Abstract IA15: Genetic screens to study cancer
We will describe our efforts to use the CRISPR/Cas9 system to systematically identify the genetic liabilities of cancer cells and the synthetic lethal relationships of common oncogenes.Citation Format: David M. Sabatini. Genetic screens to study cancer [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 IA15. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Sabatini, D. M. Tags: New Technology and Bioinformatics: Oral Presentations - Invited Abstracts Source Type: research
Abstract B15: Comprehensive cistromic characterization of SOX10, a lineage-specific genetic dependency in melanoma, via the integration of functional genomic approaches
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 ex...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Wong, T., Johannessen, C., Fan, J., Long, H., Liu, S., Garraway, L. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A15: Downregulation of c-myc is synthetic lethal with PARP inhibitors in high MYC cancers independent of BRCA status
In conclusion, we demonstrated that dual CDK + PARP inhibition is synthetic lethal in both BRCA wild-type and mutant TNBC cell lines and is dependent upon down regulation of c-myc. This study supports c-myc as predictor of response to PARP inhibitor therapy and may also serve as a biomarker of response to Dinaciclib + PARPi therapy in high MYC expressing tumors.Citation Format: Jason PW Carey, Smruthi Vjayaraghavan, Kelly Hunt, Khandan Keyomarsi. Downregulation of c-myc is synthetic lethal with PARP inhibitors in high MYC cancers independent of BRCA status [abstract]. In: Proceedings of the AACR Precision Medicine Series: ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Carey, J. P., Vjayaraghavan, S., Hunt, K., Keyomarsi, K. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR14: MEK inhibitors block growth of Ataxia Telangiectasia Mutated (ATM) mutant lung tumors
Introduction: Lung cancer is the leading cause of cancer death worldwide. In the past decade, deep sequencing projects have shed light on the molecular drivers commonly found altered in NSCLC. As a result, the first molecularly targeted agents have been approved for the treatment of tumors presenting activating oncogenic events in EGFR or EML4/ALK. However, the translation into therapies for tumors presenting loss-of-function mutations has proven challenging and constitutes an unexplored and promising field.In order to narrow the gap between cancer genomics and effective treatments for tumors harboring mutations in well-de...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Cruz, F. F. d. l., Smida, M., Nijman, S. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract IA14: Understanding the complex biology of KRAS mutant cancers using genetic screens
Apart from identifying synthetic lethal genes, genetic screens have the potential to reveal much about the basic biology of cell lines. We utilize two techniques, one analytical and one experimental, to demonstrate how genetic screens can also reveal which pathways are on in cell lines and what are the phenotypic consequences of pathway perturbation. First, we apply a clustering analysis of genome-scale CRISPR screening data to map out active pathways in cancer cell lines and to discover novel members of signaling transduction pathways and protein complexes. Secondly, we performed a combinatorial siRNA screen that knocks o...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: L, T. Tags: New Technology and Bioinformatics: Oral Presentations - Invited Abstracts Source Type: research
Abstract B14: Precision functional genomics for glioblastoma: Identifying molecular therapeutic targets using CRISPR-Cas9 and RNAi technologies in patient isolates
Glioblastoma (GBM) is the most aggressive and common form of adult brain cancer and is among the deadliest cancers, with a median survival of 15 months using standard-of-care therapies. Thus, improved treatments for GBM are desperately needed. To identify new GBM molecular therapeutic targets, our group has performed multiple functional genetic screens in patient-derived GBM stem-like cells (GSCs) and non-transformed human neural stem and progenitor cells (NPCs), which represent non-neoplastic controls. These screens, which have used both RNAi and CRISPR-Cas9 platforms, have led to the identification of several key molecul...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Hoellerbauer, P., Feldman, H., Arora, S., Carter, L., Girard, E. J., Corrin, P., Olson, J. M., Holland, E. C., Paddison, P. J. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR13: CRISPRi screening with targeted therapeutics classifies functional long non-coding RNAs in DLBCL
While tens of thousands of lncRNAs have been detected in the human genome, the functional significance of the majority of these genes remain untested. Here, we use CRISPR interference (CRISPRi) loss-of-function screening combined with targeted drug treatment to identify oncogenic and tumor suppressive lncRNAs. Integrative analysis of 417 primary human tumor and cell line RNA-seq datasets from Diffuse Large B Cell Lymphoma (DLBCL) identified 1,276 intergenic lncRNA candidates, including 59 de novo assembled transcripts. CRISPRi screening in a genetically diverse panel of 4 DLBCL cell lines identified known ABC DLBCL protein...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Webster, D. E., Phelan, J. D., Kasbekar, M., Shaffer, A. L., Staudt, L. M. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract IA13: A novel KRAS specific vulnerability in the nutrient stress response
Oncogenic KRAS has multiple effects on cellular functions. A relatively poorly understood role of oncogenic KRAS is in regulation of nutrient stress. As a strategy to identify new KRAS-specific tumor vulnerabilities, we sought to explore the role of oncogenic KRAS in mediating the response to nutrient stress. A key observation is that the gene expression signature of oncogenic KRAS is markedly different in standard tissue culture conditions compared to more physiologic levels of glutamine. Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes TCA cycle intermediates a...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Sweet-Cordero, A. Tags: Model Organisms to Identify Synthetic Lethal Interactions: Oral Presentations - Invited Abstracts Source Type: research
