tbuckley/cabot-search huggingface dataset:
Abstract 402: Biomarker-based pooled CRISPR-Cas9 screening: Platform development and validation
Authors: Tim M. Scales, Benedict C. Cross
Journal: Cancer Research (2017)

Abstract Functional genomic screening with CRISPR-Cas9 has provided a powerful and precise new way to interrogate the phenotypic consequences of gene loss in high-throughput, unbiased analyses. Rapid development of pooled lentivirus and deep-sequencing-led approaches have allowed us and others to exploit this technology in target ID, target validation, drug MOA analysis and patient stratification. Adaptation of the Cas9 nuclease by domain fusion and catalytic inactivation has further provided a novel way to both up and down-regulate gene expression using targeted, high-throughput CRISPRi and CRISPRa tools. To date, the vast majority of screens have been conducted using sgRNA abundance in surviving cell populations as an NGS-based proxy for proliferation, for example for in vitro resistance analysis to a cytotoxic treatment regimen. However, where cellular pathophysiology is uncoupled from cell health, the enormous promise of pooled CRISPR-Cas9 screening has been largely untapped. We now report on the development of a FACS-based platform that can be used to monitor biomarker-based cellular response in combination with high-throughput genetic screening. The endogenous interaction between CD28 and CD80 was used as a proof-of-concept paradigm and the performance of our platform was measured in screen-simulation conditions. We find that FACS-linked NGS was able to robustly identify the CD28 deleted cells from a complex population using a FITC-labelled CD80-Fc. Pseudo-blinding of the data yielded unambiguous identification of the expected target guides, with robust screening metrics, validating a new platform for myriad discovery programmes. Citation Format: Tim M. Scales, Benedict C. Cross. Biomarker-based pooled CRISPR-Cas9 screening: Platform development and validation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 402. doi:10.1158/1538-7445.AM2017-402
Exercise for Patients With Hypertrophic Cardiomyopathy
Authors: Alberto Soriano-Maldonado, José A. Vargas-Hitos, Juan Jiménez-Jáimez
Journal: JAMA (2017)

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Rates of EGFR, KRAS and ALK gene changes in lung cancer patients in Croatia.
Authors: Marko Jakopovic, Luka Brcic, Marija Misic, Fran Seiwerth, Gordana Drpa, Branka Cucevic, Sanja Plestina, Mihovil Roglic, Suzana Kukulj, Silvana Smojver-Jezek, Sven Seiwerth, Miroslav Samarzija
Journal: Journal of Clinical Oncology (2016)

e23238 Background: Rates in targetable gene changes varies between different populations of lung cancer patients. Targetable gene changes include changes in EGFR and ALK gene, as well as KRAS gene. Primary aim of this study was to determine mutation status in purely Caucasian Croatian population. Methods: After histological and/or cytological confirmation of lung non-sqamous non-small cell lung cancer tissue was obtained by bronchoscopy, surgery or trans-thoracic biopsy was consecutively sent for molecular testing. First we performed EGFR testing, than in negative patients KRAS testing was done, and then in double negative patients ALK immunohistochemistry was done. EGFR and KRAS testing were performed with the Cobas tissue test, and ALK was done by immunohistochemistry (IHC) with Ventana antybody. Results: During 6 months period 324 newely diagnosed primary lung adenocarcinoma were tested. Out of 324 tested patients, 194 were males (60%) and 130 females (40%) mean age 64 years (range 35 to 88 years). Vast majority of patients were in stages 3 and 4 (more than 80%). Among males, 87% of patients were ever smokers, and among females 61% of patients were ever smokers. Significantly higher rates of evers smokers were recorded among males. EGFR mutations were present in 15.7% of patients (51 patients). There was a difference in EGFR mutation rates between males and females (5.6 vs 30.8%, p < 0.0001). KRAS mutations (codones 12/12 and 61) were present in 35.8% (116) patients, and ALK translocation detected by IHC in 3.7% (12) patients. Conclusions: Molecular testing in primary lung adenocarcinoma patients was done in purely Caucasian Croatian population. EGFR mutation and ALK translocation rates were similar to previously published data. However, KRAS mutation rates were higher than previously published. This can be associated with high smoking rates in Croatian population.
Abstract 430: Combination of CB-839 and everolimus is effective in inhibiting growth of endocrine resistant breast cancer in vivo
Authors: Yassi Fallah, Diane M. Demas, Susan Demo, Ayesha N. Shajahan-Haq
Journal: Cancer Research (2017)

