tbuckley/cabot-search huggingface dataset:
Abstract 3680: Loss of ARID1A expression leads to sensitivity to ROS-inducing agents in ovarian cancer cells
Authors: Suet-Yan Kwan, Kwong-Kwok Wong
Journal: Cancer Research (2016)

Abstract AT-rich interactive domain-containing protein 1A (ARID1A) is frequently inactivated by mutations in a broad spectrum of cancer types, including ovarian and endometrial cancers. However, therapeutic strategies targeting ARID1A-mutant cancers remain limited. In this study, we aimed to identify drugs that selectively target ARID1A-mutant ovarian cancer cells. To this end, we compared the drug sensitivities of ARID1A-mutant and ARID1A-wildtype cancer cell lines using the Genomics of Drug Sensitivity in Cancer database. We found that ARID1A-mutant cancer cell lines were more sensitive to treatment with the reactive oxygen species (ROS)-inducing agent elesclomol compared to ARID1A-wildtype cancer cell lines. We validated this finding in a panel of ovarian and endometrial cancer cell lines, observing that treatment with elesclomol inhibited growth and induced apoptosis more potently in ARID1A-mutant cells than in ARID1A-wildtype cells. Knockdown of ARID1A expression in ARID1A-wildtype cells resulted in increased sensitivity to ROS-inducing agents, whereas re-expression of ARID1A in ARID1A-mutant cells resulted in decreased sensitivity. Finally, we found that knockdown of ARID1A expression resulted in increased intracellular ROS levels and subsequently promoted cell growth. In summary, we identified a novel role for ARID1A in protecting cells from oxidative stress and that ROS-inducing agents may be used to target ARID1A-mutant ovarian cancer cells. Citation Format: Suet-Yan Kwan, Kwong-Kwok Wong. Loss of ARID1A expression leads to sensitivity to ROS-inducing agents in ovarian cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3680.
Abstract 2169: High content screening in MCF7 and MCF10A cells show differential responses depending on oxygen levels and mechanistic readout for viability
Authors: Michelle Yan, Michael O’Grady, Anderson April, Scott Clarke, Quentin Low, Carolyn DeMarco, Veronica Calderon, Kathy Kihn, Leticia Montoya, Carmen Finnessy, Marcy Wickett
Journal: Cancer Research (2016)

Abstract Oxygen levels in typical cell culture conditions do not accurately reflect the oxygen levels cells are exposed to within the body. Furthermore, oxygen levels can vary within the tumor microenvironment. These variances can affect how cells respond to a variety of drugs and small molecules often used during cancer treatment. Previous studies have shown altered drug sensitivities in MCF7 cells depending on the oxygen levels the cells are grown in. To further understand how oxygen levels affect drug sensitivity, the response of tumorigenic MCF7 cells were compared to non-malignant MCF10A cells, cultured under low and high oxygen. The goal of this study was to examine the differences in the sensitivity of MCF7 and MCF10A cells to drugs from the Tocriscreen Total compound library when cultured under low and high oxygen levels and for different drug exposure time periods. Cells were grown using standard cell culture conditions (19% oxygen) or low oxygen (5%). Using high-content imaging and high-throughput analysis methods, viability was assessed using two different mechanistic readouts; cellular metabolic activity and membrane permeability. Post-screening analysis was performed to confirm positive hits by performing dose-responses and determining IC50 concentrations using the same reagents as in the screen, and reagents to assess oxidative stress and cellular proliferation. Results showed that viability differed depending on mechanistic readout and platform method used to determine hits as well as duration of exposure to compound. In addition, the response of MCF10A cells was not always identical to that of the MCF7 cells. Post-screening analysis of “hits” indicated different potencies of compounds tested depending on oxygen level and cell type. These data suggest that some drugs may affect MCF7 and MCF10A cells differently depending on environmental oxygen levels and mechanistic readout used to determine cellular health. Citation Format: Michelle Yan, Michael O’Grady, Anderson April, Scott Clarke, Quentin Low, Carolyn DeMarco, Veronica Calderon, Kathy Kihn, Leticia Montoya, Carmen Finnessy, Marcy Wickett. High content screening in MCF7 and MCF10A cells show differential responses depending on oxygen levels and mechanistic readout for viability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2169.
The RISC nomogram (RN) to predict overall survival (OS) of patients (pts) with metastatic urothelial carcinoma (mUC) receiving first-line platinum-based combination chemotherapy (CT).
Authors: Andrea Necchi, Guru Sonpavde, Salvatore Lo Vullo, Aristotelis Bamias, Simon J. Crabb, Lauren Christine Harshman, Joaquim Bellmunt, Ugo De Giorgi, Cora N. Sternberg, Sylvain Ladoire, Yu-Ning Wong, Evan Y. Yu, Simon Chowdhury, Guenter Niegisch, Sandy Srinivas, Ulka N. Vaishampayan, Sumanta K. Pal, Jonathan E. Rosenberg, Matt D. Galsky, Luigi Mariani
Journal: Journal of Clinical Oncology (2016)

