bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1292: Camalexin, an indole phytoalexin from Arabidopsis thaliana, displays activity against ovarian cancer stem cells
Authors: Mezencev Roman , McDonald John F. 
Published: July 2016

Abstract
Ovarian cancer is the most lethal of all gynecological cancers. Current treatment of advanced ovarian cancers, which includes debulking surgery and chemotherapy, is initially effective in majority of patients; however, 70-90% of them eventually develop disease recurrence with limited treatment options. This recurrence can be attributed to therapy-resistant cancer stem cells (CSC), which represent a subset of all malignant cells that form the bulk of ovarian cancers. CSC may remain as a minimal residual disease after the bulk of ovarian tumor mass has been removed by surgery and/or chemotherapy; therefore, there is considerable current interest in the development of new therapies that can effectively target this insidious subpopulation of tumor cells. Here we report on the anticancer activity of camalexin, a major indole phytoalexin of Arabidopsis thaliana, against ovarian cancer stem cells. We demonstrate that camalexin inhibits proliferation and induces cell death in ovarian cancer stem cells that exhibit various molecular mechanisms of anticancer drug resistance. Furthermore, we present the mode of action of this prospective anticancer agent identified by combined approach that included in silico predictions, comprehensive analysis of whole-genome gene expression data and target-specific assays. Lastly, we demonstrate the relevance of the identified mode of action in context of ovarian cancer cell signaling.
Citation Format: Roman Mezencev, John F. McDonald. Camalexin, an indole phytoalexin from Arabidopsis thaliana, displays activity against ovarian cancer stem 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 1292.
Abstract 1296: Vascular shutdown anti-tumor effect of tetra-arsenic oxide on cervical cancer cells
Authors: Kim. Yong-Wan 
Published: July 2016

Abstract
Background: Tetra arsenic oxide (As4O6) is a novel arsenic compound that exhibits potent anti-vascular activity and significantly suppresses solid tumor growth. The present study was conducted to investigate the vascular shutdown effects in HPV E6/E7-expressing tumors bearing mice.
Methods: After tumors reached 300-350 mm3 in volume, mice were randomly divided into four groups and treated intraperitoneally with three different dose of As4O6 at 1-week interval. Tumor blood perfusion and vascularity were visualized using Hoechst 33342, CD31 staining respectively from 1 hour to 1 week after As4O6 treatment. Histopathological features were observed following hematoxylin and eosin staining. Apoptosis, TNF-a, caspase activity and tumor regression were used to determine the mechanisms for vascular shutdown effects.
Results: As4O6 significantly suppressed tumor growth compared with control group. This tumor growth inhibition led to massive necrosis and vascular shutdown in tumor tissue, and also tumor tissue necrosis and apoptosis. Mice treated with As4O6 had a reduction in tumor vessel dimensions compared with the control animals, with CD31 stained microvessels still being apparent at the outer edge of the tumor. Additionally, in the control group, vessel area and diameter increased over time, whereas in the tumors from the As4O6-treated group, vessel area and diameter remained stable or decreased. Apoptotic cell populations induced by As4O6 were increased by double staining the TC-1 cells with annexin V and propidium iodide.
Conclusions: The results suggest that As4O6 has potential anticancer activity that is exerted by vascular shutdown in C57BL/6 mice transplanted with TC-1 cells. The study is novel in the observation of recovery of disturbed vascular function.
Citation Format: Yong-Wan Kim. Vascular shutdown anti-tumor effect of tetra-arsenic oxide on cervical 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 1296.
Abstract 1317: IT-143: A nanoparticle delivery platform that encapsulates daunorubicin and widens therapeutic window
Authors: Costich Tara Lee , Crouse Rick , Carie Adam , Buley Taylor , Ellis Tyler , Repp Lauren , Semple J.Edward , Vojkovsky Tomas , Bakewell Suzanne , Sill Kevin 
Published: July 2016

