bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4331: Discovery of potent 2-Indole-acylsulfonamide Mcl-1 inhibitors using structure guided fragment-based methods
Authors: Shaw Subrata , Tarr James Chris , Pelz Nicholas , Bian Zhiguo , Belmar Johannes , Zhao Bin , Goodwin Craig , Arnold Allison , Sensintaffar John , Rossanese Olivia , Lee Taekyu , Olejniczak Edward , Fesik Stephen 
Published: July 2016

Abstract
Mcl-1 (Myeloid cell leukemia 1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and is one of the major acquired resistance mechanisms for many anticancer therapies. Targeting Mcl-1 with small molecules is very challenging because Mcl-1 exerts its effects through protein-protein interactions. Here we describe our continuing efforts in the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. We previously described the discovery of small-molecule Mcl-1 inhibitors containing a 2-indole-carboxylic core that primarily bind to the P2 pocket. In order to enhance potency, we extend our molecules to occupy the entire BH3 binding interface. A number of P4 site hits were identified using a fragment-based screening while the P2 pocket of Mcl-1 was saturated with our previously reported lead. P4 site ligands were then linked to our initial lead guided by the ternary Mcl-1 structure containing both P2 and P4 units using an acylsulfonamide as a synthetic handle that retained the critical charged-charged interaction with R263. X-ray co-crystal structures of new inhibitors occupying both P2 and P4 sites bound Mcl-1 provided detailed information on how these small-molecules bind to the target and guided subsequent potency optimization. From the efforts, we discovered a novel series of 2-indole-acylsulfonamide containing Mcl-1 inhibitors that exhibit low nanomolar binding affinities to the target and greater than 500-fold selectivity over Bcl-xL. These compounds represent useful starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers.
Citation Format: Subrata Shaw, James Chris Tarr, Nicholas Pelz, Zhiguo Bian, Johannes Belmar, Bin Zhao, Craig Goodwin, Allison Arnold, John Sensintaffar, Olivia Rossanese, Taekyu Lee, Edward Olejniczak, Stephen Fesik. Discovery of potent 2-Indole-acylsulfonamide Mcl-1 inhibitors using structure guided fragment-based methods. [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 4331.
Abstract 4333: Identification and optimization of the first highly selective GLUT-1 inhibitors
Authors: Bauser Marcus , Buchmann Bernd , Siebeneicher Holger , Cleve Arwed , Rehwinkel Hartmut , Neuhaus Roland , Heisler Iring , Mueller Thomas , Kopitz Charlotte Christine 
Published: July 2016

Abstract
Increased glycolysis rates combined with an insufficient cellular respiration in tumor cells have been known for decades as the Warburg effect (1930). One of the key players in this metabolic alteration of cancer cells is glucose transporter 1 (or GLUT-1), which facilitates the transport of glucose across the plasma membranes of mammalian cells. Many tumor biopsies underline the crucial importance of GLUT-1 overexpression for the vitality of many tumor entities. Moreover the glucose uptake dependency of cancer cells can be visualized by the widespread clinical application of 18fluorodeoxyglucose (FDG) uptake in PET tumor imaging. Therefore, inhibition of glucose uptake for the treatment of cancer seems to be an interesting approach.
Based on our first identified GLUT-1 inhibitors (1H-pyrazolo[3,4-d]pyrimidines) with modest selectivity profile, a high throughput screen (HTS) was performed to identify new potent lead structures with unique selectivity against the other members of the GLUT-1 family (GLUT-2,-3 and -4). Among several lead structures we identified from the HTS the quinoline carboxamides with the most promising selectivity profile. Extensive SAR elaboration by synthesizing more than 1600 new derivatives of the lead structure clearly revealed the essential moieties for high activity, potency, and selectivity. Additionally, we were able to improve the in vitro and in vivo PK properties permitting in vivo animal studies. We are able to report for the first time the preclinical profile and structure of the very potent and highly selective GLUT-1 inhibitor BAY-876 representing an ideal tool to further evaluate the scope and limitations of GLUT-1 inhibition as new therapeutic option.