e16026 Background: The available prognostic models (PM) for OS of pts with mUC were derived from clinical trial populations of cisplatin (cis)-treated pts. We sought to validate and improve these PM in light of the upcoming 1st-line trials pooling cis and carboplatin (carbo)-treated pts. Methods: Individual pt-level data from 29 centers was collected by electronic data capture. Selection criteria included mUC, 1st-line CT with a cis- or carbo-based combination CT. Prior peri-operative (po)-CT was allowed. The overall sample was randomly split into a training (Tr) and testing (Te) set. Generalized Boosted Regression Modeling was used first to exclude variables not associated with OS. Backward variable selection was then undertaken based on the p values obtained from Cox regression models. Platinum-type was incorporated in the analysis and RN as a stratification factor. A RN was built for estimating 1, 2 and 5-year OS probability. Distribution of nomogram scores (NS, from the Cox model) according to objective response (OR) was also analyzed. Results: 1,020 pts were analyzed (Tr: 687; Te: 333). Median OS was 14.3 and 13.7 months (m) in the Tr and Te set. Significant differences in OS were found between cis (N = 639) and carbo-CT (N = 381, p < .001). In the platinum-stratified Cox model, significant variables were: Performance Status (p < .001), body mass index (p = 0.002), ethnicity (p = 0.008), visceral metastases (p < .001), and prior po-CT (p = 0.018). The c-index of this model was more optimal than those of previous models that were tested in cis-treated pts from this cohort (Table). The NS were associated with OR (p < .001) and incorporating OR in the model further improved the c-index (0.683, 4m landmark analysis). Conclusions: We validated and extended prior PM with a 5-factor PM for OS using a large dataset of real world generally off-trial pts receiving 1st-line platinum based CT. The RN is applicable to pts regardless of cis or carbo-CT, it accounts for novel prognostic factors and predicts for OR. Future trials should employ this optimized RN. Model Tr set Te set Bajorin 1999 0.622 0.619 Apolo 2013 0.642 0.641 Galsky 2013 0.657 0.644 Present 0.666 0.649
BISCAY, a phase Ib, biomarker-directed multidrug umbrella study in patients with metastatic bladder cancer.
Authors: Thomas Powles, Elaine Kilgour, Richard Mather, Anne Galer, Hendrik-Tobias Arkenau, Andrew Farnsworth, Jonathan Wilde, Jayantha Ratnayake, Donal Landers
Journal: Journal of Clinical Oncology (2016)

TPS4577 Background: Despite progress with immunotherapy (IO), there remains a significant unmet medical need for patients with metastatic urothelial bladder cancer (UBC). A patient's molecular tumour profile enables a targeted small molecule (SM) + IO approach to treatment, particularly in PD-L1 -ve patients. Tumour biomarker profiling to enrol for trials assessing a single targeted agent leads to high screen failure rates and disappointment for patients who are biomarker-negative. BISCAYavoids these issues through centralised screening aligned to a portfolio of targeted SM+IO treatments, such that all patients are allocated to a treatment group determined by their tumour biomarker profile. Methods: Patients with metastatic UBC who have failed at least one prior platinum regimen are eligible. The primary objective is safety and tolerability of new combinations of SM and IO durvalumab (D) PD-L1 antibody treatment. Secondary objectives include overall response rate (ORR), and evaluating markers of response to combination treatment. Tumour samples are evaluated centrally utilising next generation sequencing and biomarker results are used to allocate patients to treatment (Table 1). The study will explore whether adding a SM to IO therapy in patients with specific biomarker expression may trigger increased neoantigen release and improve immunosensitisation. Biomarker prevalence and overlap, mechanism of action and preclinical data enabled a treatment allocation algorithm to be developed with the following adjusted prevalences: AZD4547 alone or in combination with D (~11%), D+O (~19%), D+AZD1775 (~46%) and D alone (~22%). 20 patients in each cohort will detect a 20% improvement over D ORR (80% probability). Additional combinations are being considered for inclusion as faster recruiting cohorts complete. Clinical trial information: NCT02546661.Biomarkers and treatment allocation. Treatment Group Target Tumour Biomarkers Prevalence (%) AZD4547 monotherapy FGFRi FGFR3 mut/fusions 11 D + AZD4547 FGFRi FGFR3 mut/fusions 11 D + olaparib (O) PARPi HRR gene panel 28 D + AZD1775 Wee1i CDKN2A homozygous loss/inactivation mut 35 RB1 homozygous loss/inactivatuion mut 24 CCNE1 amp 11 MYC, MYCL, MYCN amp 17 D monotherapy unselected 22
Tendances évolutives des infections à Salmonella Typhimurium multirésistante en Norvège
Authors: O Alvseike, T Leegaard, P Aavitsland, J Lassen
Journal: Eurosurveillance (2002)