Abstract
Daunorubicin is an anthracycline family chemotherapeutic with a narrow therapeutic window. Employing our nanoparticle drug delivery platform we encapsulated daunorubicin non-covalently in the hydrophobic core of a polymer micelle (IT-143). IT-143 is a nanoparticle formulation comprised of a hydroxamic acid triblock polymer with ferric crosslinking that increases stability for improved drug circulation and results in a pH dependent release of the encapsulated daunorubicin. Formulation characterization demonstrates a 3.7% weight loading (v/v) of daunorubicin resulting in an average micellar size of 58 nm. In vitro cytotoxicity is comparable to daunorubicin free drug with an IC50 ranging between 60-100 nM, dependent on cell line, compared to 67-114 nM for daunorubicin. In vivo we compared IT-143 plasma pharmacokinetics to daunorubicin administered as free drug and the Cmax was extended from 0.18 μg/mL for daunorubicin to 27.0 μg/mL for IT-143 at the 3 mg/kg dose, and to 49.4 μg/mL at the 6 mg/kg dose. We increased the maximum tolerated dose (MTD) from 7.5 mg/kg to 17.5 mg/kg in mice and improved anti-tumor efficacy. Furthermore, IT-143 eliminated in vivo toxicity compared to equivalent daunorubicin dosed at its MTD. Efficacy studies in 3 xenograft models (HCT116, HT-1080 and HOS-MNNG) compared intravenous bolus administration of IT-143 at equivalent and equitoxic dose to daunorubicin treatment. IT-143 inhibited HCT116 colorectal tumor volume growth by 21% compared to 7% at the equivalent daunorubicin dose, and by 51% at the 17.5 mg/kg dose. In the HT-1080 fibrosarcoma model IT-143 inhibited tumor volume by 38% compared to 37% inhibition at the equivalent daunorubicin dose, and by 94% at the 17.5 mg/kg dose. In the HOS-MNNG osteosarcoma model IT-143 did not inhibit tumor volume compared to 21% inhibition at the equivalent daunorubicin dose, but inhibited tumor volume by 34% at the 17.5 mg/kg dose. The encapsulation of daunorubicin as IT-143 exhibits increased dosage of daunorubicin with decreased toxicities not possible with free daunorubicin. These studies indicate that IT-143 widens the therapeutic window of daunorubicin treatment, providing a safer way to reduce patient toxicity yet increasing antitumor efficacy.
Citation Format: Tara Lee Costich, Rick Crouse, Adam Carie, Taylor Buley, Tyler Ellis, Lauren Repp, J.Edward Semple, Tomas Vojkovsky, Suzanne Bakewell, Kevin Sill. IT-143: A nanoparticle delivery platform that encapsulates daunorubicin and widens therapeutic window. [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 1317.
Abstract 132: Comprehensive genomic analysis of human papillomavirus-associated oral cancers
Authors: Symer David E. , Akagi Keiko , Coombes Kevin R. , Xiao Weihong , Pickard Robert K. L. , Agrawal Amit , Gillison Maura L. 
Published: July 2016