Abstract About 70% of all breast cancers are estrogen receptor alpha positive (ER+). Anti-hormone therapy such as antiestrogens are often used to treat ER+ breast cancer but breast cancer cells can develop resistance to these drugs (endocrine resistance). Unfortunately, ~50% percent of all antiestrogen treated tumors eventually develop endocrine resistance, and therefore, there is an urgent need to find ways to treat this incurable disease. We have shown that endocrine resistant breast cancer cells show an increased dependence on the amino acid glutamine and this process is regulated by MYC activation via the unfolded protein response (UPR). Metabolites of glutamine such as glutamate and proline are significantly elevated in endocrine resistant cells. Cellular changes in glutamine are sensed by the mammalian target of rapamycin (mTOR) complex, mTORC1, which is known to be deregulated in endocrine resistant breast cancer. In this study, we used human antiestrogen (Fulvestrant/Faslodex or Tamoxifen) sensitive and resistant ER+ breast cancer cells and xenografts to test the efficacy of CB-839, an anti-glutaminase, and everolimus (Afinitor), a mTORC1 inhibitor. Combination of CB-839 and everolimus, but not each drug alone, inhibited growth of antiestrogen resistant tumors compared to vehicle alone at 4 weeks post-treatment. The combination treatment did not significantly inhibit growth of antiestrogen sensitive tumors compared with its respective vehicle alone treatment. Thus, a combination strategy that targets glutamine dependence and increased mTOR activation may be a novel strategy in treating endocrine resistant breast cancer. Citation Format: Yassi Fallah, Diane M. Demas, Susan Demo, Ayesha N. Shajahan-Haq. Combination of CB-839 and everolimus is effective in inhibiting growth of endocrine resistant breast cancer in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 430. doi:10.1158/1538-7445.AM2017-430
MVA-5T4 immunotherapy (TroVax) and low-dose cyclophosphamide for advanced colorectal cancer (TaCTiCC): an open-label, randomized phase 1/2 clinical trial
Authors: Martin Scurr, Thomas Pembroke, Anja Bloom, David roberts, Amanda Thomson, Kathryn Smart, Hayley Bridgeman, Richard Admas, Alison Brewster, Robert Jones, Sarah Gwynne, Daniel Blount, Richard Harrop, Melissa Wright, Robert Hills, Awen Gallimore, Andrew Godkin
Journal: JAMA Oncology (2017)
Abstract 3357: Heritable methylation marks associated with breast cancer risk
Authors: Melissa C. Southey, Jihoon E. Joo, James G. Dowty, Roger L. Milne, EE Ming Wong, Pierre-Antoine Dugué, Dallas English, John L. Hopper, Daivd E. Goldgar, Graham G. Giles
Journal: Cancer Research (2017)

Abstract While most epigenetic marks are reprogrammed during early embryogenesis, some studies have reported Mendelian-like inheritance of germline DNA methylation in particular cancer susceptibility genes. We aimed to identify heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multi-generational families with multiple cases of breast cancer who were not known to carry mutations in breast cancer susceptibility genes. Peripheral blood DNA methylation was measured at approximately 480,000 genetic loci (methylation sites) for 210 members of these families using the Infinium HumanMethylation450 BeadArray. We developed and applied a new statistical method to identify heritable methylation marks based on complex segregation analysis. Carrier probabilities were estimated for the 1000 most heritable methylation marks, based on family structure but not disease status, and Cox proportional hazards survival analysis was used to test for associations between these carrier probabilities and breast cancer. After correcting for multiple testing, we identified 11 methylation marks whose corresponding carriers probabilities were significantly associated with breast cancer. Three marks clustered within 200 base pairs of the noncoding RNA miR886. We found evidence for these marks to be associated with aggressive (but not non-aggressive) prostate cancer risk in a population-based prostate cancer study. The association with breast cancer risk was replicated for three of the eleven marks in an independent population-based breast cancer study. Our work demonstrates the efficacy of our novel approach for identifying heritable methylation marks associated with breast cancer. This methodology may provide insights into other disease settings where known lifestyle exposures and genetic risk variants do not fully explain the familial relative risk. Citation Format: Melissa C. Southey, Jihoon E. Joo, James G. Dowty, Roger L. Milne, EE Ming Wong, Pierre-Antoine Dugué, Dallas English, John L. Hopper, Daivd E. Goldgar, Graham G. Giles. Heritable methylation marks associated with breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3357. doi:10.1158/1538-7445.AM2017-3357
Abstract 5536: The metastasis suppressor NME1 regulates stemness in melanoma
Authors: Ying Wang, David M. Kaetzel
Journal: Cancer Research (2017)

