bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2696: Four new brain tumor entities emerge from molecular classification of CNS-PNETs
Authors: Sturm Dominik , Orr Brent , Toprak Umut H. , Hovestadt Volker , Jones David T.W. , Capper David , Lichter Peter , Korshunov Andrey , Pfister Stefan M. , Ellison David W. , Kool Marcel 
Published: July 2016

Abstract
CNS-primitive neuroectodermal tumors (CNS PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Histological diagnosis is complicated by morphological heterogeneity and divergent differentiation. Recent studies suggest the existence of molecular subgroups of CNS-PNETs sharing biological characteristics with other CNS tumors. To investigate this we have analyzed 323 fresh-frozen or paraffin-embedded institutionally diagnosed CNS-PNETs using DNA methylation and expression arrays. Data were compared to 211 reference cases of other pediatric and adult brain tumors representing more than 20 well-known entities.
DNA methylation and gene expression patterns showed that a significant proportion of CNS PNETs display molecular profiles indistinguishable from those of various other well defined CNS tumor entities. Hallmark genetic alterations for each of these well-defined entities, such as amplification of 19q13.42, mutations in IDH1 or H3F3A, mutations/deletions of the SMARCB1 locus, or RELA fusions, were frequently detected among the reclassified cases. From the remaining fraction of CNS PNETs we have identified four new CNS tumor entities, each associated with a unique recurrent genetic alteration and distinct histopathological and clinical features. Based on these findings we designated these four new entities as “CNS neuroblastoma with FOXR2 activation (CNS NB FOXR2)”, “CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT CIC)”, “CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET MN1)”, and “CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET BCOR)”.
Our findings reinforce the importance of incorporating molecular information into the next revision of the WHO classification of CNS tumors, and warrant a replacement of the term “CNS PNET” with biologically specific designations. Our study provides an innovative framework for improving diagnostic accuracy and prognostication in malignant CNS tumors. The approach is amenable to retrospective analyses of patients treated with current regimens and will facilitate the design of more meaningful clinical trials for patients with malignant brain tumors.
Citation Format: Dominik Sturm, Brent Orr, Umut H. Toprak, Volker Hovestadt, David T.W. Jones, David Capper, Peter Lichter, Andrey Korshunov, Stefan M. Pfister, David W. Ellison, Marcel Kool. Four new brain tumor entities emerge from molecular classification of CNS-PNETs. [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 2696.
Abstract 27: Understanding mechanisms of nutrient homeostasis: Amino acid availability and regulation of V-ATPase activity
Authors: Stransky Laura A. , Forgac Michael 
Published: July 2016

Abstract
Cellular homeostasis requires accurate sensing of nutrient levels and subsequent regulation of biosynthetic and catabolic cellular processes. In cancer cells, metabolism is frequently disregulated to meet the increased demand for cellular building blocks to enable growth and proliferation. Thorough understanding of how homeostatic processes are regulated is necessary to determine how these processes could be manipulated to stop tumor growth. This study aims to understand amino acid homeostasis, with particular focus on the regulation of lysosomal activity, which allows protein breakdown and release of free amino acids. We have identified a novel mechanism of amino acid homeostasis whereby amino acid starvation leads to increased activity of the Vacuolar-ATPase (V-ATPase), as indicated by measurement of V-ATPase-dependent FITC-dextran fluorescence quenching in isolated lysosomes. The V-ATPase is the proton pump responsible for acidifying intracellular compartments, which is necessary for lysosomal function and protein degradation. This increased activity is due to an increase in the amount of fully assembled holoenzymes, as detected by cell fractionation and Western blotting to assess peripheral subunit association with membranes. Assembly of V-ATPase holoenzymes is a tightly controlled process. We describe the function of these changes with respect to lysosomal protein turnover and mTORC1 activation, in which the V-ATPase plays a critical role. We have also sought to characterize the signaling events that transmit the amino acid starvation signal and controls V-ATPase activity in response to changes in amino acid availability in normal and cancer cells that rely on lysosomal function. These changes do not depend on PI3K or mTORC1 activity, both of which have been linked to changes in V-ATPase activity and assembly in other response to other stimuli, such as glucose and growth factor stimulation and are highly activated across cancers. Together, these results shed light on a poorly understood aspect of cellular biology and novel mechanisms of amino acid homeostasis.
Citation Format: Laura A. Stransky, Michael Forgac. Understanding mechanisms of nutrient homeostasis: Amino acid availability and regulation of V-ATPase activity. [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 27.
Abstract 2708: Development of an individualized 3D transport model of topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma
Authors: Shirinifard Abbas , Thiagarajan Suresh , Patel Yogesh T. , Davis Abigail D. , Jacus Megan O. , Throm Stacy L. , Roberts Jessica , Daryani Vinay , Stewart Clinton F. , Sablauer. András 
Published: July 2016

