bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C77: Oncogenic drivers reactivate kinase-inhibited focal adhesion kinase (FAK) through phosphorylation of effector residues
Authors: Figel Sheila , Lenzo Felicia , Marlowe Timothy , Cance William 
Published: May 2016

Abstract
Introduction: Focal Adhesion Kinase (FAK) is a critical signaling molecule showing elevated expression in nearly all tumor types. Phosphorylation of key tyrosine residues within FAK underlies its dual roles as both a kinase and a molecular scaffold that integrates signals from major oncogenes. Though FAK has emerged as a major drug target, inhibitors developed to date singularly target its kinase activity, leaving the scaffolding of oncogenic drivers intact. Our studies demonstrate that cells treated with FAK kinase inhibitors PF-573228, PF-562271, and defactinib retain phosphorylation of several key tyrosine residues downstream of oncogenic receptor tyrosine kinases (RTKs).
Methods: We examined the phosphorylation status of key FAK scaffolding sites Y861 and Y925 in RTK expressing normal and cancer cells treated with FAK kinase inhibitors PF-573228, PF-562271, and defactinib. As Src kinase is known to directly phosphorylate Y861 and Y925, we also tested phosphorylation of these sites by RTKs in Src/Yes/Fyn (SYF) MEFs, which lack the major Src family kinases.
Results: In cancer cells treated with FAK kinase inhibitors, multiple RTKs (HER2/3, PDGFR, and EGFR) activated FAK through the phosphorylation of effector tyrosines. Activation of HER2/3 in MDA-MB-453 breast cancer cells, PDGFR in U-87 glioblastoma cells, and EGFR in A549 lung cancer cells all stimulated Y861/Y925 phosphorylation in the presence of each of the three FAK kinase inhibitors. Moreover, Y861/Y925 phosphorylation occurred downstream of PDGFR and EGFR in Src-null SYF MEFs, demonstrating that RTK FAK targeting does not require Src. Finally, in vitro studies demonstrated that RTKs can directly phosphorylate these sites on FAK.
Conclusion: We have identified a novel mechanism through which FAK retains signaling activity in the presence of kinase inhibitors. Continued FAK signaling in tumor cells which overexpress HER2, EGFR or PDGFR may therefore be a mode of clinical resistance to FAK kinase inhibitors.
Citation Format: Sheila Figel, Felicia Lenzo, Timothy Marlowe, William Cance. Oncogenic drivers reactivate kinase-inhibited focal adhesion kinase (FAK) through phosphorylation of effector residues. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C77.
Abstract C92: HCI-2577 inhibits LSD1 and modulates histone marks in Ewing's sarcoma models
Authors: Bearss Jared J. , Neiss Adrianne , Liu Xiao-Hui , Vankayalapati Hariprasad , Sharma Sunil 
Published: May 2016

Abstract
Lysine-specific demethylase 1 (LSD1/AOF2/KDM1A) is a flavin-dependent histone demethylase that catalyzes the posttranslational oxidative demethylation of mono- and dimethylated lysines on histones. Methylation of lysine residues on histones can signal transcriptional activation or repression depending on the specific residue involved. H3K4me2 is a transcription-activating mark, and demethylation of this mark by LSD1 prevents expression of tumor suppressor genes important in human cancer. Whereas, H3K9 methylation is a repressive mark and LSD1 activity has been shown to upregulate tumor promoting pathways. This makes LSD1 emerge as an important target for the development of novel antitumor inhibitors. The compound HCI-2577 was identified as a potent reversible inhibitor of LSD1 enzymatic activity, with an IC50 of 7nM. In a diverse cell screen panel for cellular viability, Ewing's sarcoma was identified as being sensitive to HCI-2577. Here we show that HCI-2577 is efficacious in in vivo models of Ewing's sarcoma as a single agent with a favorable drug profile. In conclusion, HCI-2577 is a novel LSD-1 inhibitor with therapeutic potential in Ewing's sarcoma demonstrating promising activity in biochemical, cell-based and in vivo assays.
Citation Format: Jared J. Bearss, Adrianne Neiss, Xiao-Hui Liu, Hariprasad Vankayalapati, Sunil Sharma. HCI-2577 inhibits LSD1 and modulates histone marks in Ewing's sarcoma models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C92.
Abstract PR11: Phase 1 study of a novel PARP1/2 selective inhibitor, BGB-290
Authors: Lickliter Jason , Gan Hui , Meniawy Tarek , Yang Jason , Wang Lai , Luo Lusong , Millward Michael 
Published: May 2016

Abstract
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session.
Citation Format: Jason Lickliter, Hui Gan, Tarek Meniawy, Jason Yang, Lai Wang, Lusong Luo, Michael Millward. Phase 1 study of a novel PARP1/2 selective inhibitor, BGB-290. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR11.
Abstract PR12: Discovery and preclinical evaluation of cEt-modified KRAS antisense oligonucleotide inhibitors
Authors: Revenko Alexey S. , Ross Sarah J. , Hanson Lyndsey L. , Ellston Rebecca , May Chris , Pandey Sanjay K. , Buckett Linda K. , Klein Stephanie K. , Revill Mitchell , Hudson Kevin , Monia Brett P. , Blakey David C. , Lyne Paul , MacLeod Allan R. 
Published: May 2016