Cet article decrit la tendance de Salmonella Typhimurium multiresistant isole chez l’homme de 1998 a 2000. Le premier cas est survenu en 1990 en Norvege. La plupart des infections a S. Typhimurium multiresistantes contractees en Norvege etaient dues au lysotype DT104. Nous devons nous attendre a une augmentation des infections primaires et secondaires si les lysotypes tels que DT104 phenotype ACSSuT deviennent endemiques.
Abstract 4735: Designing novel warheads for targeted therapies: SAR and efficient strategies for the synthesis of analogues of tubulysin
Authors: Iontcho Vlahov, Fei You, Paul Kleindl, Marilynn Vetzel, Joseph Reddy, Christopher Leamon
Journal: Cancer Research (2016)

Abstract Background: Tubulysins are natural products isolated from myxobacterial species. They are potent mitotic poisons as they inhibit the polymerization of tubulin into microtubules. Structurally, tubulysins are linear tetrapeptides comprised of N-Me pipecolic acid (Mep), isoleucine (Ile), tubuvaline (Tuv) and tubutyrosine (Tut). All natural tubulysins possess an acid-, base-, and enzyme-sensitive N-acyloxymethyl substituent, as well as a labile acetate group. For the natural tubulysins, both of these functional groups are essential for their potent cytotoxicity. The focus of this presentation is on design and synthesis of chemically stable analogs of tubulysin with improved biological activity. Methods: To explore the influence of tubulysin's functional groups on its cytotoxicity, we designed novel analogs, incorporating ether, thioether, amide and carbamate-based side chains. We also suggested basic SAR-rules for the activity of these synthetic analogs. Results: Structural features, critical for the tubulysin's cytotoxicity, were investigated. e.g., changing the (R)-OAc group of Tuv to (S)-NHAc completely abolished cytotoxicity, while analogs possessing (R)-NHAc on the Tuv moiety still exhibited activity. On the other hand, exchange of Tuv's (R)-OAc group with (R)-OMe had no influence activity. Replacement of the O-acyl part of N-acyloxymethyl substituent (dotted circle) with an alkyl or alkylthiol group resulted in N,O-acetals or N,S-thioacetals possessing similar or higher activity. Tup and Tut are interchangeable in terms of the activities of their respective tubulysin analogs. Conclusion: We designed and synthesized tubulysin analogs which are less prone to degradation under acidic and basic conditions, as well as enzymic influences. Structural features, essential for the cytotoxicity of the tubulysin analogs, were established. Some of the new compounds, especially those with N,S-thioacetal side chains, have increased cytotoxicity in comparison to natural tubulysins. These novel tubulysin analogs were used as warheads for folate receptor(FR)-targeted therapy. Citation Format: Iontcho Vlahov, Fei You, Paul Kleindl, Marilynn Vetzel, Joseph Reddy, Christopher Leamon. Designing novel warheads for targeted therapies: SAR and efficient strategies for the synthesis of analogues of tubulysin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4735.
Abstract 1350: New NCI experimental therapeutics program (NExT) small molecule libraries for academic investigator hts projects
Authors: Raj N. Misra, Michael Eckert, Christian Laggner
Journal: Cancer Research (2016)