Abstract
Resistance to chemotherapeutics and targeted therapies in pediatric solid tumors including neuroblastoma is a common cause of poor clinical outcome. These failures in part stem from shortcomings in understanding inter- and intra-tumor heterogeneities of drug penetration due to heterogeneities in blood perfusion. Herein we propose to develop an individualized 3D transport model of topotecan (TPT) for a patient-derived orthotopic xenograft model of pediatric NB5 neuroblastoma to account for inter- and intra-tumor heterogeneities in blood perfusion. The transport model uses a 3D reaction-diffusion equation to simulate diffusion of TPT from blood vessels into the tumor tissue and its flux in and out of intracellular space. Our transport model takes three types of inputs to predict TPT exposure maps defined over the volume of an individual tumor: a) plasma concentration-time profiles from an individualized physiologically-based pharmacokinetic (PBPK) model of TPT (separate cohort), b) 3D blood perfusion map of the individual tumor from contrast enhanced ultrasound (CEUS) using VisualSonics VEVO 2100 imaging system, and c) in vitro TPT cellular uptake and efflux kinetics from two-photon imaging. We use in vitro pharmacodynamics (PD) experiments with NB5 cells exposed to TPT to derive probabilistic PD-rules for drug effects (e.g., γ-H2AX response). Based on these rules and the exposure maps, we then compute probabilities of effects for the entire tumor volume. We will validate the predicted drug effect maps by comparing them to the observed effects measured by immunohistochemistry marker for γ-H2AX from the same tumor (location matched) using spatial correlation techniques.
Citation Format: Abbas Shirinifard, Suresh Thiagarajan, Yogesh T. Patel, Abigail D. Davis, Megan O. Jacus, Stacy L. Throm, Jessica Roberts, Vinay Daryani, Clinton F. Stewart, András Sablauer. Development of an individualized 3D transport model of topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma. [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 2708.
Abstract 2712: Joint somatic mutation and germline variant identification and scoring from tumor molecular profiling and ct-DNA monitoring of cancer patients by high-throughput sequencing
Authors: De La Vega Francisco M. , Koehler Ryan T. , Pouliot Yannick , Bouhlal Yosr , So Austin , Goodsaid Federico , Irvine Sean , Trigg Len , Nadauld Lincoln 
Published: July 2016

