bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A177: Role of promoter methylation in regulation of Notch4 and JAG2 gene expression in human glioblastoma
Authors: Aithal Madhuri G S , Narayanappa Rajeswari 
Published: August 2018

Abstract
In cancer, DNA methylation causes alteration in gene expression affecting important signal transduction pathways. Since methylation occurs at a very early stage and is reversible, hypermethylated promoters hold great promise as biomarkers for early detection and effective drug targets for gene reactivation. The Notch signaling pathway is one such important developmental pathway governing cell fate decisions. Dysregulated Notch signaling is found to have a prominent role in the development of various cancers. Glioblastoma (GBM) is the most common primary brain tumor, with a very poor prognosis despite advanced treatment facilities due to poor molecular stratification. It is therefore important to study genetic and epigenetic events leading to gliomagenesis and to guide new treatment strategies. The aim of this study was to detect Notch pathway genes potentially regulated by promoter methylation in human GBM. We used real-time PCR and quantitative methylation-specific PCR to study methylation status of underexpressed Notch pathway genes from human GBM formalin-fixed, paraffin-embedded sections. 50% of samples showed methylation at Notch4 gene promoter at levels higher than 25 % (P &lt; 0.05). However, JAG2 gene promoter was estimated to be methylated at a negligible level (&lt;2 %) (P &lt; 0.05). Our study showed poor gene expression and high-level methylation of Notch4 gene, suggesting a possibility of epigenetic silencing. However, low JAG2 gene expression despite not being highly methylated suggests lack of correlation between gene expression and promoter methylation and the presence of alternative regulatory mechanisms. This study for the first time provides gene expression and DNA methylation profiles of Notch pathway genes from GBM patient samples. We have identified genes whose expression may be regulated by epigenetic mechanisms and thus can be used as potential biomarkers. This study will eventually give clues to improve diagnosis, prognosis, and treatment of GBM.
Citation Format: Madhuri G S Aithal, Rajeswari Narayanappa. Role of promoter methylation in regulation of Notch4 and JAG2 gene expression in human glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A177.
Abstract A185: Combining unbiased network analysis and cancer genomics to guide precision medicine-oriented early-phase clinical trials
Authors: Torres-Ayuso Pedro , Sahoo Sudhakar , Chester Christopher , Hodgkinson Cassandra , Galvin Melanie , Leong Hui Sun , Frese Kristopher , Marais Richard , Dive Caroline , Krebs Matthew , Brognard John 
Published: August 2018

Abstract
Background: Precision medicine aims to tailor cancer therapies to target specific tumor-promoting aberrations. For tumors that lack actionable drivers, extensive molecular characterization and preclinical drug efficacy studies will be required to match a patient with the appropriate targeted therapy. Patients and Methods: Next-generation sequencing, high-throughput signaling network analysis, and drug efficacy trials were used in a tumor-derived cell line and a patient-derived xenograft (PDX) model to identify actionable targets for therapeutic intervention. Results: A patient-derived xenograft (PDX) model for preclinical research was successfully established and no actionable mutations were identified after whole exome sequencing of the patient’s DNA. Whole genome sequencing revealed amplification of the 3q and 5p chromosomal arms, which include the PIK3CA and RICTOR genes, respectively. Consistent with amplification of these genes, pathway analysis revealed activation of the AKT pathway. Based on this analysis, efficacy of PIK3CA and AKT inhibitors were evaluated, and response to the AKT inhibitor AZD5363 was observed in in vitro and in vivo models established from the patient’s biopsy, indicating the patient would benefit from targeted therapies directed against the serine/threonine kinase AKT. Conclusion: High-throughput signaling pathway analysis complements next-generation sequencing approaches for detection of actionable alterations and will aid in patient stratification into early-phase clinical trials.
Citation Format: Pedro Torres-Ayuso, Sudhakar Sahoo, Christopher Chester, Cassandra Hodgkinson, Melanie Galvin, Hui Sun Leong, Kristopher Frese, Richard Marais, Caroline Dive, Matthew Krebs, John Brognard. Combining unbiased network analysis and cancer genomics to guide precision medicine-oriented early-phase clinical trials [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A185.
Abstract A186: Dual CRISPRi and CRISPRa screening reveals phenotypic switches in response to BRAF inhibition
Authors: le Sage Carlos , Panckier Prince , Cross Bendict CS 
Published: August 2018