Abstract
KRAS is one of the most frequently mutated genes in cancer and its activation is thought to underlie the pathogenesis of up to 30% of all human tumors. However, to date KRAS has proven difficult to target with traditional pharmacologic approaches. Antisense technology is particularly attractive for such difficult drug targets as antisense oligonucleotide (ASO) inhibitors can be designed based on a targets RNA sequence alone.
cEt ASOs have been recently described and demonstrated to have significantly increased potency over previous generation ASO chemistries. Moreover, STAT3Rx/AZD9150, a cEt modified ASO targeting STAT3 mRNA was recently shown to produce robust STAT3 depletion in a broad range of xenograft models (AACR 2013) and importantly has also demonstrated promising single-agent antitumor activity in patients with advanced treatment-refractory cancers in phase I studies (ASCO 2013, EORTC 2014).
Here, we describe the preclinical evaluation of potent and selective cEt ASOs targeted to human or mouse KRAS mRNA. A human-specific KRAS cEt ASO which potently and selectively down-regulated KRAS demonstrated anti-proliferative effects and the expected down-stream pathway inhibition in a panel of KRAS mutant NSCLC, CRC and PDAC cells. The KRAS ASO was differentiated from MAPK pathway inhibitors selectively inhibiting the proliferation of KRAS mutant not KRAS wild type cells and not causing feedback reactivation of the MAPK or PI3K pathways. Systemic delivery of the KRAS ASO to mice bearing KRAS mutant NSCLC or CRC xenografts resulted in significant inhibition of KRAS tumour expression and antitumor activity. Importantly, the KRAS ASO also showed significant target knockdown and antitumor effects in KRAS mutant NSCLC patient-derived xenografts (PDX).
Finally, potent and selective murine-specific KRAS ASO produced robust target knockdown in a broad set of tissues without detectable tolerability signals associated with ASO-mediated systemic KRAS inhibition.
Taken together these data suggest that KRAS ASOs are an attractive therapeutic approach to target KRAS for the treatment of human cancers.
Citation Format: Alexey S. Revenko, Sarah J. Ross, Lyndsey L. Hanson, Rebecca Ellston, Chris May, Sanjay K. Pandey, Linda K. Buckett, Stephanie K. Klein, Mitchell Revill, Kevin Hudson, Brett P. Monia, David C. Blakey, Paul Lyne, Allan R. MacLeod. Discovery and preclinical evaluation of cEt-modified KRAS antisense oligonucleotide inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR12.
Abstract A08: IGF1R as a key target in high risk, metastatic medulloblastoma
Authors: Svalina Matthew N. , Kikuchi Ken , Abraham Jinu , Lal Sangeet , Davare Monika A. , Peckham Jennifer L. , Cho Yoon-Jae , Jackson Melanie , Guillaume Daniel J. , Selden Nathan R. , Bigner Darell D. , Nazemi Kellie J. , Green Sarah C. , Corless Christopher L. , Gultekin Sakir , Rubin Brian P. , Woltjer Randall , Keller Charles 
Published: May 2016

Abstract
The risk or presence of metastasis in childhood medulloblastoma represents a substantial cause of morbidity and mortality. Relatively little has been known about the molecular mechanisms of medulloblastoma dissemination throughout the cerebrospinal axis. To determine potential interventions that address both metastasis and tumor growth, we examined the expression of cytokines and growth factors in the CSF of metastatic medulloblastoma patients that were also present in the conditioned media of metastatic, MYC amplified medulloblastoma cell lines and/or cell culture models of the leptomeninges. The presence of IGF1, the IGF-sequestering protein Igfbp3, which can be cleaved by metal metalloproteases (MMP) and the serine protease tPA, and the presence of corresponding protease modulators TIMP1 and SerpinE1/PAI-1, led us to explore the bioactivity of IGF1 in medulloblastoma. IGF1 led not only to receptor phosphorylation but also increased migration and increased relative cell growth. A tumor cell viability screen of 60 clinically-related compounds prioritized IGF1R inhibitors. Our findings support a model whereby medulloblastoma tumor cells actively migrate, rather than arrive passively, to the leptomeningeal cell surface and provide a rationale for exploring IGF1R as a target for therapeutics in future clinical trials.
Citation Format: Matthew N. Svalina, Ken Kikuchi, Jinu Abraham, Sangeet Lal, Monika A. Davare, Jennifer L. Peckham, Yoon-Jae Cho, Melanie Jackson, Daniel J. Guillaume, Nathan R. Selden, Darell D. Bigner, Kellie J. Nazemi, Sarah C. Green, Christopher L. Corless, Sakir Gultekin, Brian P. Rubin, Randall Woltjer, Charles Keller. IGF1R as a key target in high risk, metastatic medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A08.
Abstract A15: A human mini brain model of pediatric GBM
Authors: Ismail Amin 
Published: May 2016