Abstract
Human papillomavirus-associated oral cancers comprise a distinct disease that is increasing in frequency in Western countries. Recent genomic landscape studies of oral cancers and of HPV-associated cervical cancers identified the most commonly mutated genes in each. Here we report a comprehensive analysis of 83 HPV-positive oropharyngeal cancers studied by whole genome sequencing (WGS), and an additional 46 tumors evaluated by the Cancer Genome Atlas project (TCGA) by exome sequencing. We confirmed recurrent mutations in previously reported, frequently mutated candidate driver genes including PIK3CA, as well as several novel gene targets, each occurring recurrently at frequencies of more than approximately 3%. Our WGS data demonstrated recurrent focal genomic instability associated with HPV insertional mutagenesis. We observed dramatic changes in genomic copy number variants (CNVs) at chromosome 3q as well as numerous other chromosomal regions that are recurrently gained or lost in HPV-positive tumors. RNA-Seq data from this collection of oral cancers defined differentially expressed transcript levels and other molecular alterations associated with single nucleotide variants (SNVs), CNVs and other genomic structural variants in the tumors. Together, our results reveal a unique pattern of somatic variants that distinguishes HPV+ oral cancers both from HPV- oral cancers as well as other HPV+ tumors arising in distinct tissues including the uterine cervix. These data shed new light on the molecular pathogenesis of oral cancers, and provide new opportunities for development of diagnostic and therapeutic strategies for affected patients.
Citation Format: David E. Symer, Keiko Akagi, Kevin R. Coombes, Weihong Xiao, Robert K. L. Pickard, Amit Agrawal, Maura L. Gillison. Comprehensive genomic analysis of human papillomavirus-associated oral cancers. [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 132.
Abstract 1321: IT-147: A stabilized polymer micelle formulation of epothilone D for treatment of solid tumors
Authors: Carie Adam , Buley Taylor , Sullivan Bradford , Semple J.Edward , Ellis Tyler , Costich Tara Lee , Sethuraman Jyothi , Crouse Rick , Sill Kevin , Bakewell Suzanne 
Published: July 2016

Abstract
IT-147 is a formulation of epothilone D encapsulated in a stabilized polymer micelle. Epothilones are a class of cytotoxic chemotherapeutics that induce apoptosis via microtubule stabilization. Epothilone D is a poor substrate for P-glycoprotein efflux pumps and has demonstrated equivalent activity against drug-sensitive and multidrug-resistant human cancer cell lines. This offers a distinct advantage over other microtubule stabilizing agents such as taxanes, however clinical utility is limited by a narrow therapeutic window due to dose limiting toxicities such as peripheral sensory neuropathy, GI toxicities, and cognitive abnormalities. We have optimized a lead formulation comprising 2% epothilone D (w/w) encapsulated in a polymer micelle that is crosslinked with iron to provide micelle stability upon dilution. IT-147 has an average diameter of 70 nm. The iron-mediated crosslinking provides pH-dependent release of epothilone D such that drug can be released in the tumor microenvironment as well as in the endosome/lysosome upon cellular entry. In addition, the geometrical arrangement of iron molecules around the core of the micelle imparts superparamagnetic properties that allow for imaging of intact nanoparticles by MRI. IT-147 demonstrates a low nanomolar IC50 against a panel of human cancer cell lines in vitro. In vivo, IT-147 demonstrates a 4-fold increase in maximum tolerated dose in a mouse model compared to epothilone D free drug. Pharmacokinetics (PK) in a cannulated rat model for a 20 mg/kg epothilone D dose demonstrates a 6.5-fold increase in area under the time versus concentration curve (AUC), and a 14.3-fold increase in the terminal half-life compared to free drug. Dose escalation of IT-147 to 30 and 40 mg/kg epothilone D in the rat PK model results in linear increases in AUC from 53.5 h*μg/mL at 20 mg/kg to 82.9 and 110.8 h*μg/mL at 30 and 40 mg/kg, respectively. Treatment with IT-147 at the MTD in an HCT116 tumor xenograft model led to tumor stasis during the course of treatment, and MRI imaging of mice treated with IT-147 demonstrates tumor accumulation over 24 and 48 hours post administration. Taken together, data for IT-147 demonstrates successful encapsulation of epothilone D leading to a safer, more effective formulation with the potential for MRI imaging as a predictor for response.
Citation Format: Adam Carie, Taylor Buley, Bradford Sullivan, J.Edward Semple, Tyler Ellis, Tara Lee Costich, Jyothi Sethuraman, Rick Crouse, Kevin Sill, Suzanne Bakewell. IT-147: A stabilized polymer micelle formulation of epothilone D for treatment of solid tumors. [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 1321.
Abstract 133: Integrated molecular characterization of uterine carcinosarcoma in The Cancer Genome Atlas (TCGA) project
Authors: Akbani Rehan ,   The Cancer Genome Atlas Research Network, Levine Douglas A. 
Published: July 2016