Abstract
Functional genomic screening with CRISPR-Cas9 has provided a powerful and precise new way to interrogate the phenotypic consequences of gene manipulation in high-throughput, unbiased analyses. Rapid development of pooled lentivirus and deep-sequencing-led approaches has allowed us and others to exploit this technology in target ID, target validation, drug MOA analysis, and patient stratification. To date, the majority of screens have been conducted using loss-of-function perturbation driven by CRISPR-Cas9 enacted gene knockout. While powerful, this approach does not allow for the examination of activating gene function, leaving a salient hole in the functional genomic analysis. To address this, we have developed two new paired pooled screening platforms using catalytically inactivated Cas9 (dCas9) to control gene expression in both loss- and gain-of-function cell reprogramming. Our CRISPRi platform uses a streamlined and high-performance approach with an improved tracrRNA sequence incorporated into a single-shot transduction protocol. Our CRISPRa platform is based on the synergistic activation mediator (SAM) system and both platforms have been adapted to use next-generation, highly optimized whole-genome libraries in order to enact maximum gene expression modulation. Validation analysis of both tools revealed outstanding performance and sensitivity, with greater than ten-fold improvement in detection rates compared to existing platforms. We used these paired tools to explore the development of resistance mechanisms to the BRAF V600E inhibitor, vemurafenib. Unambiguous discovery of both expected hits and multiple novel genes involved in drug resistance was determined by both platforms. Those novel hits arising from the CRISPRi screen represented an enriched cohort of essential genes that have been missed by previous screens using RNAi and CRISPR-KO technologies. Most interestingly, simultaneous evaluation of both activating and inhibiting perturbations revealed direct and opposing phenotypic effects within complex gene networks, switching the response of affected cells to either sensitization or resistance. Thus, in contrast to loss-of-function-only analysis, this paired approach allows the discovery of key genes that control the drug response, but through an inhibitory mechanism. These genes were found to sit in the center of the hit nexus and revealed as key components only by the assimilation of both datasets, demonstrating the unique power of bidirectional functional genomic screening approaches.
Citation Format: Carlos le Sage, Prince Panckier, Bendict CS Cross. Dual CRISPRi and CRISPRa screening reveals phenotypic switches in response to BRAF inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A186.
Abstract A193: Quantitative global profiling reveals how RB-loss changes the metabolome, transcriptome, and proteome of cells and provides new opportunities to target RB-deficient cancer cells
Authors: Dowdle James , Nicolay Brandon , Haas Wilhelm , Dyson Nicholas , Miles Wayne O. 
Published: August 2018

