in KEGG database.
About TP53, our investigation might provide better understanding of the involvement of somatic mutations. And fluctuations in transcriptional regulation of TP53 could be predicted based on type of somatic mutation. In addition to this, analysis of allele specific expression suggested that not only somatic mutation of DNA, but also mutant allele expression should be considered to understand cancer genetic pathophysiology better and build more effective therapeutic strategies.
Citation Format: Masahiko Takahashi, Hirofumi Nakaoka, Yasunori Akutsu, Naoyuki Hanari, Kentaro Murakami, Masayuki Kano, Yasunori Matsumoto, Ryota Otsuka, Nobufumi Sekino, Masaya Yokoyama, Itsuro Inoue, Hisahiro Matsubara. Analysis of allele specific expression in esophageal squamous cell carcinoma with combination of exome sequencing and mRNA Sequencing [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 B07.
Abstract B13: Synthetic vulnerabilities in MLL3 deficient pancreatic tumors
Authors: Gupta Sonal , Ferri-Borgogno Sammy , Reisenauer Mary R. , Gupta Anvita k. , Maitra Anirban 
Published: December 2017

Abstract
Myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3) is a histone 3-lysine 4 methyltransferase, frequently mutated in a variety of solid tumors including pancreatic ductal adenocarcinoma (PDAC), a nearly lethal disease due to our current inability to therapeutically target major oncogenic proteins driving this cancer. Like other tumor suppressor genes, direct targeting of MLL3 is not feasible, and thus our objective was to find biological pathways which are synthetic lethal targets in MLL3-deficient PDAC tumors. Identification of drug targets in such a specific genetic context could potentially dictate stratification of patients based on the mutational profile of their tumor. To achieve this, we generated a novel genetically engineered mouse model (GEMM) of pancreatic cancer, in which targeted mutation of Kras (G12D) and loss of functional MLL3 was driven by Cre-recombination from early pancreatic lineage-specific transcription factor, Pdx1. Our unpublished data suggests that loss of MLL3 function in exocrine pancreas cooperates with mutant Kras to accelerate the progression of invasive pancreatic neoplasia. Using cell lines generated from spontaneous tumors arising in KC (KrasG12D alone) and KMC (KrasG12D; MLL3δ/δ) mice, we performed functional genomic analyses and found several key oncogenic pathways upregulated in MLL3-deficient cells. We selected two well-known oncogenic pathways and through a series of cellular and biochemical assays, further validated their selectively activation in KMC cells, in contrast with KC cells. Next, we picked multiple pharmacological inhibitors of these pathways, which are already approved at various phases of clinical trials, and tested for their efficacy on growth of KC and KMC cells in both two- and three-dimensional growth assays. In agreement with our data showing preferential activation in KMC cells, we found KMC cells to be significantly more sensitive than KC cells to the effect of these inhibitors. Thus, identification of synthetic lethal hits in context of MLL3 functional loss could potentially enable us to design strategies to limit metastasis in patients with surgically-resectable tumors.
Citation Format: Sonal Gupta, Sammy Ferri-Borgogno, Mary R. Reisenauer, Anvita k. Gupta, Anirban Maitra. Synthetic vulnerabilities in MLL3 deficient pancreatic tumors [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 B13.
Abstract B15: Comprehensive cistromic characterization of SOX10, a lineage-specific genetic dependency in melanoma, via the integration of functional genomic approaches
Authors: Wong Terence , Johannessen Cory , Fan Jingyu , Long Henry , Liu Shirley , Garraway Levi 
Published: December 2017

Abstract
Melanoma accounts for less than 5% of skin cancers, but a majority of skin cancer deaths. Genomic studies and drug discovery programs have led to the development of targeted therapies, including BRAF and MEK inhibitors, but the inevitable resistance to these targeted agents necessitates a greater understanding of melanoma biology and genetics. By integrating genome-wide functional genomic and transcriptomic data, we have identified SOX10 as a lineage-specific genetic dependency in melanoma independent of BRAF or NRAS mutation status. Subsequent analyses indicate that SOX10 dependency is highly correlated with SOX10 gene expression and functional in vitro experiments have confirmed the role of SOX10 in the proliferation and growth of melanoma cell lines regardless of their sensitivity to MAPK pathway inhibitors. Chromatin immunoprecipitation of endogenous SOX10 followed by sequencing (SOX10 ChIP-seq) combined with transcriptomic profiling (RNA-seq) following SOX10 depletion by shRNA in a panel of melanoma cell lines determined the SOX10 cistrome, the set of SOX10 target genes across the melanoma genome. Integration of the SOX10 cistrome with genetic dependency data may lead to novel therapeutic approaches in melanoma.
Citation Format: Terence Wong, Cory Johannessen, Jingyu Fan, Henry Long, Shirley Liu, Levi Garraway. Comprehensive cistromic characterization of SOX10, a lineage-specific genetic dependency in melanoma, via the integration of functional genomic approaches [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 B15.
Abstract B17: Identification of Druggable Targets through Functional Multi-Omics in Renal Medullary Carcinoma
Authors: Hong Andrew L. , Tseng Yuen-Yi , Kynnap Bryan D. , Doshi Mihir B. , Sandoval Gabriel , Oh Coyin , Sayeed Abeer , Shubhroz Gill , Church Alanna J. , Keskula Paula , Peng Anson , Clemons Paul A. , Tsherniak Aviad , Vazquez Francisca , Rodriguez-Galindo Carlos , Janeway Katherine A. , Garraway Levi A. , Schreiber Stuart L. , Root David E. , Mullen Elizabeth , Stegmaier Kimberly , Kadoch Cigall , Roberts Charles W.M. , Boehm Jesse S. , Hahn William C. 
Published: December 2017

