tbuckley/cabot-search huggingface dataset:
Abstract 5411: Demonstrated improvements in tumor profiling with enzymatic ribosomal RNA depletion and streamlined RNA-sequencing library preparation
Authors: Nancy H. Nabilsi, Drew Cheney, Leendert Cloete, Ida van Jaarsveld, Rachel Kasinskas, Jennifer Pavlica
Journal: Cancer Research (2017)

Abstract High resolution RNA analysis using next-generation sequencing (RNA-seq) is a rapidly growing application in cancer research. Formalin-fixed paraffin-embedded (FFPE) tissue is a ubiquitous resource for clinical studies. However, the ability to generate high quality libraries is confounded by the low quality and yield of RNA extracted from FFPE specimen. To enable optimal interrogation of such a clinically-relevant tissue resource, it is critical to identify RNA-seq library construction workflows that improve performance using challenging and degraded sample types. In this study, the effects of RNA type, quality, and quantity on RNA-seq library construction are assessed, and expectations regarding sequencing data quality are addressed. Included are recommendations for quality control measures and input-specific modifications that may improve performance Three workflows employing either bead-based or enzymatic strategies for the removal of ribosomal RNA content were used to prepare RNA-seq libraries from degraded paired breast normal and tumor samples. Enzymatic depletion followed by library preparation using the KAPA RNA HyperPrep1 workflow identified the highest number of transcripts for each sample, translating to a 4.9-fold increase in number of differentially expressed transcripts detected between normal and tumor samples. Of the transcripts identified as differentially expressed exclusively by Kapa, 174 are protein-coding RNAs, many of which are frequently dysregulated in breast cancer. In contrast, only two protein-coding RNAs were identified exclusively by the alternative workflows. RealTime Ready Custom panels were used for independent quantitative rt-PCR assessment. Of a subset of 71 transcripts identified exclusively by Kapa, up to 69 (97%) were validated as differentially expressed. Additional performance improvements of the KAPA RNA HyperPrep workflow include coverage balance across transcripts, lower duplication rate, technical replicate reproducibility, agreement across input quantities, and gene expression concordance between paired fresh frozen and FFPE samples. 1For Research Use Only. Not for use in diagnostic procedures. Citation Format: Nancy H. Nabilsi, Drew Cheney, Leendert Cloete, Ida van Jaarsveld, Rachel Kasinskas, Jennifer Pavlica. Demonstrated improvements in tumor profiling with enzymatic ribosomal RNA depletion and streamlined RNA-sequencing library preparation [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 5411. doi:10.1158/1538-7445.AM2017-5411
When Insulin Therapy Fails: The Impact of SGLT2 Inhibitors in Patients With Type 2 Diabetes
Authors: Stewart B. Harris, Selam Mequanint, Kristina Miller, Sonja M. Reichert, Tamara Spaic
Journal: Diabetes Care (2017)

Insulin is the most effective therapy for achieving optimal glycemic control; however, many patients with type 2 diabetes on an intensified treatment regimen fail to achieve the recommended HbA1c target (1,2) and face the risk of adverse effects such as hypoglycemia and weight gain (3). The addition of sodium–glucose cotransporter 2 (SGLT2) inhibitors to a regimen of insulin therapy in this patient population has the potential to mitigate insulin-related weight gain and risk of hypoglycemia, with the added benefit of insulin dose reduction (4). Randomized controlled trials (RCTs) have shown improved clinical outcomes of SGLT2 inhibitors as monotherapy and as an add-on to oral and insulin therapy, but there is a paucity of real-world (RW) studies evaluating similar outcomes.

