bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5009: Self-renewal of hypoxic glioma stem-like cells is facilitated by secretion-mediated STAT3 activation
Authors: Bonnin Damian A. Almiron , Havrda Matthew C. , Liu Huan , Lee Myung Chang , Ung Matthew H. , Cheng Chao , Israel Mark A. 
Published: July 2017

Abstract
Glioblastoma, a type of high-grade glioma, is the most common and the most aggressive primary brain tumor of adults. The median survival is 12-15 months. Despite multimodality treatment, most high-grade gliomas eventually recur and are ultimately incurable. Several studies suggest that the initiation, progression, and recurrence of gliomas are driven at least partly by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew. We have identified a pathway dependent upon tumor hypoxia, a commonly found pathologic feature of GBM, that promotes self-renewal through the HIF1α-JAK1/2-STAT3 axis. Under hypoxic conditions, the expression of HIF1α is greatly increased in GBM stem-like cells leading to the activation of JAK1/2-STAT3 which mediates enhanced tumor stem-like cell self-renewal. Our data further demonstrate the importance of VEGF secretion for this pathway of hypoxia-mediated self-renewal. Using tumor stem-like cells derived from the S100β-v-erbB/p53-/- mouse model of spontaneous high-grade glioma, we have discovered that the activation of STAT3 through hypoxia-mediated VEGF secretion is required for self-renewal of glioma stem-like cells. Media conditioned by these S100β-v-erbB/p53-/- tumor sphere cells cultured under hypoxic conditions promoted self-renewal in S100β-v-erbB/p53-/- glioma stem-like cells and depletion of VEGF from this media was sufficient to inhibit STAT3 phosphorylation. Moreover, we have been able to identify two drugs: Brefeldin A and EHT-1864, that significantly inhibit VEGF secretion, decrease stem cell self-renewal, inhibit tumor growth, and increase the survival of mice allografted with S100β-v-erbB/p53-/- glioma stem-like cells. Cells treated with these drugs express molecular signatures that correlated strongly with the increased survival of GBM patients. These findings suggest a novel treatment strategy to inhibit hypoxia-mediated self-renewal of glioma stem-like cells in high-grade gliomas by targeting the secretion of extracellular, paracrine mediators of self-renewal.
Citation Format: Damian A. Almiron Bonnin, Matthew C. Havrda, Huan Liu, Myung Chang Lee, Matthew H. Ung, Chao Cheng, Mark A. Israel. Self-renewal of hypoxic glioma stem-like cells is facilitated by secretion-mediated STAT3 activation [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 5009. doi:10.1158/1538-7445.AM2017-5009
Abstract 5010: Activation of the notch signaling pathway confers a tumor-suppressive phenotype on melanoma-associated fibroblasts
Authors: Shao Hongwei , Moller Mecker G. , Cai Long , Zhang Leiming , Liu Zhao-Jun 
Published: July 2017

Abstract
Objectives. The tumor microenvironment (TME) is an emerging therapeutic target for cancer treatment. Cancer-associated fibroblasts (CAF) play a crucial role in cancer progression. We aim to target TME by altering intracellular signaling which determines the biological function of CAF. We have recently showed that the Notch signaling pathway likely functions as a molecular switch in controlling the tumor regulatory role of CAF in animal models and experimentally created “CAF”. Here, we investigated the status of Notch signaling in human melanoma-associated fibroblasts (MAF) versus their normal counterparts and tested whether manipulation of the Notch pathway activity in MAF alter their tumor-regulating function.
Methods. We examined levels of Hes1, a canonical Notch target, in MAF of human malignant melanoma at different stages (I-IV) and fibroblasts in either adjacent or non-adjacent normal skin tissues using tissue microarray. MAF were isolated from human metastatic melanoma tissues. Notch pathway RT2-PCRArray and immunoblot were used to assess Notch pathway activity in MAF versus normal human dermal fibroblasts. Activation of Notch signaling pathway in MAF was achieved by lentiviral vector encoding active form of Notch1 (NIC). The effect of Notch1-engineered MAF on melanoma growth was tested by in vitro co-cultures and in a mouse co-xenograft model (n=6/group). Tumor angiogenesis was analyzed by immunochemistry.
Results. MAF expressed decreased levels of Hes1 compared with adjacent skin fibroblasts. Isolated MAF also exhibited lower Notch activity than normal human dermal fibroblasts. Notch1-engineered MAF significantly inhibited melanoma cell growth in vitro (p&lt;0.01) and suppressed melanoma growth and tumor angiogenesis in mice (p&lt;0.05).
Conclusions. Notch pathway activity is down-regulated in MAF. Increase of Notch pathway activity confers MAF with inhibition to melanoma growth and tumor angiogenesis. Our study demonstrates that Notch signaling is a critical molecular switch in determining the tumor regulatory role of MAF and provides potential targets for cancer therapeutic interventions on the TME.
Citation Format: Hongwei Shao, Mecker G. Moller, Long Cai, Leiming Zhang, Zhao-Jun Liu. Activation of the notch signaling pathway confers a tumor-suppressive phenotype on melanoma-associated fibroblasts [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 5010. doi:10.1158/1538-7445.AM2017-5010
Abstract 5014: Drug discovery for NF1-associated malignant peripheral nerve sheath tumors using the zebrafish model
Authors: Ki Dong Hyuk , He Shuning , Look A. Thomas 
Published: July 2017