Abstract
Renal medullary carcinoma is a rare kidney cancer that is primarily seen in adolescent and young adult African American patients with sickle cell trait. Prognosis is poor and treatment options are limited. We have developed several cell line models that recapitulate the primary and relapsed metastatic samples from a patient who succumbed to this disease. We have confirmed by whole exome sequencing that our models have sickle cell trait and loss of heterozygosity of the SMARCB1 loci, both hallmarks of this disease. By RNA-sequencing, we see a lack of SMARCB1 transcription. We have further shown dependency of our models to SMARCB1 re-expression thus suggesting that this cancer is indeed driven by loss of SMARCB1 at a functional level. We performed pooled CRISPR-Cas9 and RNAi loss of function screens and a small molecule screen focused on druggable cancer targets based on our previous work in parallel to a genome-wide pooled CRISPR-Cas9 loss of function screen. Integrating these complementary and orthogonal methods, we identified a number of targets for further validation. These targets, when combined may provide a rational approach to therapeutic targeting for this rare kidney cancer.
Citation Format: Andrew L. Hong, Yuen-Yi Tseng, Bryan D. Kynnap, Mihir B. Doshi, Gabriel Sandoval, Coyin Oh, Abeer Sayeed, Gill Shubhroz, Alanna J. Church, Paula Keskula, Anson Peng, Paul A. Clemons, Aviad Tsherniak, Francisca Vazquez, Carlos Rodriguez-Galindo, Katherine A. Janeway, Levi A. Garraway, Stuart L. Schreiber, David E. Root, Elizabeth Mullen, Kimberly Stegmaier, Cigall Kadoch, Charles W.M. Roberts, Jesse S. Boehm, William C. Hahn. Identification of Druggable Targets through Functional Multi-Omics in Renal Medullary Carcinoma [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 B17.
Abstract B39: Small Molecule Disruption of RAD52 Rings as a Mechanism for Precision Medicine in BRCA Deficient Cancers
Authors: Pomerantz Richard T. 
Published: December 2017

Abstract
Suppression of RAD52 causes synthetic lethality in BRCA deficient cells. Yet pharmacological inhibition of RAD52, which binds single-strand DNA (ssDNA) and lacks enzymatic activity, has not been demonstrated. Here, we identify the small molecule 6-hydroxy-dopa (6-OH-dopa) as a major allosteric inhibitor of the RAD52 ssDNA binding domain. For example, we find that multiple small molecules bind to and completely transform RAD52 undecamer rings into dimers, which abolishes the ssDNA binding channel observed in crystal structures. 6-OH-dopa also disrupts RAD52 heptamer and undecamer ring superstructures, and suppresses RAD52 recruitment and recombination activity in cells with negligible effects on other double-strand break repair pathways. Importantly, we show that 6-OH-dopa selectively inhibits the proliferation of BRCA deficient cancer cells, including those obtained from leukemia patients. Taken together, these data demonstrate small molecule disruption of RAD52 rings as a promising mechanism for precision medicine in BRCA deficient cancers.
Citation Format: Richard T. Pomerantz. Small Molecule Disruption of RAD52 Rings as a Mechanism for Precision Medicine in BRCA Deficient 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 B39.
Abstract IA09: Genome-wide CRISPR screens illuminate lymphoma pathogenesis and therapeutic resistance
Authors: Staudt Louis M. 
Published: December 2017

Abstract
While the genetic aberrations in cancer cells have been revealing, many malignant phenotypes are regulated by genes that are not genetically altered. To gain insight into these pathways, we have employed genome-wide genetic screens using CRISPR-Cas9 technology. In one type of screen, lentiviral libraries expressing small guide RNAs (sgRNAs) are used to direct the endonuclease Cas9 to particular genomic locations, leading to the cutting and inactivation of the targeted gene. An alternative approach, called CRISPRi, uses a catalytically-dead Cas9 isoform fused to a KRAB transcriptional repressor domain. sgRNAs are used to guide this fusion protein to gene promoters, leading to their silencing. We are utilizing both screening methodologies in a variety of cell line models of various genetic subtypes of diffuse large B cell lymphoma, T cell lymphomas, and multiple myeloma, looking for essential genes that control proliferation and/or survival in a cancer subtype-specific fashion. We are also using these screens to uncover genes that synergize or antagonize targeted agents that are in clinical development in these lymphoid malignancies. I will present new Insights from these screens into the mechanisms by which lymphomas acquire sensitivity to therapeutic agents targeting B cell receptor signaling, such as ibrutinib, and how they subsequently may develop resistance.
Citation Format: Louis M. Staudt. Genome-wide CRISPR screens illuminate lymphoma pathogenesis and therapeutic resistance [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 IA09.
Abstract PR18: Leveraging synthetic lethality to target convergent therapeutic resistance
Authors: Wood Kris C. 
Published: December 2017