Data extracted from WebDR (5) was used to evaluate the RW clinical impact of SGLT2 inhibitors (initiation of canagliflozin or dapagliflozin between February 2014 and December 2016) as an add-on to insulin therapy in patients with type 2 diabetes not achieving glycemic targets (those with HbA1c >7% [>53 mmol/mol]). Empagliflozin was excluded because of inadequate sample size. Ethical approval …
Abstract 2660: PD-1 blockade in combination with zoledronic acid to enhance the antitumor efficacy in the breast cancer mouse model
Authors: Yuan Li, Yang Du, Ting Sun, Huadan Xue, Jie Tian, Zhengyu Jin
Journal: Cancer Research (2017)

Abstract Purpose: Blockade of PD-1 receptor may provide proof of concepts for the activity of an immune-modulation approach for the treatment of a breast cancer (BC). Zoledronic acid (ZA) has been proven to inhibit angiogenesis, invasion, and adhesion of tumor cells. The aim of this study was to investigate the potential of antibody treatment towards the T-cell checkpoint inhibitor PD-1 alone or in combination with ZA in BC mouse model. Experimental Design: The 4T1-Luc mouse mammary tumor model was used in this study. The anti-tumor efficacy of anti-PD-1 antibody alone or in combination with ZA was monitored by measuring tumor volume and bioluminescence imaging (BLI). At the end of study, the tumor immunohistochemistry was performed to confirm the in vivo observation and flow cytometry was used to determine the immune cell population in tumors. The survival rate was also calculated to evaluate the treatment efficacy. Results: The results showed that mice treated with the combination therapy exhibited the best antitumor response compared to untreated controls or single therapy. Furthermore, Combination therapy inhibited tumor regrowth as determined by BLI imaging, and thus significantly improved the median overall survival compared to other groups. Conclusions: Our study provides evidence for enhanced clinical BC treatment benefit from targeting co-signal molecules by combining PD-1 blockade with ZA treatment. Citation Format: Yuan Li, Yang Du, Ting Sun, Huadan Xue, Jie Tian, Zhengyu Jin. PD-1 blockade in combination with zoledronic acid to enhance the antitumor efficacy in the breast cancer mouse model [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 2660. doi:10.1158/1538-7445.AM2017-2660
Abstract 2106: In-depth profiling of the energy depletion-mediated cancer cytotoxicity by passively delivered zinc complexes via PARP1 activation
Authors: Jinhyuk F. Chung, Tae Jung Park, Yoko Norihisa
Journal: Cancer Research (2017)

Abstract Dysfunctional apoptotic function from impaired p53 tumor suppressor activity leads to poorer prognosis in cancer patients by compromising drug sensitivity and promoting drug resistance development. Programmed necrosis following energy crisis is a theoretically proposed cytotoxic mechanism for circumventing this problem. Herein we demonstrate that a biodegradable zinc complex is capable of triggering the programmed necrosis via activation of PARP1/PARG/MPTP, which consistently resulted in p53-independent broad spectrum cytotoxicity in vitro across all 20 cancer cell lines tested including many with reported drug resistance phenotypes. Additionally, we investigated its possible interaction with agents that influence p53 for possible antagonism/synergism. Supporting in vivo evidence in both animal models and clinical case studies involving terminal chemo-resistant gastric cancer patients upon oral administration (30 mg Zn/day) are presented. These results implicate macromolecular biodegradable zinc complexes as promising antitumor agents of simple compositions for overcoming the current hurdles in clinics, and warrant further clinical investigations. We plan to advance the studies through non-invasive smart devices reporting real-time blood glucose, blood pressure, microperfusion, and other hemodynamic parameters. Citation Format: Jinhyuk F. Chung, Tae Jung Park, Yoko Norihisa. In-depth profiling of the energy depletion-mediated cancer cytotoxicity by passively delivered zinc complexes via PARP1 activation [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 2106. doi:10.1158/1538-7445.AM2017-2106
Abstract 2418: Characterization of the PAX8 regulatory network in epithelial ovarian cancer
Authors: Rosario I. Corona, Emily Adler, Janet M. Lee, Norma Rodriguez-Malave, Paulette Mhawech-Fauceglia, Heidi Sowter, Dennis J. Hazelett, Kate Lawrenson, Simon A. Gather
Journal: Cancer Research (2017)