Abstract
We used array- and sequencing-based technologies to perform an integrated genomic, epigenomic, transcriptomic, and proteomic characterization of the rare tumor type uterine carcinosarcoma (UCS) within the context of The Cancer Genome Atlas (TCGA) project using 57 cases that had stringent histopathologic review. Cohort samples had extensive copy number alterations and highly recurrent somatic mutations. Nearly all (91%) cases had TP53 mutations, similar to ovarian and serous uterine carcinomas, and frequent mutations were also found in PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong EMT gene signature in a subset of 17 (30%) cases, and cases with EMT signatures had decreased expression of mir-200 family members that was attributable to epigenetic alterations at miRNA promoters. The range of EMT signatures scores in UCS was the largest among all the TCGA tumor types studied. UCS shared proteomic features with both gynecologic carcinomas and non-gynecologic mesenchymal-like tumors. Our results indicate that UCS tumors share many features with serous-like endometrial carcinomas, including frequent TP53 mutations and extensive somatic copy number alterations, though with greater EMT features. Multiple somatic mutations and copy number alterations in genes that are therapeutic targets were identified. There was a high degree of mutational clonality, consistent with tumors being derived from a single cell of origin. Taken together, these data suggest that while some UCS tumors develop from an endometrioid lineage, the majority likely de-differentiate from a serous precursor, potentially accounting for their clinical aggressiveness and poor response to treatment.
Citation Format: Rehan Akbani, The Cancer Genome Atlas Research Network, Douglas A. Levine. Integrated molecular characterization of uterine carcinosarcoma in The Cancer Genome Atlas (TCGA) project. [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 133.
Abstract 1338: Ferulic acid as a natural bioactive compound enhances PARP inhibitor sensitivity in breast cancer cells
Authors: Park Eunmi , Lee Hyuna 
Published: July 2016

Abstract
Homologous-recombination (HR)-dependent repair defective cells are hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Combinations of defective HR pathway and PARP inhibitors have been an effective chemotherapy strategy. We previously showed that knockdown of the WD40-repeat containing protein, Uaf1, is HR repair defect in mouse embryo fibroblast cells and is sensitive to ABT-888, a chemotherapy drug commonly used for inhibiting PARP. Consistent with the HR defective mouse genetic study, here, we show that ferulic acid inhibits Rad 51 foci formation and accumulates γ-H2AX in breast cancer cells. Ferulic acid treatment reduces HR repair and causes breast cancer cells to become hypersensitive to ABT-888 treatment. Our study indicates that ferulic acid with PARP inhibitor treatment may be useful for the combination chemotherapy as a natural bioactive compound.
Citation Format: Eunmi Park, Hyuna Lee. Ferulic acid as a natural bioactive compound enhances PARP inhibitor sensitivity in breast 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 1338.
Abstract 1343: P32-targeting TT1 peptide delivers nanoparticles to intracranial glioblastomas
Authors: Säälik Pille , Hunt Hedi , Tobi Allan , Willmore Anne-Mari Anton , Toome Kadri , Sharma Shweta , Kotamraju Ramana , Bergers Gabriele , Bjerkvig Rolf , Ruoslahti Erkki , Teesalu Tambet , Teesalu Tambet 
Published: July 2016

