bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 959: Targeting neuronal activity regulated neuroligin-3 dependency for high-grade glioma therapy
Authors: Venkatesh Humsa S. , Tam Lydia T. , Woo Pamelyn J. , Monje Michelle 
Published: July 2017

Abstract
Neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (Nlgn3), but the therapeutic potential of targeting Nlgn3 in glioma remains to be defined. Here, we demonstrate a striking dependence of HGG growth on microenvironmental Nlgn3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) fail to grow in Nlgn3 knock out mice. Using genetic mouse models, we illustrate that Nlgn3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of an ADAM10 inhibitor robustly blocks pGBM and DIPG xenograft growth via modulation of the tumor microenvironment. This work defines the therapeutic potential of and an effective strategy for targeting Nlgn3 secretion in the glioma microenvironment, which could prove transformative for treatment of HGG.
Note: This abstract was not presented at the meeting.
Citation Format: Humsa S. Venkatesh, Lydia T. Tam, Pamelyn J. Woo, Michelle Monje. Targeting neuronal activity regulated neuroligin-3 dependency for high-grade glioma therapy [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 959. doi:10.1158/1538-7445.AM2017-959
Abstract 96: Didhydropyrimdine dehydrogenase (DPYD) provides resistance to 5-flurouracil in mutant p53 (mtp53) expressing colorectal cancer cells
Authors: Gokare Prashanth Ravishankar , Finnberg Niklas , Dicker David , Murphy Maureen 
Published: July 2017

Abstract
5-Flurouracil (5-FU) is a mainstay of colorectal cancer therapy. Even though much is known about the 5-FU mechanism of action, very little is known about the genetic determinants which provide sensitivity and resistance to 5-FU. Here we provide first insights into p53, a major predictor of 5-FU response, modulating nucleotide catabolism specifically through the control of the rate limiting enzyme dihydropyrimidine dehydrogenase (DPYD). Colorectal cancer cells expressing mtp53 specifically show higher expression of DPYD as compared to the wildtype p53 (wtp53) carrying cells. Higher expression of DPYD in mtp53 cells specifically provides increased resistance to 5-FU as indicated by cellular proliferation and long term clonogenic assays. Furthermore, knockdown of DPYD in mtp53 cells preferentially resensitizes them to 5-FU as opposed to cells expressing Wtp53 by decreasing the viability and increasing apoptosis observed in these cells. Pharmacological inhibition of DPYD with gimeracil, clinical inhibitor of 5-FU phenocopies the effects seen by siRNA/shRNA mediated knockdown of DPYD. Finally, invivo studies with tumor xenograft from mtp53 carrying cells shown increase resistance to 5-FU therapy which is abrogated by stable knockdown of DPYD expression or in combination gimeracil. Preliminary analysis of TCGA patients treated with 5-FU indicate differential expression of DPYD based on specific Tp53 mutation status. Taken together our study provides first insights into crosstalk between nucleotide catabolism and mtp53 under conditions of DNA damage and metabolic stress having major implications on the therapeutic response to 5-FU the in the clinic.
Citation Format: Prashanth Ravishankar Gokare, Niklas Finnberg, David Dicker, Maureen Murphy. Didhydropyrimdine dehydrogenase (DPYD) provides resistance to 5-flurouracil in mutant p53 (mtp53) expressing 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 96. doi:10.1158/1538-7445.AM2017-96
Abstract 968: Podoplanin's diverse potential as a chemotherapeutic target for oral squamous cell carcinom
Authors: Retzbach Edward P. , Krishnan Harini , Ochoa-Alvarez Jhon A. , Shen Yongquan , Nevel Evan , Kephart David J. , Kalyoussef Evelyne , Baredes Soly , Fatahzadeh Mahnaz , Yin Kingsley , Shienbaum Alan J. , Kato Yukinari , Jensen Lasse , Goldberg Gary S. 
Published: July 2017