Abstract
Children and young adults with type 1 neurofibromatosis (NF1) are at risk to develop plexiform neurofibromas, which can undergo malignant transformation to malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are among the most frequently occurring sarcomas in children and young adults and are especially problematic in NF1 patients. Currently, complete surgical excision is the only curative therapy for NF1-associated MPNST, but these tumors are often not completely resectable. Therefore, it is very important to identify promising drugs that can be rapidly moved into clinical trials to improve the therapy of patients with MPNSTs. We have developed a faithful zebrafish model of NF1-associated MPNST by using genome engineering to develop zebrafish lines harboring loss-of-function mutations of the duplicated nf1a and nf1b genes and p53. Our nf1 and p53 deficient zebrafish models develop MPNSTs that are very similar to human NF1-associated MPNST, and thus are ideal for experiments to test the efficacy of FDA-approved small molecule drugs in vivo. To test the FDA-approved drugs for activity against MPNST tumor cells, about 100 Sox10:mCherry expressed MPNST primary tumor cells were transplanted into dechorionized 2 day-post-fertilization (dpf) larval fish using a micro-injector. MPNST-implanted embryos were exposed to individual test compounds added to the fish water at a range of concentrations and to the vehicle control. After 4-days of treatment, quantitative assessment of the remaining mCherry-labeled tumor cell numbers were measured using the ImageJ software for each treated embryo. Currently, trametinib and sunitinib caused marked antitumor effects indicated by reduced numbers of mCherry-labeled nf1-deficient MPNST cells compared to the DMSO control in this study. We are now applying this embryonic implantation assay to identify combinations of FDA-approved drugs that have a high degree of efficacy against MPNST and can be rapidly “repurposed” to improve the treatment of this disease.
Citation Format: Dong Hyuk Ki, Shuning He, A. Thomas Look. Drug discovery for NF1-associated malignant peripheral nerve sheath tumors using the zebrafish model [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 5014. doi:10.1158/1538-7445.AM2017-5014
Abstract 5017: Visualization of the mechanisms of metastasis within a biomimetic engineered tumor microenvironment encompassing a perfusable cylindrical 3D microvessel
Authors: Wong Andrew D. , Silvestri Vanesa , Ewald Anderw J. , Searson Peter C. 
Published: July 2017