Abstract PAX8 is a lineage-restricted transcription factor expressed in a large proportion of epithelial ovarian cancers (EOCs). PAX8 is commonly upregulated in EOCs relative to precursor tissues, suggesting it functions as an oncogene. However, the biological role of PAX8 during cancer initiation and development is poorly understood, and the genome-wide transcriptional targets have yet to be comprehensively catalogued. Using stable models of PAX8 knockdown in HEYA8 and IGROV1 EOC cell lines we show that PAX8 knockdown reduces cell proliferation in vitro and tumor growth in vivo. To understand how PAX8 regulates neoplastic phenotypes in cancer cells we performed RNA expression profiling by microarray in HEYA8 and IGROV1 before and after PAX8 knockdown. We also performed chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) for PAX8 and a marker of active chromatin (H3K27ac) in both cell lines. De novo motif discovery in the ChIP-seq profiles identified a PAX-like binding motif and several potential PAX8 cofactors in IGROV1 that are not enriched in HEYA8. These cofactors include members of the TEAD and Sp/KLF families of transcription factors. We divided the genes from our differential expression (DE) analysis in PAX8 knockdown into three non-overlapping categories: (a) direct regulatory targets (RTs), i.e. DE genes with PAX8 binding sites in their promoter regions; (b) putative enhancer RTs, where DE genes and PAX8 binding sites reside within the same topological association domain (TAD) defined from embryonic stem cells; and (c) indirect RTs. Our findings reveal that PAX8 can function as either an activator or a repressor, and that PAX8 regulates a very different set of genes in each cell line, as only a small fraction RTs (~50) is shared between HEYA8 and IGROV1. Nonetheless, independent pathway enrichment analysis reveals four pathways downstream of PAX8 that are common to both cell lines: DNA replication, cellular response to lipopolysaccharides, TNFA signaling via NFKB and anatomical structure morphogenesis. Individually, we discovered enrichment for G2M checkpoint and EMT signaling in HEYA8, and tissue morphogenesis and mesenchymal cell development in IGROV1. Collectively, our results suggest that PAX8 regulates cell proliferation and cancer promoting processes via highly tissue-specific regulation of common oncogenic pathways. Citation Format: Rosario I. Corona, Emily Adler, Janet M. Lee, Norma Rodriguez-Malave, Paulette Mhawech-Fauceglia, Heidi Sowter, Dennis J. Hazelett, Kate Lawrenson, Simon A. Gather. Characterization of the PAX8 regulatory network in epithelial ovarian 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 2418. doi:10.1158/1538-7445.AM2017-2418
Risk of cutaneous squamous cell carcinoma after treatment of basal cell carcinoma with vismodegib
Authors: Tina Bhutani, Michael Abrouk, Camelia S. Sima, Natalia Sadetsky, Jeannie Hou, Ivor Caro, Mary-Margaret Chren, Sarah T. Arron
Journal: Journal of the American Academy of Dermatology (2017)
Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring <i>MET</i> Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models
Authors: Lars D. Engstrom, Ruth Aranda, Matthew Lee, Elizabeth A. Tovar, Curt J. Essenburg, Zachary Madaj, Harrah Chiang, David Briere, Jill Hallin, Pedro P. Lopez-Casas, Natalia Baños, Camino Menendez, Manuel Hidalgo, Vanessa Tassell, Richard Chao, Darya I. Chudova, Richard B. Lanman, Peter Olson, Lyudmilla Bazhenova, Sandip Pravin Patel, Carrie Graveel, Mizuki Nishino, Geoffrey I. Shapiro, Nir Peled, Mark M. Awad, Pasi A. Jänne, James G. Christensen
Journal: Clinical Cancer Research (2017)