Abstract The NCI Experimental Therapeutics Program (NExT) is making available two new smaller (3.5K) screening libraries suitable for academic investigator HTS drug discovery programs. The NExT program is a partnership between NCI's Division of Cancer Treatment and Diagnosis (DCTD) and the Center for Cancer Research (CCR). NExT consolidates NCI's anticancer drug discovery and development resources with the goal of maintaining a robust and balanced therapeutics pipeline. It encompasses tasks from new target validation through Phase III clinical trial evaluation. The Program is designed to streamline development and testing of promising new anticancer drugs and to expedite their delivery to the bedside. As part of the Program to support HTS drug discovery, NCI has previously offered academic oncology investigators access to our full 83K NExT Diversity Library in single-use, 384-well plate format. The set was designed to identify lead small molecules for drug discovery programs. We are now making available 2 smaller pre-plated subsets of this library, the NExT Diversity 3500 and NExT Diversity 3500 SAR, for when screening the full set is not appropriate. Each library contains 3,500 compounds: NExT Diversity 3500 is a diverse sampling across the entire 83K library while the NExT Diversity 3500 SAR is designed to facilitate rapid SAR follow-up by sampling only those compounds that have at least 5 close neighbors in the 83K library. The new libraries were designed by initially filtering the full NExT Diversity Library for undesirable compounds such as PAINS. Both atom-pair based 2D pharmacophore fingerprints and ECFP6 topological fingerprints from ChemAxon were then employed to generate the two non-overlapping subset libraries. The NExT screening libraries are provided as a resource to academic oncology investigators through the NExT Program (see NExT Resources: http://next.cancer.gov/). The design details and physiochemical characteristics of the two new sets, NExT Diversity 3500 and NExT 3500 SAR, and procedures and criteria for accessing this resource are presented along with several other screening sets available through the Developmental Therapeutics Program (DTP). Citation Format: Raj N. Misra, Michael Eckert, Christian Laggner. New NCI experimental therapeutics program (NExT) small molecule libraries for academic investigator hts projects. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1350.
Simultaneously Photo‐Cleavable and Activatable Prodrug‐Backboned Block Copolymer Micelles for Precise Anticancer Drug Delivery
Authors: Dongfang Zhou, Jinshan Guo, Gloria B. Kim, Jizhen Li, Xuesi Chen, Jian Yang, Yubin Huang
Journal: Advanced Healthcare Materials (2016)

A simultaneously photo-cleavable and activatable prodrug-backboned block copolymer (BCP) micelle strategy is demonstrated. Without light treatment, the micelles stay silent and inactivated, being biocompatible to normal tissues. Concurrent chain cleavage of BCP micelles and the activation of Pt(IV) prodrug could be temporally and spatially triggered by UV or even visible light for precise anticancer drug delivery. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Abstract 4797: Mutation signature and intratumor heterogeneity of esophageal squamous cell carcinoma in a Chinese cohort
Authors: Qingxuan Song, Mengfei Liu, Jian Bai, Amir Abliz, Wenqing Yuan, Zhen Liu, Jingjing Liu, Changhong Zeng, Hong Cai, Yang Ke, Jun Li
Journal: Cancer Research (2015)