Abstract
Oral cancer is diagnosed in over 300 thousand people, and kills over 100 thousand people, around the world each year. Current treatments rely on radiation and surgery procedures that often decrease the quality of life for oral cancer survivors. There is a clear need to improve treatments for these patients. Over 90% of oral cancers are oral squamous cell carcinoma (OSCC). Most OSCC cells express the transmembrane receptor podoplanin (PDPN), which has emerged as a promising target for OSCC treatment. The PDPN receptor promotes tumor cell invasion and metastasis which leads to the vast majority of cancer deaths. Here, we describe efforts to target PDPN in order to prevent and treat oral cancer. PDPN can be targeted with Maackia amurensis seed lectin (MASL) to inhibit tumor cell migration and viability. Recent evidence also suggests that PDPN may undergo cancer specific changes, which indicates another potential route for targeting PDPN in oral cancer. Taken together, these data indicate that PDPN can serve as a functionally relevant target to prevent and combat oral cancer.
Citation Format: Edward P. Retzbach, Harini Krishnan, Jhon A. Ochoa-Alvarez, Yongquan Shen, Evan Nevel, David J. Kephart, Evelyne Kalyoussef, Soly Baredes, Mahnaz Fatahzadeh, Kingsley Yin, Alan J. Shienbaum, Yukinari Kato, Lasse Jensen, Gary S. Goldberg. Podoplanin's diverse potential as a chemotherapeutic target for oral squamous cell carcinom [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 968. doi:10.1158/1538-7445.AM2017-968
Abstract 972: Improving pre-clinical cancer pharmacogenomics with novel drug sensitivity metrics based on growth rate inhibition
Authors: Hafner Marc , Niepel Mario , Sorger Peter K. 
Published: July 2017

Abstract
Drug sensitivity in growing cells is conventionally quantified by IC50, AUC, or Emax values, but these metrics suffer from a fundamental flaw: they highly depend on the division rate of cell lines. This dependency creates artefactual correlations between genetic alterations and drug sensitivity which impede biomarker discovery. To address this issue, we recently developed novel drug response metrics insensitive to the number of divisions occurring during the assay. These are based on estimating growth rate inhibition (GR) under treatment using fixed assays.
Here, we illustrate the flaws of using IC50 values for pharmacogenomic studies by reanalyzing a recently published large dataset of drug sensitivity and showing cases in which differences in division rates drive associations between IC50 values and tissue type or genetic alterations. Using GR50 values prevents these artificial correlations and restores known associations between drug resistance and genomic markers such as PTEN loss driving lapatinib resistance in breast cancer cell lines. We also show how use of GRmax values, a measure of drug efficacy, allows quantifying differences in the phenotypes and distinguishing cytostatic from cytotoxic response. For drugs that have a narrow range of GR50 values like taxanes, efficacy is the most relevant metric: in many ovarian BCL2-deleted cell lines, docetaxel induces a cytotoxic response (negative GRmax values), whereas wild-type lines elicit a cytostatic response (positive GRmax values). Because efficacy (GRmax) varies independently of potency (GR50), we conclude that both metrics are complementary for pharmacogenomics and should be studied jointly.
Adopting GR metrics requires only modest changes in experimental protocols and analysis is facilitated by our interactive website: GRcalculator.org. We expect GR metrics to improve the identification of reliable drug response biomarkers and enhance the reproducibility of large-scale sensitivity studies.
Citation Format: Marc Hafner, Mario Niepel, Peter K. Sorger. Improving pre-clinical cancer pharmacogenomics with novel drug sensitivity metrics based on growth rate inhibition [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 972. doi:10.1158/1538-7445.AM2017-972
Abstract 974: Automating deconvolution of heterogeneous bulk tumor genomic data
Authors: Roman Theodore , Xiao Brenda , Schwartz Russell 
Published: July 2017