Citation Format: Marcus Bauser, Bernd Buchmann, Holger Siebeneicher, Arwed Cleve, Hartmut Rehwinkel, Roland Neuhaus, Iring Heisler, Thomas Mueller, Charlotte Christine Kopitz. Identification and optimization of the first highly selective GLUT-1 inhibitors. [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 4333.
Abstract 4352: Discovery of the first cell-active inhibitors of poly(ADP Ribose) glycohydrolase through high-throughput screening and computational approaches
Authors: Waszkowycz Bohdan , James Dominic , Durant Steven , Hamilton Nicola , Jones Cliff , Jones Stuart , Jordan Allan , Lau Alan , MGonagle Alison , O’Connor Mark , Smith Kate , Stowell Alex , Tucker Julie , Waddell Ian , Ogilvie Donald 
Published: July 2016

Abstract
DNA repair is a critical process for the survival and normal proliferation of healthy cells. However, given the enhanced levels of cellular stress and genomic instability, these repair processes are even more critical to the survival of malignant cells, where rates of DNA damage are considerably increased. Given this, inhibitors of DNA damage repair have seen a resurgence of interest in recent years in an effort to exploit tumour cell vulnerabilities. One such example of this approach has resulted in the recent approval of the PARP inhibitor olaparib (Lynparza™) for women with advanced ovarian cancer associated with defective BRCA genes.
Olaparib acts against the poly(ADP-ribose)polymerase (PARP) enzymes, more recently re-defined as the ARTD (Diphtheria toxin-like human ADP-ribosyltransferase) enzyme class. Whilst PARP is widely known to play critical and well-understood roles in DNA repair, poly(ADP ribose) glycohydrolase (PARG) is less well known but equally essential for effective DNA repair, degrading PAR chains and facilitating effective DNA repair. However, its inhibition may offer several key advantages over PARP inhibition. Most critically, whilst there are 18 isoforms, there exists only a single PARG protein, offering a specific point of therapeutic intervention. However, due to the open nature of the PARG binding cleft and the nature of the binding site, this protein has been considered to be difficult to inhibit with small, drug-like small molecules, particularly in the cellular context.
This poster will describe our efforts to overcome these challenges against this challenging target and report our early successes achieved through innovative computational chemistry strategies. These efforts have delivered several credible, drug-like startpoints for further medicinal chemistry optimisation.
Citation Format: Bohdan Waszkowycz, Dominic James, Steven Durant, Nicola Hamilton, Cliff Jones, Stuart Jones, Allan Jordan, Alan Lau, Alison MGonagle, Mark O’Connor, Kate Smith, Alex Stowell, Julie Tucker, Ian Waddell, Donald Ogilvie. Discovery of the first cell-active inhibitors of poly(ADP Ribose) glycohydrolase through high-throughput screening and computational approaches. [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 4352.
Abstract 4362: T cell repertoire diversification is associated with immune related toxicities following immune checkpoint inhibition in metastatic cancer patients
Authors: Oh David Y. , Cham Jason , Zhang Li , Fong Grant , Klinger Mark , Faham Malek , Fong Lawrence 
Published: July 2016

Abstract
Immune checkpoint inhibitors can induce clinical responses to a broad range of tumor types by presumably enhancing T cell responses against the tumor. These treatments are also associated with certain side effects that are also thought to be immune mediated (termed immune-related adverse events, or IRAEs). The mechanism by which IRAEs occur, and biomarkers that may predict IRAE development, are unknown. In prior work (Cha et al. Sci Transl Med 2014), we demonstrated that treating metastatic cancer patients with checkpoint inhibitors blocking CTLA-4 can lead to T cell repertoire diversification. However, we found that prolonged survival was not associated with the induction of high frequency clonotypes, but rather the maintenance of a pre-existing T cell response. Here, we examined whether treatment-induced TCR diversification is related to another clinical outcome: the development of IRAEs. We find that IRAEs are specifically associated with a more diverse T cell repertoire and with an increase in the number of T cell clonotypes, including the generation of de novo clones. This broadening of the circulating T cell repertoire occurred early with treatment, preceding the development of IRAEs. While IRAE patients demonstrate markedly greater diversity in their CD4+ T cells, they demonstrate a greater degree of change in clonal frequencies in their CD8+ T cells after ipilimumab, which may have key implications in the pathogenic mechanism of IRAE development. Finally, clinical response to checkpoint blockade is also associated with increased diversity. These results indicate that immune repertoire diversity following immune checkpoint inhibition can be both detrimental and beneficial to patients with metastatic cancer.