Abstract Esophageal squamous cell carcinoma (ESCC) is one of the most common and most aggressive cancers. The epidemiological features of ESCC are extremely complex, with remarkable geographic differentiation among world's populations. While rural Anyang in the Henan Province of China is a well-known high-incidence area, the causal factors in this population remain elusive. We performed exome sequencing of 81 tumor-normal pairs, identified TP53, PIK3CA and NOTCH1 as significantly mutated genes, and observed highly recurrent aberrations in several other genes previously reported for ESCC (ZNF750, MLL2, FAT1, FAT2, and FAT3). Our catalog of ∼7,000 single-nucleotide mutations revealed two main signatures: C&amp;gt;T transitions due to spontaneous deamination of 5-methyl-cytosine, and C&amp;gt;T and C&amp;gt;G mutations at TpCpN attributed to the APOBEC family of cytidine deaminases. Per-sample loadings of these two signatures are uncorrelated with the patient's smoking and drinking status. Since APOBEC activities are associated with exogenous viruses, the prominence of this signature suggests a role of HPV in ESCC etiology, consistent with our previous studies that detected HPV DNA in tumor samples and anti-HPV-E7 antibody in patient's blood. To characterize intratumoral heterogeneity we applied our newly developed method, CHAT, to summarize the clonal frequencies of copy number alternations and single nucleotide mutations in each tumor. Many tumors show a multi-modal distribution of the clonal frequencies, suggesting extensive within-tumor diversity. To better understand the patterns of growth, migration and metastatic potential among different cells within a tumor we performing exome sequencing to compare multiple samples in 10 ESCC patients. For each, we analyzed 4-6 sectors of the tumor, 2-4 samples of adjacent normal tissue, and 1-2 nearby lymph nodes. The spatial heterogeneity of molecular lesions within each tumor is expected to uncover major genes and pathways affected in each patient, as well as the temporal progression of tumorigenic events that may have driven the initiation and outgrowth of ESCC. By integrating the mutation signatures, introtumoral clonal heterogeneity, and clinical outcomes, we aim to gain a better understanding of the molecular bases and evolutionary path of this lethal disease. Citation Format: Qingxuan Song, Mengfei Liu, Jian Bai, Amir Abliz, Wenqing Yuan, Zhen Liu, Jingjing Liu, Changhong Zeng, Hong Cai, Yang Ke, Jun Li. Mutation signature and intratumor heterogeneity of esophageal squamous cell carcinoma in a Chinese cohort. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4797. doi:10.1158/1538-7445.AM2015-4797
Abstract 3464: Low concordance with CEA tumor marker monitoring in colorectal cancer survivors
Authors: Guadalupe Palos, Katherine R. Gilmore, Patricia Chapman, Paula Lewis-Patterson, Weiqi Bi, Maria Alma Rodriguez
Journal: Cancer Research (2016)

Abstract Purpose: To assess providers’ concordance with surveillance and risk reduction recommendations for colorectal cancer (CRC) survivors after completion of their curative treatment. Patients and Methods: This was a longitudinal study of survivors who met the following eligibility criteria: diagnosed with a primary colon or rectal cancer before their first visit (V) to the CRC Survivorship Clinic, adult survivor ≥ 18 years old, no evidence of disease, alive at the time of data abstraction, and 1-3 clinic visits between 9/01/2011 and 8/31/2014. Data were collected at V1 scheduled between 9/1/2011 and 8/31/2012. V2 was scheduled 9-15 months after the first visit. V3 was also scheduled 9-15 months after V2. Data sources were survivorship care plans, electronic medical records, and CRC survivorship algorithms. For an annual visit, CRC algorithms recommended history/physical exams (H &amp; PEs), carcinoembryonic antigen (CEA) testing when previously elevated, and colonoscopies for surveillance of cancer recurrence. Concordance rates (CR) were measured as the percent of yes/no responses to whether the providers followed minimum standards for the 3 procedures. Demographic and clinical characteristics were also collected. Descriptive statistics were used to summarize all data. Results: 81 of 117 CRC survivors who met all eligibility criteria were included in this sub-analysis. The number of survivors visits varied across time, V1 = 81, V2 = 56, and V3 = 36. Most survivors were male (51.9%) and Caucasian (66.7%). 67.9% reported being 5-8 years post-treatment. 58% were diagnosed with colon cancer and of those 61.7% were Stage IIIA-IV compared to 55.8% of rectal cancer survivors with advanced disease. Table 1 summarizes the percentage of CR rates across the 3 visits. Conclusion: CRs for H &amp; PEs and colonoscopies remained high across the 3 visits. CRs were lowest for CEA recommendations. These low rates suggest further work is needed to determine barriers in clinical practice that limit use of CEA tumor marker monitoring in CRC survivors. Percent of Providers ConcordanceAlgorithm RecommendationVisit 1Visit 2Visit 3H &amp; PE100100100CEA53.338.322.2Colonoscopy97.598.2100 Citation Format: Guadalupe Palos, Katherine R. Gilmore, Patricia Chapman, Paula Lewis-Patterson, Weiqi Bi, Maria Alma Rodriguez. Low concordance with CEA tumor marker monitoring in colorectal cancer survivors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3464.
Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis
Authors: Gabriela Pavlasova, Marek Borsky, Vaclav Seda, Katerina Cerna, Jitka Osickova, Michael Doubek, Jiri Mayer, Raffaele Calogero, Martin Trbusek, Sarka Pospisilova, Matthew S. Davids, Thomas J. Kipps, Jennifer R. Brown, Marek Mraz
Journal: Blood (2016)