Abstract
Tumor heterogeneity has been linked to many measures of poor patient outcome. Despite numerous recent methodological advances, though, reliable estimates of clonal and subclonal architecture remain elusive. We present advances in computational deconvolution of tumor heterogeneity, aimed at better handling complex substructure, more automated inference, and increased flexibility to heterogeneous genomic data sources. Our methods make use of geometric models of mixture substructure, a specialized form of a strategy called manifold learning, to better resolve clonal substructure shared across genomic samples. We validate the methods on breast tumor dataset from the Cancer Genome Atlas (TCGA). We find statistically significant Spearman correlation between inferred mixture models and independently derived clinical subtype across DNA, RNA, and combined datasets. DAVID tissue term enrichment, applied to inferred amplified gene sets, further yields significant correlation (p&lt; 0.01) with various ontological terms expected for breast tumors, for example, "Breast Carcinoma". We further verified the ability of the mixture modeling to classify tumors by progression state, showing cross-validated k-fold loss of 0.2538 in separating tumors by early (Stage I - II) vs. late (Stages III-IV) stage, corresponding to significant (p&lt;0.001) separation by chi-squared test. The results demonstrate the effectiveness of our improved geometric deconvolution approach in resolving clonal structure to separate tumors by biologically relevant pathways and degrees of progression.
Citation Format: Theodore Roman, Brenda Xiao, Russell Schwartz. Automating deconvolution of heterogeneous bulk tumor genomic data [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 974. doi:10.1158/1538-7445.AM2017-974
Abstract 981: The design and characterization of a selective TRIM24 degrader
Authors: Gechijian Lara N. , Buckley Dennis , Lawlor Matthew , Scott Thomas , Paulk Joshiawa , Reyes Jaime , Winter Georg , Erb Michael , Ott Chris , Dhe-Paganon Sirano , Bradner James 
Published: July 2017

Abstract
A fundamental biological understanding of the individual contributions of functional domains within multidomain proteins is critical to inform therapeutic approaches to targeting mechanisms driving human disease. TRIM24 is a multi-domain protein that has been broadly characterized as a co-regulator of transcription. It is therapeutically relevant as it is implicated as a dependency in many human cancers, however, the potent and selective inhibitors of the TRIM24 bromodomain do not have well-characterized phenotypic consequences. Where inhibition of one activity of a protein does not appear to be efficacious, chemical knockdown tools allow for the acute depletion of the entire protein, therefore eliminating all protein activities. In this study, we have used chemical degradation as one strategy to target the entire TRIM24 protein, where we have shown that a bifunctional degrader molecule hijacks the ubiquitin ligase machinery for targeted TRIM24 degradation. We have shown that TRIM24 degradation is required to perturb the oncogenic state in leukemia. In this context, TRIM24 degradation rather than bromodomain inhibition alone is required to displace TRIM24 from chromatin. Using this probe, a further understanding of the contribution of TRIM24 domains to its transcriptional activation function will provide mechanistic insight as to how TRIM24 promotes a gene expression program permissive of the oncogenic state, as well as inform a therapeutic approach to target multidomain proteins, such as TRIM24, that are tightly linked to disease.
Citation Format: Lara N. Gechijian, Dennis Buckley, Matthew Lawlor, Thomas Scott, Joshiawa Paulk, Jaime Reyes, Georg Winter, Michael Erb, Chris Ott, Sirano Dhe-Paganon, James Bradner. The design and characterization of a selective TRIM24 degrader [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 981. doi:10.1158/1538-7445.AM2017-981
Abstract 99: Identify potential kinetochore protein inhibitors to overcome cisplatin resistance
Authors: Yin-Ju Chen , Chiou Jeng-Fong 
Published: July 2017