Abstract
Metastasis is responsible for the majority of cancer related deaths; however, many of the biological and physical details surrounding the critical steps (e.g. invasion and intravasation) are largely unknown, in part due to the difficulty in recapitulating and visualizing these dynamic processes. To elucidate these mechanisms, we have developed an in vitro model of invasion and intravasation that comprises tumor cells embedded within an extracellular matrix (ECM) surrounding an engineered microvessel. The microvessel is cylindrical, 150 µm in diameter, and lined with endothelial cells forming a functional barrier that is maintained under constant perfusion at a shear stress of 2-8 dyne cm-2. Using this biomimetic tumor-microvessel platform, we have previously visualized invasion and intravasation of single MDA-MB-231 breast cancer cells into the microvessel and escape into flow. Here, we present mechanistic details of intravasation from both single tumor cells (MDA-MB-231) and mouse mammary tumor organoids (MMTV-PyMT). For single cells, we observe a mitosis-mediated mechanism of intravasation where tumor cell entry into flow is prefaced by cell division at the ECM-vessel interface. For tumor organoids, we see vascular deformation and destabilization from growing tumors that impinge upon proximal vessels, and that bulk intravasation is mediated by shear stress and tumor cell adhesion. As we characterize the various ways in which tumor cells interact with the vessel endothelium and intravasate, we can explore strategies involving the tumor vasculature and clinically relevant drugs to inhibit critical steps in the metastatic cascade.
Citation Format: Andrew D. Wong, Vanesa Silvestri, Anderw J. Ewald, Peter C. Searson. Visualization of the mechanisms of metastasis within a biomimetic engineered tumor microenvironment encompassing a perfusable cylindrical 3D microvessel [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 5017. doi:10.1158/1538-7445.AM2017-5017
Abstract 5023: Disruption of Monocarboxylate transporter-4 Basigin interaction as an effective strategy to inhibit hypoxic response, tumor growth and vascularization, and stem cell phenotype in human glioblastoma in vitro and in vivo
Authors: Spina Raffaella , Voss Dillon M. , Lim Kah Suan , Jeffery Constance J. , Bar Eli E. 
Published: July 2017

Abstract
Monocarboxylate transporters, constitute a family (SLC16) of proton-linked plasma membrane transporters that carry molecules containing a single carboxylate group across biological membranes. Basigin (CD147), is involved in many physiological functions during early stages of development and in cancer. Basigin has been shown to be required for functional plasma membrane expression of Monocarboxylate transporter-1 and Monocarboxylate transporter-4. Using a cell-based screening assay, we identified acriflavine, a small molecule that inhibits the binding between Basigin and Monocarboxylate transporters in vitro and in vivo. Surface Plasmon Resonance analysis confirmed direct binding of acriflavine to Basigin’s immunoglobulin extracellular domain with a low binding constant (kD) of 0.16µM. Acriflavine inhibits normoxic growth of glioma stem cells in vitro and this activity is augmented by hypoxia or by expression of oxygen-stable mutant forms of HIF-1α or HIF-2α. Treatment of mice bearing established glioma stem cell-derived xenografts resulted in inhibition of tumor growth. Acriflavine treatment inhibited intratumoral expression of the angiogenic cytokine vascular endothelial growth factor and tumor vascularization. Our work shows that disruption of monocarboxylate transporter binding to Basigin is an effective approach to target glioma stem cells.
Citation Format: Raffaella Spina, Dillon M. Voss, Kah Suan Lim, Constance J. Jeffery, Eli E. Bar. Disruption of Monocarboxylate transporter-4 Basigin interaction as an effective strategy to inhibit hypoxic response, tumor growth and vascularization, and stem cell phenotype in human glioblastoma in vitro and in vivo [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 5023. doi:10.1158/1538-7445.AM2017-5023
Abstract 5027: Exome sequencing of cancer-related genes to identify genetic markers for sensitivity to cytotoxic anticancer drugs
Authors: Udagawa Chihiro , Sasaki Yasushi , Suemizu Hiroshi , Ohnishi Yasuyuki , Ohnishi Hiroshi , Tokino Takashi , Zembutsu Hitoshi 
Published: July 2017