Abstract Melanoma is a lethal skin cancer that is highly resistant to therapy and prone to metastasize to distant organs. The quiescence melanoma stem cells are believed to account for the resistance to therapies. Traditional chemotherapies designed to target fast-proliferative tumor cells tend to miss quiescent stem cells. The escaped quiescent stem cells may accumulate oncogenic mutation from common mutagenic sources and finally lead to tumor relapse. NME1 is a metastasis suppressor gene that inhibits the metastatic potential in melanoma and other cancers. In this study, we focus on the role of NME1 in the regulation of stemness and quiescence of melanoma stem cells. We find that the genesis and growth of stem cell spheroids derived from melanoma cell lines are abrogated after knockdown of NME1. We also find that the mRNA level of several melanoma stem cell markers are elevated when we knockdown NME1. These results suggest that NME1 regulates the survival and stemness of melanoma stem cells. In addition, we demonstrate that melanoma stem cells are heterogeneous in NME1 expression. Specifically, the NME1 expression is markedly elevated in a highly proliferative subpopulation in the spheroids that express the stem cell markers OCT4, SOX2 and SOX10. Conversely, we observe another subpopulation of these spheroids that exhibits low NME1 expression and is non-proliferative. We hypothesize that this subpopulation consists quiescent melanoma stem cells that are more resistance to therapies, and that their quiescent status is controlled by the level of NME1. We are now employing CRISPR technology to separately study potentials in tumorigenesis, metastasis, and therapy-resistance of the stem cell subpopulations. Citation Format: Ying Wang, David M. Kaetzel. The metastasis suppressor NME1 regulates stemness in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5536. doi:10.1158/1538-7445.AM2017-5536
Abstract 4436: Novel microRNA signature score to predict bone metastasis and prognosis of breast cancer
Authors: Tstutomu Kawaguchi, Li Yan, Qianya Qi, Song Liu, Kazuaki Takabe
Journal: Cancer Research (2017)

Abstract Backgrounds: 40,000 US women still die with breast cancer every year. Vast majority of death occur after they develop metastasis, where bone is the most frequent site for breast cancer. New measures to identify the patients who develop metastasis allow us to intervene early, which is expected to prolong survival. The aim of this study is to establish a microRNA (miRNA) signature scoring system that can predict bone metastasis and survival utilizing integrated transcriptomics analyses in breast cancer. Materials and Methods: Both clinical and RNA expression data, including microRNA and mRNA, of 1051 patients were retrieved from The Cancer Genome Atlas (TCGA). 1) Multivariate Cox proportional hazard model and Kaplan-Meier for overall survival were performed to construct and identify novel models of miRNAs signature for predicting patient survival. 2) Competing risk analysis using the miRNAs signature was conducted to clarify its association with metastatic distributions. 3) Gene Set Enrichment Analysis (GSEA) was performed to identify the genome-epigenome significance of the miRNAs signature. Results: 1) Utilizing Cox model on TCGA cohort, we established a novel risk scoring system with three miRNAs signatures (miR-19a, miR-93, and miR-106a) that identified the patients population with extremely poor overall survival (p = 0.0004; 5-y survival rate, 49.2%). This result was reproduced in two other completely independent cohorts with microarray datasets (GSE19536, p = 0.0009; GSE22220, p = 0.0003, respectively). 2) Utilizing competing risk analysis for each metastatic sites of breast cancer, we found that the patients with bone metastasis demonstrated significantly high scores (p = 0.0052). The evaluation also showed a statistical tendency of association with lung metastasis (p = 0.0854). 3) We found that high score is associated with several critical gene sets such as angiogenesis (p &amp;lt; 0.0001) or epithelial mesenchymal transition (p = 0.0155) by GSEA that suggests that high signature score is associated with enhanced metastasis in breast cancer patients. Conclusions: We established a miRNAs signature scoring system to predict bone metastasis and poor overall survival in breast cancer using novel integrated transcriptomics concept. Citation Format: Tstutomu Kawaguchi, Li Yan, Qianya Qi, Song Liu, Kazuaki Takabe. Novel microRNA signature score to predict bone metastasis and prognosis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4436. doi:10.1158/1538-7445.AM2017-4436
Abstract 4070: Salternamide A, a marine natural product, suppresses hypoxia-induced accumulation of HIF-1α and induces apoptosis in human colorectal cancer cells
Authors: Duc-Hiep Bach, Woong Sub Byun, Seong-Hwan Kim, Ji-Young Hong, Hyen Joo Park, Dong-Chan Oh, Sang Kook Lee
Journal: Cancer Research (2017)