Abstract
Cancer tumor profiling by targeted resequencing of actionable cancer genes is rapidly becoming the standard approach for selecting targeted therapies and clinical trials in refractory cancer patients. In this clinical scenario, a tumor sample is obtained from an FFPE block and sequenced by targeted next-generation sequencing (NGS) to uncover actionable somatic mutations in relevant cancer genes. Some of the challenges that arise in analyzing tumor-derived NGS data include distinguishing between somatic and germline variants in the absence of normal tissue data, recognizing pathogenic germline variants, and identifying sequencing errors (which occur at about 0.5% rate). Additional challenges arise when considering other clinical applications of NGS such as sequencing cell-free tumor DNA (cf-DNA) from plasma samples to monitor disease response or disease recurrence. Here we present a principled approach to identify both single-nucleotide and small insertion/deletion somatic mutations and germline variants from NGS data of tumor tissue that leverages the allelic fraction patterns in tumors and prior information from external databases through the use of a Bayesian Network algorithm. Our approach allows us to score each putative mutation or variant with respect to its probability of belonging to each variant class, versus classification as a sequencing error. The method enables the joint calling of related samples form the same patient, such as cases where a cf-DNA sample and primary tumor sample are both profiled improving sensitivity and specificity. We validated our method by analyzing data obtained with the TOMA OS-Seq targeted sequencing RUO assay for 98 cancer genes from a mixture of well-known genomes, patient case triads (where normal, tumor and cf-DNA are available), and a retrospective analysis of tumor patient data that underwent clinical tumor profiling for therapy selection.
Citation Format: Francisco M. De La Vega, Ryan T. Koehler, Yannick Pouliot, Yosr Bouhlal, Austin So, Federico Goodsaid, Sean Irvine, Len Trigg, Lincoln Nadauld. Joint somatic mutation and germline variant identification and scoring from tumor molecular profiling and ct-DNA monitoring of cancer patients by high-throughput sequencing. [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 2712.
Abstract 2716: Lipid mediated “nutrients sensing” checkpoint in G1 phase of the cell cycle
Authors: Patel Deven , Foster David 
Published: July 2016

Abstract
One of the hallmarks of cancers is dysregulation of G1 phase cell cycle progression- where cells decide their fate whether they should divide, arrest or undergo apoptosis. There is a growth factor-dependent Restriction point (R), where cells commit to replicate its genome or to enter a state of quiescence. Unicellular organisms only respond to the nutrients, a point known as START. In mammalian system, we have shown equivalent to START, “Cell Growth” checkpoints, where it senses Essential Amino Acids (EAAs), a “Conditionally” EAA glutamine (Q), and at last a checkpoint regulated by mTOR, which we think it senses nutrients and is the final arbitrator of the G1-S phase progression. mTOR- mammalian/mechanistic target of rapamycin integrates the growth factor signaling with nutrient sensing signaling and known to be involved in protein translation and proliferation. Another key nutrient needed for cell growth is lipids which is required as building blocks for plasma membrane synthesis and signaling molecules. Phosphatidic acid has been shown to be required for the activity of mTORC1 and mTORC2. In this study, we investigated the involvement of lipids in the cell cycle progression and how the signals are integrated. Upon lipid deprivation, normal fibroblasts cells arrest in G1-phase of the cell cycle. There is a distinct and distinguishable lipid sensing checkpoint from EAAs and Q. Temporally it is different from other nutrient sensing checkpoints in the late G1-phase of the cell cycle. In summary, there is a series of “nutrient sensing” checkpoints late in the G1-phase followed by mTOR “Growth” checkpoint. Dysregulation of these checkpoints in cancer cells may present better opportunity to target them with different therapeutic approach.
Citation Format: Deven Patel, David Foster. Lipid mediated “nutrients sensing” checkpoint in G1 phase of the cell cycle. [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 2716.
Abstract 2718: Synthesis and characterization of novel benzylpyrazole-based BUB1 kinase inhibitors with anti-tumor activity
Authors: Hitchcock Marion , Siemeister Gerhard , Briem Hans , Fernandez-Montalvan Amaury Ernest , Holton Simon , Mengel Anne , Mönning Ursula , Brands Michael , Ziegelbauer Karl , Mumberg Dominik , Nussbaum. Franz von 
Published: July 2016