Abstract
Although the progress in moving from a one-size-fits-all cytotoxic approach to personalized molecular medicine, majority of the patients with cancer receive chemotherapy with cytotoxic anticancer drugs. Exome sequencing of 409 cancer related genes was conducted using 59 DNAs extracted from human tumor xenografts implanted into nude mice, of which sensitivity to nine cytotoxic anticancer drugs (5-fluorouracil (5FU), Nimustine (ACNU), adriamycin (ADR), cyclophosphamide (CPM), cisplatin (DDP), mitomycin C (MMC), methotrexate (MTX), vincristine (VCR), and vinblastine (VLB)) had been examined. We investigated the relationship between the sensitivities of the xenografts to the nine anticancer drugs and single nucleotide variants (SNVs) by classifying them into three groups according to the allele frequency (≤10%, 10-90%, ≥90%). We further carried out replication study using additional set of 20 xenografts. We also estimated the correlation between the expression levels of the 409 genes and sensitivities to the nine drugs in the above xenografts. In the screening stage using 59 xenografts, three SNVs, which were associated with sensitivity to VCR or MMC, showed P &lt; 0.001. We further carried out a replication study of 596 SNVs showing P &lt; 0.05 in the screening stage using independent samples of 20 xenografts. A combined result of the screening and replication studies suggested possible associations of 35 SNVs with sensitivities to the nine anticancer drugs (Pcombined = 0.0011 - 0.035). A total of 35 SNVs showed possible association with sensitivity to at least one of the nine drugs. Of the 35 SNVs, SNV-1 and SNV-2 in a tumor suppressor gene and a oncogene were commonly associated with sensitivity to two or four anticancer drugs, respectively. These findings provide new insights into precision anticancer therapy for the patients with cancer.
Citation Format: Chihiro Udagawa, Yasushi Sasaki, Hiroshi Suemizu, Yasuyuki Ohnishi, Hiroshi Ohnishi, Takashi Tokino, Hitoshi Zembutsu. Exome sequencing of cancer-related genes to identify genetic markers for sensitivity to cytotoxic anticancer drugs [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 5027. doi:10.1158/1538-7445.AM2017-5027
Abstract 5031: Distribution of single nucleotide polymorphisms related to paclitaxel and carboplatin toxicity in ovarian cancer patients
Authors: Cordova Miguel , Bravo Maria L. , Arriagada Isidora , Cumsille Elisa , Quiñones Luis , Bravo Erasmo , Correa Raimundo , Leiva Juan E. , Paredes Cesar , Cuello Mauricio , Ibañez Carolina , Garrido Marcelo , Owen Gareth I. 
Published: July 2017

Abstract
Introduction: Standard first-line treatment for ovarian cancer consists in the combined use of taxanes and platinum, with neuropathies and neutropenia the most frequent and complex adverse drug reactions (ADRs) requiring clinical management. These adverse effects may be related to differing levels of drug transport and metabolism brought about by intrinsic genetic characteristics of the patients. Single nucleotide polymorphisms (SNPs) are now recognized as key factors in the variability of drug response. In a cohort of Chilean ovarian cancer patients we analyzed the frequencies of several SNPs previously reported to be associated with paclitaxel and carboplatin ADRs.
Methods: Blood samples were obtained with informed consent from adult ovarian cancer patients (n = 120). DNA was extracted and SNPs within the ABC transporter and CYP P450 gene families were genotyped. High specificity Taqman probes were used.
Results: Four SNPs associated with risk of ADR within the ABC transporter family showed genotypic frequencies ranging between 0 - 23%. Frequencies for the ADR-associated variants in the CYP P450 family were 4 - 90%. Finally, for the CYP2C8 enzyme, whose function is essential in paclitaxel metabolism, the frequencies of risk-associated SNPs ranged from 2.10% to 13.6%.
Conclusions: SNPs associated with paclitaxel and carboplatin ADRs are highly prevalent in the Chilean population of ovarian cancer patients studied. The identification of these variants may help avoid severe ADRs associated with chemotherapy regimes. Funding: CORFO 13CTI21526-P6 & 13IDL2-18608
Citation Format: Miguel Cordova, Maria L. Bravo, Isidora Arriagada, Elisa Cumsille, Luis Quiñones, Erasmo Bravo, Raimundo Correa, Juan E. Leiva, Cesar Paredes, Mauricio Cuello, Carolina Ibañez, Marcelo Garrido, Gareth I. Owen. Distribution of single nucleotide polymorphisms related to paclitaxel and carboplatin toxicity in ovarian cancer patients [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 5031. doi:10.1158/1538-7445.AM2017-5031
Abstract 504: Quantification of nucleic acid quality in postmortem tissues from a cancer research autopsy program
Authors: Fan Jun , Khanin Raya , Sakamoto Hitomi , Zhong Yi , Michael Chelsea , Pena Derwin , Javier Breanna , Wood Laura , Iacobuzio-Donahue Christine 
Published: July 2017