Abstract
Cisplain is the most commonly used chemotherapeutic drug for cancer, while the resistance causes treatment failure. Cisplatin resistance may involve in many molecular changes so identify aberrations in cisplatin-resistant (CR) genes and find new therapeutic strategies could provide valuable information to reduce therapeutic resistance. The aim of this study is to search CR genes and identify potential novel drugs to overcome cisplatin resistance. To identify aberrations in CR genes, three CR genetic signatures were collected and analyzed differential expression genes from lung, ovarian and oral cancer cells. After integration of CR signatures, the kinetochore associated proteins, including NUF2, SPC25, PC24, DSN1, SKA2, KNTC1, MIS18A and SKA1 were up-regulated in various CR cells. Silencing of kinetochore associated proteins increased cisplatin sensitivity. For identification of kinetochore associated protein inhibitors to overcome cisplatin resistance, CR signatures were queried to the Connectivity map (Cmap) database to search for potential drugs which may reverse cisplatin resistance. 3 compounds exhibited cytotoxicity effect on the cisplatin-resistant cells and reduced kinetochore associated proteins expression level. Taking together, this study demonstrates kinetochore associated proteins participate in cisplatin resistance and identify potential inhibitors to overcome cisplatin resistance.
Citation Format: Chen Yin-Ju, Jeng-Fong Chiou. Identify potential kinetochore protein inhibitors to overcome cisplatin resistance [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 99. doi:10.1158/1538-7445.AM2017-99
Abstract 994: Diagnosing leukemia structural variations via a novel genome mapping approach
Authors: Pool Christopher , Xu Jie , Bann Darrin , Goldenberg David , Sharma Arati , Claxton David , Yue Feng , Broach James 
Published: July 2017

Abstract
Identification of structural variants (SVs) is critical to the prognosis of AML. SVs are not readily identified by next generation sequencing methods and are currently diagnosed by cytogenetics, an intrinsically low resolution tool. We have adapted a new method for determining large SVs as a clinical tool for evaluating AML and other cancer genomes. The Bionano Irys images in microfluidic nanochannels large (&gt;150 Kb) segments of genomic DNA that have been bar coded by site specific nicking and local incorporation of fluorescent label. The complement of individual molecules can be assembled through matching bar codes to create a de novo map of the genome from which, by matching to a reference genome, identifies and catalogs structural variants at resolution of ca. 1 Kb.
With this technology, we characterized structural variants signatures in breast cancer, renal clear cell carcinoma, and CML cell lines. Structural variants were then validated via PCR/Sanger sequencing, fluorescent in situ hybridization and whole genome sequencing. We identified a thorough compendium of consistent false positive rearrangements identified by this technology, most of which reflect errors in the reference human genome assembly. We then applied this methodology to ten AML patient samples, seven from archived blood samples and three directly obtained from newly diagnosed patients. Karyotyping on one archived sample identified a t(6:9) translocation in the majority of cells. We identified that rearrangement at a much higher resolution than cytogenetics, which allowed us to map the breakpoint via PCR/Sanger sequencing to nucleotide resolution and confirm a fusion of NUP214 to DEK, a known oncogene. We also discovered the reciprocal t(9:6) translocation, which had not been identified by cytogenetics. In the six other cases from archived samples, we have confirmed the translocation identified by cytogenetic karyotyping and in several cases found additional rearrangements. Moreover, in the first pediatric case, which we completed within five days of obtaining the sample, we have identified four distinct translocations, all of which have been associated previously with AML.
Overall, this is technology has the ability to quickly and accurately identify SVs in cancer cell lines and AML patient samples with higher resolution than cytogenetics, demonstrating its clinical usefulness in the diagnosis and subsequent treatment of leukemia.
Citation Format: Christopher Pool, Jie Xu, Darrin Bann, David Goldenberg, Arati Sharma, David Claxton, Feng Yue, James Broach. Diagnosing leukemia structural variations via a novel genome mapping approach [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 994. doi:10.1158/1538-7445.AM2017-994
Abstract CT051: Tumor treating fields in pediatric recurrent high-grade glioma and ependymoma
Authors: Goldman Stewart , Onar-Thomas Arzu , Dunkel Ira , Hwang Eugene 
Published: July 2017