Abstract
Disruption of the RB/E2F pathway is one of the hallmarks of cancer cells. There are, however, very few treatment options available to specifically target RB-deficient tumor cells. We hypothesized that was likely due to gaps in our knowledge about how RB-inactivation reprograms cells. To fill this void, we used a doxycycline-inducible shRNA system to deplete either RB or a negative control from non-tumorigenic human cells and profiled how RB-loss changed the metabolome (LCMS), transcriptome (RNA-seq), and proteome (mass spectrometry). By combining these quantitative approaches, we have identified statistically significant changes in 84 metabolites, 1257 mRNAs, and 527 proteins in RB-deficient cells, suggesting that RB-depletion results in widespread cellular reprogramming. Our analysis has identified (1) a number of new RB/E2F responsive pathways including the Interferon Response genes, extracellular matrix (ECM) proteins, and the Golgi apparatus; (2) significant increases in glucose metabolites and glucose metabolism proteins, independent of mRNA changes; (3) E2F target genes, which are well transcribed but show poor protein correlations; and (4) widespread increases in the purine and pyrimidine scavenging and synthesis pathways and their products. We have extended these experiments to confirm that these new pathways contribute to the phenotypes of RB-deficient cancer cells. Importantly, we then determined whether these mRNA and protein changes caused by RB-loss in cells are also seen in tumors. To do this we profiled RB1-/- retinoblastomas and normal retinal tissue. From these samples, we were able to characterize a number of highly homologous changes to the Interferon Response, purine/pyrimidine biosynthesis, ECM, glucose metabolism, and the RB/E2F target genes. Our results show that RB-loss effects many more biologic and potentially targetable pathways other than just pro-proliferation and apoptotic genes in both cell lines and tumors. We hope that this in-depth profiling of how RB-deficiency changes cells will provide new opportunities to develop methods to exploit the biologic dependencies caused by RB-loss.
Citation Format: James Dowdle, Brandon Nicolay, Wilhelm Haas, Nicholas Dyson, Wayne O. Miles. Quantitative global profiling reveals how RB-loss changes the metabolome, transcriptome, and proteome of cells and provides new opportunities to target RB-deficient cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A193.
Abstract A194: Transcriptome evaluation of papillary thyroid cancer with TERT promoter mutation
Authors: Cheng Shih-Ping , Chien Ming-Nan , Liu Chien-Liang , Hsu Yi-Chiung , Yang Po-Sheng , Lee Jie-Jen 
Published: August 2018

Abstract
Background: Mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene have recently been described in thyroid cancer and have been linked with poor prognosis. The mutations result in cancer-specific telomerase reactivation. However, functional effects of TERT promoter mutations other than telomere maintenance remain elusive. Methods: We examined papillary thyroid cancer data from The Cancer Genome Atlas. Clinicopathologic characteristics were compared between patients with or without TERT promoter mutations. A control cohort was selected from patients without TERT promoter mutations by propensity score matching. Differentially expressed genes were generated by comparing transcriptome profiling between the two groups. Results: A total of 382 patients with papillary thyroid cancer were included for analysis. TERT promoter mutations were identified in 36 patients. TERT promoter mutations were associated with older age, larger tumor size, the presence of extrathyroidal extension, more advanced TNM stage, and high risk of recurrence. Following propensity score matching, pathway analysis of differentially expressed genes indicated that TERT promoter mutations were associated with upregulation of DNA damage response and downregulation of nitric oxide signaling and fatty acid β-oxidation. Conclusion: Our results confirmed that acquisition of TERT promoter mutations in papillary thyroid cancer leads to bypass of replicative senescence. Furthermore, the mutations may be associated with other signaling and metabolic alterations. Our findings can potentially identify extended therapeutic targets.
Citation Format: Shih-Ping Cheng, Ming-Nan Chien, Chien-Liang Liu, Yi-Chiung Hsu, Po-Sheng Yang, Jie-Jen Lee. Transcriptome evaluation of papillary thyroid cancer with TERT promoter mutation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A194.
Abstract A196: Nano-diamino-tetrac (NDAT) enhances resveratrol-induced antiproliferation by reducing RRM2 expression in colorectal cancer cells
Authors: Chin Yu-Tang , Lin Chi-Yu , Shih Ya-Jung , Lin Shin-Ying , Chen YiRu , Mousa Shaker A. , Tang Heng-Yun , Lin Hung-Yun , Davis Paul J. 
Published: August 2018