Abstract
BUB1 (budding uninhibited by benzimidazoles 1) is a serine/threonine protein kinase. The protein is bound to kinetochores and plays a key role in the establishment of the mitotic spindle checkpoint and chromosome congression prior to anaphase.
Inhibition of BUB1 kinase represents a novel approach for cancer treatment: whereas cell cycle arrest is the predominant mode of action of a number of antimitotic cancer drugs (e.g. taxanes and vinca alkaloids), BUB1 inhibition results in aneuploidy and cell death by driving cells through mitosis irrespective of DNA damage and misattached chromosomes.
Here, we report the characterization of a novel benzylpyrazole lead-structure series inhibiting BUB1 exemplified by BAY-320, a novel, first-in-class small molecule inhibitor of BUB1 kinase. This structure class was initially discovered as a single hit in a high-throughput screen, and resulted in a lead compound by chemical optimization. Benzylpyrazole BAY-320 is highly selective for BUB1 with single digit nanomolar biochemical potency and single-digit micromolar cellular potency (HeLa proliferation assay). Synergistic effects can be observed when BUB1 inhibitor BAY-320 is combined with low doses of paclitaxel affecting chromosome segregation and cell proliferation. X-ray data of benzylpyrazoles allowed for a better understanding the binding mode for rational property design. Further data on structure-activity relationship including pharmacokinetic, drug metabolism and the synthesis of BAY-320 and analogues will be presented.
These results validate the benzylpyrazoles as novel selective BUB1 inhibitors and BUB1 as a promising approach for cancer treatment.
Citation Format: Marion Hitchcock, Gerhard Siemeister, Hans Briem, Amaury Ernest Fernandez-Montalvan, Simon Holton, Anne Mengel, Ursula Mönning, Michael Brands, Karl Ziegelbauer, Dominik Mumberg, Franz von Nussbaum. Synthesis and characterization of novel benzylpyrazole-based BUB1 kinase inhibitors with anti-tumor activity. [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 2718.
Abstract 2721: Discovery and development of orally available subnanomolar potent checkpoint kinase 1 inhibitors as potential anticancer therapies
Authors: Vo Alex C. , Taylor Janelle , Rosler Robert , Leviten Dina , Sierra Teresa , Boyce Richard , Boyle Robert , Peterson Scott , Klucher Kevin 
Published: July 2016

Abstract
Checkpoint kinase 1 (Chk1) is a serine/threonine protein kinase that regulates cell division by arresting progression in the S & G2 phases of the cell cycle in response to genotoxic stress. Pharmacological inhibition of Chk1 selectively uncouples the completion of DNA replication from G2/M phase transition in tumor cells lacking parallel cell cycle checkpoint controls, resulting in mitotic catastrophe and cell death. These properties make Chk1 inhibition a unique therapeutic approach as a single agent or as a means to enhance the efficacy of DNA-targeted chemotherapeutic drugs.
In this report, we describe our progress in the development of orally bioavailable, potent and selective Chk1 inhibitors derived from an aminopyrazole chemical scaffold. Starting with the lead compound, ONT-2409 (IC50 of &lt;0.1 nM against the Chk1 enzyme), a series of Chk1 inhibitors have been developed. Lead candidates have been generated with potent biochemical IC50s against Chk1 (IC50s = 0.1-0.3 nM). In a panel of 125 protein kinases the top candidates were shown to be highly selective for Chk1, with little appreciable activity against Chk2 or other kinases involved in cell cycle control/DNA damage response. The lead candidates have potent single agent activity against a panel of diverse cancer cell lines (EC50s = 0.03-0.4 μM) and show synergistic enhancement in the activity of clinically relevant DNA targeted chemotherapeutics. Mechanistically, the lead candidates abrogate gemcitabine-induced cell cycle arrest and induce apoptotic cell death. Biomarker studies show the lead candidates inhibit gemcitabine-induced auto-phosphorylation of Chk1 at S296 and reduce phosphorylation of CDK1 at Y15. Compared with ONT-2409, the optimized candidates display improved cell permeability/efflux ratios, superior intrinsic microsomal and hepatic half-lives, and have excellent oral bioavailability in mice and rats. Lead candidate Chk1 inhibitors have also demonstrated potent potentiation of DNA targeted chemotherapies and single agent activity in xenograft tumor models
Citation Format: Alex C. Vo, Janelle Taylor, Robert Rosler, Dina Leviten, Teresa Sierra, Richard Boyce, Robert Boyle, Scott Peterson, Kevin Klucher. Discovery and development of orally available subnanomolar potent checkpoint kinase 1 inhibitors as potential anticancer therapies. [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 2721.
Abstract 2722: Reviving kinesin-5 inhibitors: Evidence for a powerful combinatorial strategy
Authors: Sturgill Emma G. , Ohi Ryoma 
Published: July 2016