Abstract B13: Synthetic vulnerabilities in MLL3 deficient pancreatic tumors
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 pat...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Gupta, S., Ferri-Borgogno, S., Reisenauer, M. R., Gupta, A. k., Maitra, A. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR12: Genome-wide in-vivo tumor xenograft CRISPR knockout screening for identifying KRAS mutant synthetic lethal interactions
The KRAS oncogene is frequently mutated in many of the most lethal human cancers and has been resistant to targeted therapies, leading to efforts to identify synthetic lethal genetic interactions in large-scale screens. These screens have been carried out largely in in-vitro cell culture systems using RNA interference (RNAi). Functional genomic screening using the bacterial type II clustered regularly interspaced short palindrome repeats and their associated proteins (CRISPR-Cas9) system has proven to be more powerful than RNAi for systematic genomic perturbation due to its simplicity, decreased off-target effects, and the...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Yau, E. H., Rana, T. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract IA12: Widespread rewiring of genetic interaction networks upon cancer pathway activation
Genetic interactions can reconstruct the wiring diagram of biological processes in health and disease. Gene-gene interactions are identified by simultaneously perturbing multiple gene products and identifying instances when the expected and experimentally measured phenotypes differ, e.g. aggravating or buffering phenotypic outcomes. Systematic gene-gene depletion experiment have been used to build comprehensive maps of cellular processes in unicellular and multicellular organisms, to place novel components into the context of known pathways and delineate epistatic relationships between components.Cellular signaling network...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Boutros, M. Tags: Model Organisms to Identify Synthetic Lethal Interactions: Oral Presentations - Invited Abstracts Source Type: research
Abstract B12: Analysis of Lipid Metabolism and Gene Expression in Hepatocellular Carcinoma Reveals Mitochondrial Function as a Potential Target for Combinatorial Treatment
Conclusion: These data point to the importance of lipid metabolic and mitochondrial oxidative dysfunction in the pathogenesis of hepatocellular carcinoma. We anticipate combining the inhibition of oxidative phosphorylation with the standard of care treatment consisting of sorafenib to allow for a much lower and better tolerated dose of both drugs while maintaining anti-tumor efficacy.Citation Format: Ali Zarrinpar, Tiziana Palumbo, Dinesh Barupal. Analysis of Lipid Metabolism and Gene Expression in Hepatocellular Carcinoma Reveals Mitochondrial Function as a Potential Target for Combinatorial Treatment [abstract]. In: Proc...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Zarrinpar, A., Palumbo, T., Barupal, D. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA11: Combinatorial screens in Drosophila cells
Our laboratory is combining a number of omics approaches (Mass Spec, RNAi, phosphoproteomics, and transcriptomics) to expand our understanding of the structure of signaling networks. Applying these approaches has allowed us to identify additional components of a number of signaling networks including the MAPK/ERK, AKT/PI3K, Hippo, Insulin and autophagy pathways (Friedman et al., 2011; Vinayagam et al., 2013; Neumüller et al., 2013; Kwon et al., 2013; Zirin et al., 2015; Vinayagam et al., 2016). An important finding from large-scale studies is that we could only functionally validate about half of the network compon...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Perrimon, N. Tags: Model Organisms to Identify Synthetic Lethal Interactions: Oral Presentations - Invited Abstracts Source Type: research
Abstract PR10: ScreenBEAM: a Novel Meta-Analysis Algorithm for Functional Genomics Screens via Bayesian Hierarchical Modeling
Motivation: Functional genomics (FG) screens, using RNAi or CRISPR technology, have become a standard tool for systematic, genome-wide loss-of-function studies for therapeutic target discovery. As in many large-scale assays, however, off-target effects, variable reagents' potency, and experimental noise must be accounted for appropriately control for false positives. Indeed, rigorous statistical analysis of high-throughput FG screening data remains challenging, particularly when integrative analyses are used to combine multiple sh/sgRNAs targeting the same gene in the library.Method: We use large RNAi and CRISPR repositori...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Yu, J., Silva, J. M., Califano, A. Tags: New Technology and Bioinformatics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract IA10: Finding vulnerabilities of drug resistant cancers
Intrinsic and acquired drug resistance represent major obstacles to effective cures for cancer. Understanding these mechanisms is instrumental for the design of strategies to counter these resistance mechanisms.In my presentation, I will focus on an example of intrinsic drug resistance and one of acquired drug resistance. As an example of intrinsic drug resistance, I will discuss the lack of response to MEK inhibitors seen in KRAS mutant tumors of various. The consistently poor response of KRAS mutant tumors to inhibition of its downstream kinases is unexpected, as it defies the concept of oncogene addiction. Nevertheless,...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Bernards, R. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Oral Presentations - Invited Abstracts Source Type: research