Abstract
Tetraiodothyroacetic acid (tetrac) and its nanoparticulate derivative (Nano-diamino-tetrac, NDAT) inhibit cancer cell proliferation by multiple mechanisms. Resveratrol causes inducible COX-2-dependent antiproliferation in multiple types of cancer cells. Both agents suppress tumorigenesis in xenograft models. In the current study, we demonstrated the potentiating effect of NDAT on resveratrol-induced antiproliferation in human colorectal cancer cells. Induction of antiproliferation by resveratrol was shown by induction of COX-2, by increased expression of of antiproliferative genes and by reduction of transcription of pro-proliferative genes. Antiproliferation induced by NDAT was associated with downregulation of ribonucleoside-diphosphate reductase subunit 2 (RRM2), an inhibitor of resveratrol-induced COX-2 accumulation. Interestingly, resveratrol itself induced RRM2 expression in a concentration-dependent manner that was variable among different colorectal cancer cells. Knockdown of RRM2 by shRNA increased resveratrol-induced COX-2 expression. Combined treatment with resveratrol and NDAT in shRNA-transfected colorectal cancer cells resulted in further enhancement of COX-2 accumulation and antiproliferation. In summary, RRM2 is a target of NDAT and may contribute to increased resveratrol-induced antiproliferation in colorectal cancer cells in the presence of NDAT. From these studies, we expect to develop a cellular and molecular mechanistic framework for better delineation of the chemotherapeutic activities of NDAT with resveratrol against colorectal carcinogenesis. Novel biomarkers may also emerge from such studies.
Citation Format: Yu-Tang Chin, Chi-Yu Lin, Ya-Jung Shih, Shin-Ying Lin, YiRu Chen, Shaker A. Mousa, Heng-Yun Tang, Hung-Yun Lin, Paul J. Davis. Nano-diamino-tetrac (NDAT) enhances resveratrol-induced antiproliferation by reducing RRM2 expression in colorectal cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A196.
Abstract A205: Q701, a selective Axl and Mer inhibitor as an immune checkpoint inhibitor
Authors: Yang Yeong-In , Kang Hwankyu , Park Dongsik , Ahn Jiye , Choi Jinho , Ahn Seohyun , Kim Jaeseung , Nam Kiyean 
Published: August 2018

Abstract
Axl and Mer receptors are reported to have many functions, including promotion of epithelial-mesenchymal transition (EMT), resistance to antitumor therap,y and negative regulation of the innate immune response. Particular attention has been given to Axl and Mer receptor tyrosine kinase's (RTK) roles in regulating macrophage and NK cell activation as tumor cells exploit Axl and Mer signaling pathway to downregulate antitumor immunity, constituting an immune checkpoint. Q701 is a highly potent, selective, orally available Axl and Mer RTK inhibitor that can relieve immune suppression through innate immunity activation leading to T-cell activation. In various syngeneic mouse models, Q701 shows tumor regression activities by treatment of compound alone or in combination with other treatments, while Q701 has no direct cytotoxic activity against tested cell lines. Q701 treatment also show immune activation profile in tumor leading to T-cell activation. Q701 is under IND-enabling studies and a back-up program with Axl, Mer, and CSF1R inhibitors is in candidate nomination stage.
Citation Format: Yeong-In Yang, Hwankyu Kang, Dongsik Park, Jiye Ahn, Jinho Choi, Seohyun Ahn, Jaeseung Kim, Kiyean Nam. Q701, a selective Axl and Mer inhibitor as an immune checkpoint inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A205.
Abstract A210: Evaluation and comparison of the CDK 4/6 inhibitor palbociclib in a panel of PDX models representing hormone-positive and -negative breast cancer
Authors: Moriarty Alyssa , Mangold Amanda , Munoz Ileana , Groves Megan , Guerra Marcus , Rundle Melissa , Papadopoulos Kyriakos P. , Rasco Drew , Tolcher Anthony W. , Patnaik Amita , Wick Michael J. 
Published: August 2018