Abstract
Background
Recurrent or progressive pediatric CNS tumors have a poor prognosis under current treatment regimens. For children with high-grade gliomas (HGG), once progression occurs, most patients cannot be cured, and median survival remains &lt; 1-2 years; overall survival of recurrent/progressive ependymoma is also poor in children. Tumor Treating Fields (TTFields) is an anti-mitotic cancer therapy for the treatment of recurrent (supratentorial) glioblastoma (GB).) A phase 3 clinical trial comparing TTFields monotherapy with physician’s choice chemotherapy in adult patients with recurrent GB demonstrated comparable overall survival and improved quality of life. In this multicenter feasibility trial we plan to examine the feasibility and device-related toxicity of TTFields in children with supratentorial HGG and ependymoma. The secondary objectives include: response rate, Event-Free Survival, compliance on use of device and Quality of Life (QoL) of tehe children (aged 8+) and families.
Methods
The Optune device will be worn ≥ 18 hours/day for at least 23 days out of 28 days of cycle one. Patients will have Brain MRI with and without contrast performed prior to therapy, after cycles 2, 4, 6, 9, then every 3 cycles thereafter until time of progression or completion of treatment. For those patients who complete at least 9 cycles of therapy, an MRI will be performed every 3 cycles for 2 years then every 4 months after completion of treatment.Treatment may continue up to 26 cycles pending observed benefit and safety. A sample size of 20 patients is needed with an interim analysis conducted after the first 11 patients. Kaplan-Meier estimates of EFS for all eligible patients who use the device for &lt; 1 day will be provided separately for the HGG and Ependymomahistology-based cohorts. We will also estimate the rates of confirmed sustained objective responses (CR+PR) observed during treatment. All PROMIS and Neuro-QoL scores will be reported using T-score matrix (mean=50 and SD=10). The projected accrual rate is 1.5-2.5 patients per month. Patients will be followed for 2 years.
Citation Format: Stewart Goldman, Arzu Onar-Thomas, Ira Dunkel, Eugene Hwang. Tumor treating fields in pediatric recurrent high-grade glioma and ependymoma [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 CT051. doi:10.1158/1538-7445.AM2017-CT051
Abstract CT061: Novel safety of high dose ascorbic acid and induction chemotherapy for high risk pancreatic cancer
Authors: Bruckner Howard W. , Hirschfeld Azriel , Gurell Daniel , Lee King 
Published: July 2017

Abstract
Background: High dose ascorbic acid has been reported to have in vitro anticancer activity. Low dose combination chemotherapy with GFLIP (gemcitabine, 5fu, leucovorin, irinotecan, oxaliplatin) is an effective regimen for patients with pancreatic cancer. Combining high dose ascorbic acid with GFLIP may be a synergistic and well tolerated treatment regimen.
Methods: High dose ascorbic acid with a range of 75-100 grams IV given on an average 1-2 times per week was combined with GFLIP given on a 2 week schedule for patients with pancreatic cancer. Eligibility criteria include locally advanced, unresectable, recurrent and metastatic disease. Patients who progressed on prior treatment, ECOG 0-2, were also included. There was no age cut off.
Results: 26 patients were treated, 9 patients were ≥ 70 years of age (35%). 25 out of 26 patients had stage IV disease (96%). Nine out of 26 patients had received at least one prior chemotherapy regimen (35%). Five out of 26 patients had a grade 3 neutropenia (19%) there was no grade 4 neutropenia. One out of 26 patients (4%) had a grade 3 anemia and thrombocytopenia. There was no neutropenic fever and no limiting gastrointestinal (diarrhea, stomatitis) toxicity. This study included patients with a performance status of 2, patients who had progressed on prior chemotherapy and older patients.
Conclusion: High dose ascorbic acid combined with GFLIP chemotherapy is a safe and well tolerated treatment regimen for high risk patients with pancreatic cancer. This level of safety justifies the further study of this treatment regimen especially for high risk patients who would not be eligible for standard high dose combination chemotherapy in pancreatic cancer.
Citation Format: Howard W. Bruckner, Azriel Hirschfeld, Daniel Gurell, King Lee. Novel safety of high dose ascorbic acid and induction chemotherapy for high risk pancreatic 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 CT061. doi:10.1158/1538-7445.AM2017-CT061