Abstract
Our laboratory uses genomic and pharmacological methods to define the pathways of resistance to targeted anticancer therapies. Toward this end, we recently developed a technique in which engineered lentiviral cDNAs encoding activators of major oncogenic signaling pathways are introduced into cells and then profiled to identify those capable of conferring resistance to drugs. In parallel, we have also developed analogous loss-of-function screening approaches based on CRISPR/Cas9 gene editing, and have used these approaches to map the pathways supporting intrinsic resistance to targeted therapies. Using these tools in conjunction with data and mouse models derived from human tumors, we recently discovered that major pathways of resistance frequently converge onto common downstream effectors, the targeting of which can forestall resistance. Here, I will describe the discovery of common resistance effectors in JAK2-driven myeloproliferative neoplasms, EGFR-driven colorectal cancers, and BRAF-driven melanomas. Focusing particularly on melanoma, I will describe the discovery that major pathways of resistance converge to activate the transcription factor c-MYC (MYC). MYC expression and gene signatures were suppressed following initial drug treatment, then rebounded during tumor progression in each member of a large panel of human patients, independent of the upstream pathway driving resistance. MYC suppression using either genetic approaches or BET bromodomain inhibition was sufficient to both resensitize diverse BRAFi/MEKi-resistant models and delay resistance in treatment naïve models. Although direct pharmacological inhibition of MYC remains difficult, the BRAFi/MEKi-resistant, MYC-activated state harbors synthetic lethal signaling and metabolic dependencies, including those involving SRC family and c-KIT tyrosine kinases and glucose, glutamine, and serine pathways, that can be targeted to create combination therapies that uniquely select against resistance evolution.
Citation Format: Kris C. Wood. Leveraging synthetic lethality to target convergent therapeutic resistance [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 PR18.
Abstract 13: Next generation sequencing of cell free circulating tumor DNA in blood samples of recurrent and metastatic head and neck cancer patients
Authors: Porter Ashleigh , Daniels Gregory A. , Patel Sandip Pravin , Sacco Assuntina , Banks Kimberly C. , Cohen Ezra E. W. 
Published: December 2017

Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is an increasingly prevalent disease but effective targeted therapy is lacking. The use of next generation sequencing (NGS) in the identification of novel targets has been suggested as a way to potentially expand therapeutic options and thereby improve outcomes.
Methods: Data were collected on patients with recurrent and metastatic (R/M) head and neck cancers who underwent molecular profiling of blood samples utilizing Guardant360, a 70-gene circulating tumor DNA (ctDNA) NGS platform. CtDNA sequencing data was compared to tumor NGS data, when available. Best response to therapy was assessed using RECIST measures.
Results: 60 HNSCC patients were evaluated from February 2015 to June 2016. The most common tumor type and histology was oropharyngeal squamous cell carcinoma (n=21), which was commonly human papillomavirus (HPV) positive (n=15). Other cancer types included salivary gland and thyroid cancers. The most common mutations identified by ctDNA analysis were TP53 (98%), PIK3CA (43%), NOTCH1 (38%), and ARID1A (36%). These findings were consistent with results from tumor sequencing data (n=29) where TP53 (48%) and PIK3CA (24%) were also reported with the highest frequency. Importantly, 73% (n=22) of patients had alterations identified in ctDNA that were not present in tumor specimens. Actionable mutations were identified in 66% of HNSCC and in 50% salivary gland cancer patients. Of patients with actionable mutations, 10% (n=6) received matched targeted therapy (MTT): 3 (50%) had stable disease (SD), 1 had progressive disease (PD), and 2 were not evaluated. Of those who did not receive targeted therapy (n=23), 1 (4.3%) patient had a complete response treated with immunotherapy, 11 (47%) had SD, and 11 (47%) had PD.
Conclusions: Analysis of ctDNA may play a role in management decisions in R/M HNSCC. The majority of patients had unique mutations identified on ctDNA. The utility of ctDNA NGS and its role in patient management should be explored in future studies.
Citation Format: Ashleigh Porter, Gregory A. Daniels, Sandip Pravin Patel, Assuntina Sacco, Kimberly C. Banks, Ezra E. W. Cohen. Next generation sequencing of cell free circulating tumor DNA in blood samples of recurrent and metastatic head and neck cancer patients [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 13.