Abstract
Background: Palbociclib is a CDK 4/6 inhibitor approved in combination with letrozole in hormone-positive breast cancer. The START PDX platform comprises over 1300 fully annotated models, including a breast cancer panel of over 100 models representing each disease subtype: ~35 ER+, 20 HER2+, and 45 TNBC models. To better understand activity of CDK 4/6 inhibitors in breast cancer we screened our breast panel with single-agent palbociclib. The goal of this study was to determine and compare efficacy of a CDK 4/6 inhibitor in models representative of relevant subtypes of human breast cancer. Methods: START-PDX models were established from tissue biopsies or tissue samples taken from breast cancer patients. Sensitivity of 100 breast tumor models to single-agent palbociclib administered orally once daily at 75 mg/kg for a minimum of twenty-eight days was evaluated in a coclinical screen format. Study endpoints included mean tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion. Results: ER+ models showed variable sensitivity to palbociclib treatment, including ST897, ST986, and ST313, which reported tumor regressions. Interestingly, two ER+ harboring an ESR1 mutation and developed in the presence (ST941 and ST2177) or absence (ST941/HI and ST2177/HI) of exogenous estradiol reported differential sensitivity with the hormone-independent (HI) models more sensitive. Several TNBC models including ST319 and ST1394 reported sensitivity to palbociclib with %T/C values of 20% and 25%, respectively. Conclusion: We screened a panel of breast PDX models with the CDK 4/6 inhibitor palbociclib and identified activity in all breast cancer subtypes. In addition, we found a differential response in ER+, ESR1-mutant models developed in the presence and absence of exogenous estradiol. Exploration of biomarkers of sensitivity is ongoing.
Citation Format: Alyssa Moriarty, Amanda Mangold, Ileana Munoz, Megan Groves, Marcus Guerra, Melissa Rundle, Kyriakos P. Papadopoulos, Drew Rasco, Anthony W. Tolcher, Amita Patnaik, Michael J. Wick. Evaluation and comparison of the CDK 4/6 inhibitor palbociclib in a panel of PDX models representing hormone-positive and -negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A210.
Abstract B015: An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer
Authors: Xue Yaohua , Martelotto Luciano , Baslan Timour , Vides Alberto , Solomon Martha , Chadalavada Kalyani , DeStanchina Elisa , Nanjangud Gouri , Berger Michael , Lowe Scott , Reis-Filho Jorge S. , Rosen Neal , Lito Piro 
Published: August 2018

Abstract
Tumors evolve as they adapt to environmental cues. The principles governing evolution of tumors under the selective pressure of targeted therapy are not well understood. We aimed to evaluate the evolution of resistance and to identify therapeutic modalities that prevent this process in BRAFV600E-mutant tumors. We modeled the selection and propagation of BRAFV600E amplification (BRAFamp) in patient-derived tumor xenografts (PDX) treated with a direct ERK inhibitor. Single-cell sequencing and multiplex-fluorescence in situ hybridization mapped the emergence of extra-chromosomal amplification in multiple subclones of the same tumor shortly after treatment. The evolutionary selection of BRAFamp is determined by the fitness threshold, the barrier subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for ERK signaling inhibitors, and single-cell sequencing of a melanoma PDX model showed that drugs of the same pathway do not necessarily select for the same subclones. These data suggest that sequential monotherapy is not optimal, but concurrent targeting of RAF, MEK, and ERK, however, imposes a sufficiently high fitness threshold to prevent the propagation of subclones with high-level amplification. Administered on an intermittent schedule, this treatment inhibited tumor growth without apparent toxicity in 11/11-lung cancer and melanoma PDX models with various additional alterations. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose a high fitness threshold, such as our intermittent triple therapy, will likely prevent the evolution of resistance-causing alterations and merit testing in patients.
Citation Format: Yaohua Xue, Luciano Martelotto, Timour Baslan, Alberto Vides, Martha Solomon, Kalyani Chadalavada, Elisa DeStanchina, Gouri Nanjangud, Michael Berger, Scott Lowe, Jorge S. Reis-Filho, Neal Rosen, Piro Lito. An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B015.