Citation Format: David Y. Oh, Jason Cham, Li Zhang, Grant Fong, Mark Klinger, Malek Faham, Lawrence Fong. T cell repertoire diversification is associated with immune related toxicities following immune checkpoint inhibition in metastatic cancer patients. [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 4362.
Abstract 4368: High-throughput phenotyping of lung cancer somatic mutations
Authors: Berger Alice H. , Brooks Angela N. , Wu Xiaoyun , Shrestha Yashaswi , Chouinard Candace , Piccioni Federica , Bagul Mukta , Kamburov Atanas , Imielinski Marcin , Hogstrom Larson , Zhu Cong , Yang Xiaoping , Pantel Sasha , Sakai Ryo , Kaplan Nathan , Root David , Narayan Rajiv , Natoli Ted , Lahr David , Tirosh Itay , Tamayo Pablo , Getz Gad , Wong Bang , Doench John , Subramanian Aravind , Golub Todd R. , Meyerson Matthew , Boehm Jesse S. 
Published: July 2016

Abstract
Recent cancer genome sequencing and analysis has identified millions of somatic mutations in cancer. However, the functional impact of most variants is poorly understood, limiting the use of this genetic knowledge for clinical decision-making. Here we describe a new high-throughput approach, expression-based variant impact phenotyping (eVIP), which uses gene expression changes to infer somatic mutation impact. We generated a lentiviral expression library representing 53 genes and 194 somatic mutations identified in primary lung adenocarcinomas. Next, we introduced this library into A549 lung adenocarcinoma cells and 96 hours later performed gene expression profiling using Luminex-based L1000 profiling. We built a computational pipeline, eVIP, to compare mutant and wild-type expression signatures to infer whether variants were gain-of-function, change-of-function, loss-of-function, or neutral. Overall, eVIP identified 69% of mutations as impactful whereas 31% appeared functionally neutral. A very high rate, 92%, of missense mutations in the KEAP1 and STK11 tumor suppressor genes were found to inactivate or diminish protein function. As a complementary approach, we assessed which mutations are epistatic to EGFR or capable of initiating xenograft tumor formation in vivo. A subset of the impactful mutations identified by eVIP could induce xenograft tumor formation in mice and/or confer resistance to cellular EGFR inhibition. Among these mutations were 20 rare or non-canonical somatic variants in clinically-actionable or -relevant oncogenes including EGFR S645C, ARAF S214C and S214F, ERBB2 S418T, and PIK3CA E600K. eVIP can, in principle, characterize any genetic variant, independent of prior knowledge of gene function. Further application of eVIP should significantly advance the pace of functional characterization of mutations identified from genome sequencing.
Citation Format: Alice H. Berger, Angela N. Brooks, Xiaoyun Wu, Yashaswi Shrestha, Candace Chouinard, Federica Piccioni, Mukta Bagul, Atanas Kamburov, Marcin Imielinski, Larson Hogstrom, Cong Zhu, Xiaoping Yang, Sasha Pantel, Ryo Sakai, Nathan Kaplan, David Root, Rajiv Narayan, Ted Natoli, David Lahr, Itay Tirosh, Pablo Tamayo, Gad Getz, Bang Wong, John Doench, Aravind Subramanian, Todd R. Golub, Matthew Meyerson, Jesse S. Boehm. High-throughput phenotyping of lung cancer somatic mutations. [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 4368.