Abstract
Targeted delivery of cancer therapeutics using affinity ligands can dramatically improve antitumor efficacy. Over the years a number of homing peptides that upon systemic injection accumulate in solid tumors have been identified by in vivo peptide phage display. In a quest to find homing peptides optimally suited for drug delivery to high-grade gliomas, our laboratories are using advanced mouse models of glioblastoma (GBM) to systematically audit known tumor-homing peptides and to perform new in vivo screens using peptide phage libraries.
P32 is a mitochondrial chaperone that is aberrantly expressed on the cell surface in activated malignant and stromal cells in tumors. P32 is a receptor for widely used LypP-1 peptide and for recently identified TT1 peptide. Here we show that iron oxide nanoworms (IONW) functionalized with linear TT1 peptide (CKRGARST) strongly home to intracranial GBMs grafted in immune deficient mice. IONW are paramagnetic nanoparticles that are PEGylated to extend blood half-life, and have, because of their elongated shape, more effective targeting properties than spherical nanoparticles. Five hours after intravenous injection of IONW (7.5 mg/kg), macroscopic fluorescence imaging demonstrated robust homing of TT1-IONW in GBMs of murine origin (WT GBM and VEGF KO GBM from the G. Berger lab) and in a patient-derived glioma model (P13 model from the Bjerkvig lab). Confocal microscopy confirmed the presence of TT1 but not control IONW in gliomas, with TT1-IONW signal showing partial overlap with blood- and lymphatic vessel markers (CD31 and LYVE-1) in WT GBM and P13 gliomas, whereas lower level of colocalization with these markers was detected for mouse GBM not expressing VEGF. In addition, moderate colocalization between TT1-IONW and the macrophage marker CD11b was detected in the P13 tumors. Detailed phenotyping and functional characterization of TT1-positive macrophages is ongoing.
Our data suggest that TT1 peptide has potential applications as a glioma-targeting vehicle. Currently, we are evaluating TT1-targeted IONWs as a contrast agent for glioma MRI and as carriers for cytotoxic compounds.
Citation Format: Pille Säälik, Hedi Hunt, Allan Tobi, Anne-Mari Anton Willmore, Kadri Toome, Shweta Sharma, Ramana Kotamraju, Gabriele Bergers, Rolf Bjerkvig, Erkki Ruoslahti, Tambet Teesalu, Tambet Teesalu. P32-targeting TT1 peptide delivers nanoparticles to intracranial glioblastomas. [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 1343.
Abstract 1352: High-throughput matrix screening reveals synergistic chemotherapeutic combinations with blockade of CD47 to enhance cytotoxicity in breast cancer
Authors: Roberts David D. , Smith Ashley , Sipes John M. , Wilson Adam , Mathews-Griner Lesley , Guha Rajarshi , Thomas Craig J. , Ferrer Marc , Soto-Pantoja David R. 
Published: July 2016

Abstract
CD47 is a widely expressed cell surface receptor that serves as a counter-receptor for SIRPα in recognition of self by the innate immune system. On the other hand CD47 also serves as a signaling receptor for the matricellular protein thrombospondin-1 (TSP-1), regulating cell growth and survival. Clinical studies consistently show that increased expression of CD47 is an independent poor prognosis factor in several types of cancer, including breast cancer. Moreover elevated expression of CD47 is associated with development of resistance to chemotherapy by inhibiting cell death pathways. Therefore, agents targeting CD47 are attractive to overcome therapeutic resistance in breast cancer. Using a high-throughput assay in a 1536-well microplate format we screened a comprehensive set of approved and late stage development oncology drugs in combination with an anti-CD47 morpholino to find combinatorial strategies that are more cytotoxic against breast cancer cells. Potency and efficacy measurements during the primary screen identified compounds that synergized with anti-CD47 to augment their cytotoxicity effect. One of the compound groups that demonstrated increased synergism with CD47 were the anthracycline family of drugs. We further validated these results in a syngeneic model of breast cancer and demonstrated that blockade of CD47 in combination with doxorubicin improves chemotherapeutic response when compared to mice administered doxorubicin alone. Furthermore the anti-tumor response with anti-CD47 combination is associated with a reduction in glycolytic flux and a selective up regulation of mitophagy. Overall this indicates that blockade of CD47 in the clinic may synergize with chemotherapeutic strategies to improve patient curative responses.
Citation Format: David D. Roberts, Ashley Smith, John M. Sipes, Adam Wilson, Lesley Mathews-Griner, Rajarshi Guha, Craig J. Thomas, Marc Ferrer, David R. Soto-Pantoja. High-throughput matrix screening reveals synergistic chemotherapeutic combinations with blockade of CD47 to enhance cytotoxicity in breast 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 1352.