Abstract Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non–small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del–positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors. Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials. Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA. Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661–72. ©2017 AACR.
Abstract 328: PARP inhibitors suppress growth of EGFR-mutant cancers by targeting nuclear PKM2
Authors: Nan Li, Steven H. Lin
Journal: Cancer Research (2017)

Abstract Poly(ADP-robose) polymerase-1 (PARP1) or ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1) is the most abundant and the best understood member of the 17 PARP family proteins. PARP1 binds to both single strand breaks (SSBs) and double-strand breaks (DSBs) and participates in the recognition, excision and repair of DNA damage. The most extensively studied role of PARP1 is its involvement in base excision repair (BER) and PARP inhibition induced-trapping of PARP1 during BER. Moreover, suppression of PARP1/2 leads to synthetic lethality in BRCA1/2-defecient tumors, indicating that PARP1-dependent BER and BRCA-dependent homologous repair pathway have overlapping and redundant functions in DNA repair. Recent studies have also pointed to a broader utility of PARP inhibitors beyond hereditary BRCA-deficient cancers. Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme that converts phosphoenolpyruvate (PEP) into pyruvate. Up-regulation of PKM2 has been shown recently to be an important feature of tumorigenesis. In tumor cells, PKM2 forms a dimmer that is catalytically inactive as a glycolysis enzyme, but provides advantage for tumor progression due to Warburg effect. In this report, we demonstrated that poly-ADP-ribose (PAR) is required for nuclear retention and nuclear function of PKM2. PKM2 translocates into nucleus and binds to PAR upon EGF stimulation. PARP inhibition, or the PKM2-C/A mutant, which abolishes the PKM2/PAR interaction, suppresses the nuclear function of PKM2. In addition, PARP inhibition also diminishes the nuclear PKM2-dependent glycolysis and tumor growth. Moreover, we showed that nuclear localization of PKM2 correlates with PAR expression in EGFR-mutant human lung cancer tissues. Interestingly, PARP inhibition leads to growth suppression of some EGFR-mutant lung cancer cells, which are resistant to EGFR inhibitor. These data together support an unexpected function of PARP inhibition in tumor suppression and indicate that nuclear PKM2 may serve as a promising biomarker for the further development of PARP inhibitor-based therapies. Note: This abstract was not presented at the meeting. Citation Format: Nan Li, Steven H. Lin. PARP inhibitors suppress growth of EGFR-mutant cancers by targeting nuclear PKM2 [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 328. doi:10.1158/1538-7445.AM2017-328
Abstract 5214: Activation of WNT/b-catenin signaling results in resistance to PI3K/mTOR dual inhibitor in co-existing KRAS and PIK3CA mutant colorectal cancer cells
Authors: Ye-Lim Park, Hwang-Phill Kim, Seul-Ki Cheon, Jun-Kyu Kang, Yoojoo Lim, Sang-Hyun Song, Sae-Won Han, Tae-you Kim
Journal: Cancer Research (2017)