Abstract
The last decade has seen a marked rise in the use of cancer tissues obtained from research autopsies. Such resources have been invaluable for studying cancer evolution or the mechanisms of therapeutic resistance to targeted therapies. Degradation of biomolecules is a potential challenge to usage of cancer tissues obtained in the post-mortem setting and remains incompletely studied. We analysed the nucleic acid quality in 371 different frozen tissue samples collected from 80 patients who underwent a research autopsy, including eight normal tissue types, primary and metastatic tumors. Our results indicate that RNA integrity number (RIN) of normal tissues decline with the elongation of post-mortem interval (PMI) in a tissue-type specific manner. Unlike normal tissues, the RNA quality of cancer tissues is highly variable with respect to post-mortem interval. The kinetics of DNA damage also has tissue type-specific features. Moreover, while DNA degradation is an indicator of low RNA quality, the converse is not true. Finally, we show that despite RIN values as low as 5.0, robust data can be obtained by RNA sequencing that reliably discriminates expression signatures. Based on this promising pilot data, we are currently identifying samples for multiregion RNA sequencing of pancreatic cancers with divergent morphologies within the primary and/or metastatic sites. Thus far we have screened 554 RNA samples from 10 autopsy cases. These samples represent 198 geographically distinct regions of tumor with duplicate or triplicate RNA extractions. The number of samples per patient ranges from 17 to 86 with an average of 55. Our data shows that high quality RNA can be acquired from cases with long PMI (&gt;48h). While extensive screening of samples is required to identify those with optimal quality, the downstream data produced is of high quality and can support novel hypotheses or validations of experimental data.
Citation Format: Jun Fan, Raya Khanin, Hitomi Sakamoto, Yi Zhong, Chelsea Michael, Derwin Pena, Breanna Javier, Laura Wood, Christine Iacobuzio-Donahue. Quantification of nucleic acid quality in postmortem tissues from a cancer research autopsy program [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 504. doi:10.1158/1538-7445.AM2017-504
Abstract 5040: The plasma and cerebrospinal fluid pharmacokinetics of pegylated liposomal doxorubicin after intravenous administration in non-human primates
Authors: Higham Christine , Murphy Robert , McCully Cynthia , Warren Katherine , Widemann Brigitte 
Published: July 2017

Abstract
Background: Pegylated liposomal doxorubicin (PLD) exhibits altered plasma pharmacokinetics (PK) compared to doxorubicin, with a longer half-life (55 hours), large area under the concentration-time curve (AUC), lower rate of clearance, and markedly smaller volume of distribution. The cerebrospinal fluid (CSF) PK of PLD are unknown. We evaluated the plasma and CSF PK of PLD in a non-human primate (NHP) model.
Methods: PLD was given as single dose (1 mg/kg = low adult recommended dose of 20 mg/m2) intravenously over 60 minutes to 3 NHP with indwelling central venous catheters and central nervous system ventricular reservoirs or lumbar ports. Serial blood and CSF samples were obtained for 96 hours after completion of the infusion. The total doxorubicin concentration (liposome bound + protein bound + free) was quantified with a validated liquid chromatography/tandem mass spectrometry assay (lower limit of quantification plasma=0.29 ng/mL, and CSF=0.06 ng/mL). PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUCCSF:AUCplasma.
Results: PLD was well tolerated. Total doxorubicin plasma concentration time curves were characterized by sustained PLD exposure, comparable to the exposure observed in humans at a similar dose. The terminal elimination phase was not captured. In CSF, doxorubicin was measurable and still present at the last time point in all animals, but the CSF penetration was limited (Table).
Conclusions: Using a sensitive assay, we could quantify doxorubicin in CSF. However, the CSF penetration is limited in NHP with intact blood brain barrier. Our assay analyzed the total doxorubicin concentration in plasma. It is unknown if PLD can penetrate into the CSF, therefore we could not determine if the CSF penetration represents total versus free.
Plasma and CSF PK of pegylated liposomal doxorubicin in NHPAnimalCmax Plasma(ng/mL)Tmax Plasma(h)AUC0-96h Plasma(ng*h/mL)Cmax CSF (ng/mL)Tmax CSF (h)AUC0-96h CSF (ng*h/mL)CSF Penetration (%)19396487.24E+051.84524.210.3323044901.76E+060.71618.750.113374670.081.91E+063.251036.410.2Mean25770161.46E+061.93726.460.21
Citation Format: Christine Higham, Robert Murphy, Cynthia McCully, Katherine Warren, Brigitte Widemann. The plasma and cerebrospinal fluid pharmacokinetics of pegylated liposomal doxorubicin after intravenous administration in non-human primates [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 5040. doi:10.1158/1538-7445.AM2017-5040