Abstract 4372: MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism
Authors: Ramkissoon Lori , Bandopadhayay Pratiti , Jain Payal , Bergthold Guillaume , Resnick Adam , Beroukhim Rameen , Ligon Keith 
Published: July 2016

Abstract
Diffuse pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children. While BRAF mutations and MYBL1 rearrangements have recently been identified as diagnostic and treatment related oncogenic drivers in pediatric gangliogliomas and diffuse astrocytomas, respectively, for the majority of diffuse PLGGs the oncogenic driver(s) remain unknown. Recent efforts to identify new oncogenic drivers lack sufficient power to determine the true frequency of alterations in genes or to associate specific alterations with rare histological subtypes, such as Angiocentric gliomas (AGs). To address this issue, we performed genomic analysis of new and published data from 249 PLGGs including 19 AGs. We identified MYB-QKI fusions as a specific, recurrent, single candidate driver event in AGs. Although MYB is expressed during early brain development in a subset of progenitor cells, it is not known to play a role in normal cortical brain where AGs frequently occur. In vitro functional studies show MYB-QKI rearrangements promote tumorigenesis in mouse neural stem cells (mNSCs) through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI. Expression of the MYB-QKI fusion increases mNSC proliferation and activates known MYB target genes including KIT and CDK6. H3K27ac enhancer profiling of AG tumors demonstrate active enhancer elements are translocated proximally to the MYB promoter while in vitro promoter assays confirmed that QKI enhancer sequences activate the MYB promoter. Together with functional studies demonstrating that MYB-QKI can also bind and activate the MYB promoter, these data support a positive auto-regulatory feed-back loop model in which active MYB-QKI is able to drive its own expression through enhanced MYB-promoter-activation. Furthermore, when injected orthotopically into immunodeficient mice, expression of truncated MYB or MYB-QKI is sufficient to induce tumor formation that recapitulate histologic and immunophenotypic characteristics of AGs. Analysis of AG specific MYB-QKI fusion represents the first example of how a single driver rearrangement simultaneously transforms cells via three genetic and epigenetic mechanisms in a cancer.
Citation Format: Lori Ramkissoon, Pratiti Bandopadhayay, Payal Jain, Guillaume Bergthold, Adam Resnick, Rameen Beroukhim, Keith Ligon. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. [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 4372.
Abstract 4379: Exosomes isolated from ovarian cancer cells transfer oncogenic features to the target cells promoting epithelial to mesenchymal transition
Authors: Kobayashi Miharu , Cohelo Laura , Guanzon Dominic , Scholz-Romero Katherin , Brown Melissa , Kline Richard , Li Li , Rice Gregory , Salomon Carlos 
Published: July 2016

Abstract
Introduction: Recent studies establish the role of exosomes in cell-cell communication in cancer. As adaptation to hypoxia is a critical step in tumor progression, the aim of this study was to test the hypotheses that hypoxia promotes epithelial to mesenchymal transition (EMT) and that exosomes isolated from hypoxic cancer cells transfer oncogenic properties to target cells.
Methods: CaOV-3 cell line was used as model of ovarian cancer. Cells were cultured under 8% O2 (normoxia) and 1% O2 (hypoxia) for 48 hours. Exosomes were isolated from cell-conditioned media by differential and buoyant density centrifugation. Exosomes were characterised by the presence of TSG101 using Western Blot, size distribution (Nanosight™) and morphology by electron microscopy. Exosomal protein and miRNA content were determined using liquid chromatography mass spectrometry (5600 Triple TOF, AB Sciex,) and an Illumina NextSeq 500 Platform, respectively. The effects of exosomes released from CaOV-3 incubated under 1% O2 on EMT induction in CaOV-3 cells cultured under 8% O2 were assessed by the measuring the ratio of E-cadherin (epithelial marker) to N-cadherin (mesenchymal marker) by Wester Blot and the expression of 84 key genes involve in the EMT (RT2 Profiler™ PCR Array, QIAGEN).