Abstract
Mitosis serves as a powerful opportunity for therapeutic intervention in the treatment of neoplastic diseases like cancer. Anti-mitotic pharmacological agents tame the proliferative capacity of tumor cells by interfering with proper function of the mitotic spindle. Several next generation anti-mitotics target kinesins involved in assembling the mitotic spindle. Of these mitotic kinesins, the kinesin-5 Eg5 (also known as KSP) is perhaps the most compelling because of its primacy during spindle assembly in animal cells. Indeed, Eg5-inhibitors (K5Is) induce a potent and lethal mitotic arrest in cell culture and murine xenografts; however, K5Is failed to induce tumor regression during Phase II trials. This devastating clinical performance has halted further development of K5I monotherapies and motivated investigation into the underlying reason(s) for K5I inefficacy.
We previously showed that tumor cells in culture are capable of acquiring K5I resistance by employing parallel spindle assembly pathways. By studying a limited number of K5I-resistant cell lines, we showed that resistance involved the kinesin-12 Kif15; however, the generality of this finding was unclear. In this study we capitalize on the latest methodologies in targeted genome editing to study mechanisms of K5I resistance on a broader cell population level. We find that cells require Kif15 in all cases of K5I resistance, and that rescue is sensitive to the timing and extent of Kif15 expression. We propose that K5Is steer cells into an evolutionary bottleneck that requires Kif15, and that adaptive changes occur during passage through the bottleneck that enable populations to recover and diversify. These findings prompt a search for pharmacological inhibitors of Kif15 to test in combination with K5Is as an anti-mitotic chemotherapeutic regimen.
Citation Format: Emma G. Sturgill, Ryoma Ohi. Reviving kinesin-5 inhibitors: Evidence for a powerful combinatorial strategy. [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 2722.
Abstract 2730: Association of TERT promoter mutations with telomerase expression in melanoma
Authors: Lee Seungjae , Opresko Patricia , Pappo Alberto , Kirkwood John , Bahrami Armita 
Published: July 2016

Abstract
Telomerase reverse transcriptase (TERT) promoter mutations occur at a high frequency in melanoma, but the functional consequences of these mutations in melanoma remain to be clarified. In a large study of melanoma samples by The Cancer Genome Atlas network, mRNA expression analysis using RNA sequencing data showed that only TERT promoter mutations at C228T were associated with high TERT expression levels. The effect of hotspot C250 or C242T/C243T tandem mutations on telomerase expression has not yet been determined. To assess telomerase expression levels in melanomas harboring C250 or C242T/C243T mutations, we used real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) in a sample set of pediatric melanocytic tumors for which the methylation status and the mutational profile of the TERT promoter were known. We previously showed that in a subset of melanoma, TERT expression is mediated epigenetically by promoter hypermethylation rather than by promoter point mutations. Formalin-fixed paraffin-embedded (FFPE) tissues from 10 metastatic melanomas, of which 8 harbored a hotspot TERT promoter mutation (5 C250T; 2 C228; 1 C242T/C243T) and 2 carried a hypermethylated wild-type TERT promoter were examined. For controls, 9 atypical Spitz tumors with a wild-type unmethylated TERT promoter were also studied. Total RNA was isolated from FFPE tumor tissues and converted to cDNA. TERT expression levels were determined by RT-qPCR by using the TaqMan® Gene Expression Assay and normalized with GAPDH as the endogenous control. In the atypical Spitz tumor samples, TERT mRNA expression was undetectable or negligible. In contrast, TERT expression in all melanoma samples was elevated, ranging from 3- to 71-fold (median, 25-fold) when compared to an atypical Spitz tumor as a reference. Our data support that in melanoma, TERT promoter hotspot C250 and C242T/C243T mutations, similar to C228T mutations, correlate with TERT overexpression and that C250 and C242T/C243T mutations likely contribute biologically to tumorigenesis in melanoma.
Citation Format: Seungjae Lee, Patricia Opresko, Alberto Pappo, John Kirkwood, Armita Bahrami. Association of TERT promoter mutations with telomerase expression in melanoma. [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 2730.