Abstract Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents. Acknowledgment This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) (MRC No. 2009-0083533) Citation Format: Duc-Hiep Bach, Woong Sub Byun, Seong-Hwan Kim, Ji-Young Hong, Hyen Joo Park, Dong-Chan Oh, Sang Kook Lee. Salternamide A, a marine natural product, suppresses hypoxia-induced accumulation of HIF-1α and induces apoptosis in human colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4070. doi:10.1158/1538-7445.AM2017-4070
Abstract 5335: Dissecting the ubiquitin pathway using homogenous and sensitive bioluminescent assay
Authors: Said A. Goueli, Kevin Hsiao, Subhanjan Mondal
Journal: Cancer Research (2017)

Abstract Post-translational modification of target proteins by ubiquitin (Ub) and ubiquitin-like (Ubl) proteins is a fundamental mechanism for regulating protein functions and protein stability thus affecting diverse cellular processes. Several ubiquitin-like (Ubl) molecules have been identified including SUMO, NEDD8, ATG8/15 and ISG15 which share the ubiquitin fold Ub/Ubl proteins are conjugated to lysine residues in substrate proteins through an ATP-dependent enzymatic cascade involving E1-activating enzyme, E2-conjugating enzyme and E3-ligase. To mark proteins for degradation, multiple ubiquitins are covalently attached to produce a Lys48 linked poly-ubiquitin chain. The poly-ubiquitinated proteins are recognized by the 26S proteasome system and deubiquitinated and destroyed. Substrates with ubiquitin chains linked through Lys 6, 11, 27, 29, 33 also regulate protein degradation. Substrates marked with mono-ubiquitination or Lys63 ubiquitin chains are involved in cell signaling independent of degradative functions. Many diseases are associated with dysfunction of ubiquitin signaling, with the E3 ligase class of enzymes are considered to be the most important target. However, in recent years, evidence have accumulated demonstrating the significance of E2 class of enzymes where mutations and impairment of this class lead to severe diseases states including chromosomal instability, cancer predisposition, neurological syndromes, and immunological disorders. Thus, in addition to E3, E2 group of enzymes represent important class of therapeutic targets. To address the need for developing drugs targeting these enzymes, we have developed a novel assay that can be used to screen for modulators of these enzymes by taking advantage of the first ubiquitin activating enzyme E1 which activates free Ub forming a high-energy thioester bond between E1’s active site Cys and the C-terminus of Ub, generating AMP and pyrophosphate (PPi) as products of the reaction. We monitor the activity of these enzymes by determining the concentration of AMP generated in the reactions in a luminescence-based assay. Our assay interrogate not only E1 but also E2 and E3 in a very robust and sensitive manner. The assay is homogenous, bioluminescent, and show a very high signal to background in a very selective manner for each class of the ubiquitin pathway. The assay was successfully tested for ubiquitination, SUMOlyation and Neddylation reactions and thus can be used for screening of enzymes targeting these pathways. Citation Format: Said A. Goueli, Kevin Hsiao, Subhanjan Mondal. Dissecting the ubiquitin pathway using homogenous and sensitive bioluminescent assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5335. doi:10.1158/1538-7445.AM2017-5335