Results: Exosomes were identified as spherical vesicles with a typical cup-shape, diameters ranging from 50 to 100 nm with the expression of TSG101. Exosome release from ovarian cancer cells was ∼4-fold higher under hypoxic than normoxic conditions (p &lt;0.001). Hypoxia-specific exosomal proteins and miRNAs were identified. Hypoxia induced EMT (increased N-cadherin/E-cadherin ratio) on CaOV-3 cells compared to cells cultured under 8% O2. Interestingly, exosomes isolated from hypoxic conditions mimic the effect of hypoxia on cells cultured under 8% O2, involving the unregulated of a set of transcription factors associated with EMT such as SNAIL1/SNAIL2, bHLH (E47, E2-2, and TWIST1/TWIST2), and ZEB1/ZEB2.
Conclusion: The data obtained is consistent with the hypothesis that exosomes released from cancer cells modify the phenotype of target cells by transferring pro-oncogenic molecules inducing cancerous phenotype of receipt cells, contributing to tumour growth and metastasis.
Citation Format: Miharu Kobayashi, Laura Cohelo, Dominic Guanzon, Katherin Scholz-Romero, Melissa Brown, Richard Kline, Li Li, Gregory Rice, Carlos Salomon. Exosomes isolated from ovarian cancer cells transfer oncogenic features to the target cells promoting epithelial to mesenchymal transition. [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 4379.
Abstract 438: Development of an autoantibody panel that reflects disease pathogenesis in ovarian cancer
Authors: Kobayashi Makoto , Boldt Clayton R. , Yang Wei-Lei , Aguilar-Bonavides Clemente , Wang Hong , Lu Zhen , Bast Robert C. , Hanash Samir M. 
Published: July 2016

Abstract
Introduction
The serous subtype of ovarian cancer is responsible for most ovarian cancer deaths. When patients are diagnosed with early stage disease localized to the ovary or pelvis, current therapies can achieve survival rates up to 75-90%. However, approximately 70% of cases are diagnosed at an advanced stage, with a 5-year survival rate of less than 20%. A strategy based on autoantibodies which occur early during tumor development has merit for early cancer detection. We have applied a combined approach of mass spectrometry of circulating antigen-antibody complexes and with high-density protein microarrays to develop ovarian cancer serum markers based on autoantibody reactivity.
Materials and methods
Serum samples were obtained from women diagnosed with ovarian cancer (cases) and healthy controls undergoing ovarian cancer screening, women undergoing gynecologic surgery for various conditions but with normal ovarian pathology (surgical controls), and women without malignancy but with benign ovarian disease (benign controls). All samples were obtained following Institutional Review Board approval and informed consent. For autoantibody analysis, we used recombinant protein arrays containing 5,005 recombinants arrayed in duplicate and Alexa 647-labeled anti-human IgG were purchased from Invitrogen. Circulating Immunoglobulin (Ig) bound antigen analysis was performed using LC-MS/MS.
Results
Autoantibodies against 20 targets were identified in ovarian cancer patients compared to healthy, surgical and benign controls by protein array analysis with P&lt;0.01. Ingenuity Pathway Analysis of these 20 antigens, exhibited major nodes of p53, MYC, and ESR1 associated networks reflecting ovarian cancer pathogenesis. Concordant findings were observed with LC-MS/MS analysis of Ig-antigen complexes.
Conclusion
We have uncovered a set of 20 protein antigens associated with the development of autoantibodies in ovarian cancer that reflect disease pathogenesis and that have potential relevance for early detection.
Citation Format: Makoto Kobayashi, Clayton R. Boldt, Wei-Lei Yang, Clemente Aguilar-Bonavides, Hong Wang, Zhen Lu, Robert C. Bast, Samir M. Hanash. Development of an autoantibody panel that reflects disease pathogenesis in ovarian cancer. [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 438.