Abstract KRAS is a frequently mutated gene in colorectal cancer. In addition, PIK3CA mutations commonly co-exist with KRAS mutations and lead to additive activation of the PI3K/mTOR signaling pathway. Here, we investigated preclinical activity of gedatolisib, a PI3K/mTOR dual inhibitor, to identify mechanism of inhibition of PI3K/mTOR in 28 colorectal cancer (CRC) cells. Cells specifically with PIK3CA mutation were sensitive while those with KRAS mutation were resistant to gedatolisib. 9 out of 28 CRC cells harbor PIK3CA &amp; KRAS co-mutation and 7 out them were shown to be sensitive to gedatolisib. However, HCT15 and LS174T cells were resistant. We identified that resistant cell lines have high activity of GSK3B and TCF7 frameshift mutation (465insertC466;H155fs*), which functions as positive regulator of WNT/b-catenin pathway. The effects of GSK3B-knockdown showed decreased activity of mTOR downstream molecules in gedatolisib-treated resistant cells. Interestingly, these effects also caused a decrease in activity of WNT/b-catenin pathway. In addition, combination treatment of gedatolisib and CHIR-99021, GSK3B inhibitor, resulted in significantly enhanced cytotoxicity against gedatolisib-resistant TCF7 frameshift mutant cells. Taken together, these show that aberrant regulation of WNT/b-catenin pathway and high activity of GSK3B by TCF7 frameshift mutation cause resistance to PI3K/mTOR dual inhibitor. Inhibition of GSK3B activity in colorectal cancer cells with KRAS and PIK3CA co-mutations increases sensitivity to PI3K/mTOR dual inhibitor. Citation Format: Ye-Lim Park, Hwang-Phill Kim, Seul-Ki Cheon, Jun-Kyu Kang, Yoojoo Lim, Sang-Hyun Song, Sae-Won Han, Tae-you Kim. Activation of WNT/b-catenin signaling results in resistance to PI3K/mTOR dual inhibitor in co-existing KRAS and PIK3CA mutant 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 5214. doi:10.1158/1538-7445.AM2017-5214
Abstract 789: Establishment of an <i>in vitro</i> model for the study of vasculogenic mimicry in ovarian and gastrointestinal cancer cells
Authors: Andres Valdivia, Dusan Racordon, Raul Aravena, Gabriel Mingo, Alejandra Sandoval, Maria Loreto Bravo, Mauricio A. Cuello, Sumie Kato, Rafaela Erices, Carolina Ramirez, Pamela Gonzalez, Beatriz Sanchez, Alejandro H. Corvalan, Gareth I. Owen
Journal: Cancer Research (2017)

Abstract Introduction: A key step in cancer progression is tumor irrigation. The process of angiogenesis can be complemented in sub-sets of highly aggressive cancers by the process of vasculogenic mimicry, which is the formation of tubular structures by tumor cells. Herein, we sought to establish an in vitro assay of vasculogenic mimicry and determine the percentage of ovarian and gastrointestinal primary cultures capable of undergoing this process. Materials &amp; Methods: Gastric cancer cell lines, AGS and Hs746T, and the ovarian cancer cell lines SKOV-3 and HEY were used in conjunction with gastrointestinal and ovarian primary cultured cancer cells extracted from peritoneal fluid. Cells were seeded on matrigel and monitored for a week. Hollow channels formation was evaluated by fluorescent dye microinyection, periodic acid Schiff staining, confocal microscopy and X-Ray microtomography (Micro-CT). Results: SKOV-3, HEY and AGS cell lines underwent the process of vasculogenic mimicry. Both confocal microscopy and Micro-CT reconstruction were able to show the presence of a lumen of the structures in 3D. In 22 primary cancer cultures (Ovarian, Colon and Gastric) only 38% could underwent vasculogenic mimicry. Discussion: We have standardized an in vitro assay to assay and quantify vasculogenic mimicry. Regardless of origin, only a low percentage of cultures have the ability to undergo vasculogenic mimicry. An understanding of this process could shed light on new therapies for this sub-set of highly aggressive cancers. Funding: FONDECYT 1120292, 3150028 &amp; 1140970. CORFO L2 13IDL2-18608, BMRC 13CTI 21526-P6, IMII P09/016-F, CONICYT-FONDAP #1513001 Citation Format: Andres Valdivia, Dusan Racordon, Raul Aravena, Gabriel Mingo, Alejandra Sandoval, Maria Loreto Bravo, Mauricio A. Cuello, Sumie Kato, Rafaela Erices, Carolina Ramirez, Pamela Gonzalez, Beatriz Sanchez, Alejandro H. Corvalan, Gareth I. Owen. Establishment of an in vitro model for the study of vasculogenic mimicry in ovarian and gastrointestinal 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 789. doi:10.1158/1538-7445.AM2017-789