Abstract
Glioblastoma (GBM) is the most devastating brain cancer with dismal prognosis both in adults and children and accounts for 16% of primary brain tumors. Despite aggressive therapeutic approaches, the majority of patients die within one year after diagnosis. Giving the limitation of current GBM mouse models, which do not reflect the biological properties of human tumors, in particular, tumor heterogeneity and pathogenesis, there is a growing need for new models. Current in vitro 3D models involve the use of hydrogel scaffolds and cell lines, which do not represent a viable developmental context where the tumor mass interacts with and invades the surrounding brain tissues. Starting with pluripotent human embryonic stem cells we reproduced a 3D tissue structure (so-called cerebral organoid) representing a developing human brain in vitro. We engineered these mini-brains to express oncogenic hits responsible for the derivation of tumors in pediatric GBM patients. Pediatric GBM is driven by a combination of epigenetic and genetic hits including the expression of a mutant histone H3 variant H3F3A (mutated at K27M or G34R) or a gain of function mutant isocitrate dehydrogenase IDH1R132H in combination with the loss of the histone remodeling factor ATRX and/or p53 tumor suppressor. We used a combination of these oncogenic hits to create a model of tumor engineering representing the first 3D human tissue model of GBM. This model combines the accurate multi-lineage differentiation and physiology of human brain with the easiness of manipulation of in vitro systems.
H&E staining of the modified organoids shows remarkable dysplasia reminiscent of human primary glioma. Different genetic hits result in different type of dysplasia with IDH1R132H showing distinct morphology, suggestive of a broad range of applicability to model oncogenic-dependence in pediatric GBM.
Cerebral organoids may also be used as a model to study tumor invasion starting with glioma stem-like cells (GSCs, which are believed to be the tumor-initiating cells in GBM). Indeed 923 GSCs (which are not invasive in mice brain) quickly and spontaneously (within few days) invade a co-cultured cerebral organoid.
This study is the first to engineer a human CNS tumor in vitro. The model carries a tremendous potential to uncover the pathogenesis and initiation of brain cancer in a pediatric setting.
Note: This abstract was not presented at the conference.
Citation Format: Amin Ismail. A human mini brain model of pediatric GBM. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A15.
Abstract A23: Bone marrow derived myeloid cells orchestrate resistance to antiangiogenic therapy in novel chimeric mouse model of glioblastoma
Authors: Achyut B.R , Shankar Adarsh , Iskander Asm , Ara Roxan , Angara Kartik , Knight Robert , Scicli Alfonso , Arbab Ali 
Published: May 2016

Abstract
Glioblastoma (GBM) is considered as hypervascular form of brain tumors. Anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels. Surprisingly, AAT resulted into marked hypoxia and recruited bone marrow derived cells (BMDCs) to the tumor microenvironment (TME). Nonavailability of in vivo model limits investigation of BMDCs in AAT resistance. We established a novel chimeric mouse model using as low as 5x106 BM cells from GFP+ transgenic mice, administered through i.v route in athymic nude mice following whole body irradiation, which resulted in &gt;70% engraftment within 14 days. We exploited chimeric mouse model to develop orthotopic U251 tumor and tested receptor tyrosine kinase inhibitors and CXCR4 antagonist against GBM. Increased infiltration of GFP+ BMDCs acquiring suppressive myeloid and endothelial phenotypes in TME, and increased tumor growth were observed following treatments. Inhibition of CSFR1+ myeloid cells using GW2580 reduced tumor growth by decreasing myeloid and angiogenic cells in TME. This was followed by decreased inflammatory, proangiogenic and immune suppressive factors compared to vehicle and other treated groups. In conclusion, we developed preclinical chimeric model of GBM and role of tumor infiltrated BMDCs were investigated in context of resistance of AATs by utilizing state of art multispectral optical and MR imaging. Study suggests that inhibiting immune suppressive myeloid cells could provide a better therapeutic benefit in GBM.
Citation Format: B.R Achyut, Adarsh Shankar, Asm Iskander, Roxan Ara, Kartik Angara, Robert Knight, Alfonso Scicli, Ali Arbab. Bone marrow derived myeloid cells orchestrate resistance to antiangiogenic therapy in novel chimeric mouse model of glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A23.
Abstract A34: Id-1 mediates glioma stem cell chemoresistance to temozolomide
Authors: Celebre Angela , Wu Megan YiJun , Remke Marc , Taylor Michael , Karamchandani Jason , Das Sunit 
Published: May 2016

Abstract
Introduction: Id-1 (inhibitor of differentiation and DNA binding) is a transcriptional regulator involved in stem cell maintenance. It has previously been shown to regulate self-renewal and confer chemoresistance in colon cancer stem cells. Id-1 has not been studied within the context of glioblastoma (GBM). We hypothesized that Id-1 mediates glioma stem cell (GSC) survival in response to chemotherapy and subsequently promotes tumour recurrence.
Methods: To study the role of Id-1 in response to chemotherapy in vitro, three GSC lines were treated with the chemotherapy agent, temozolomide (TMZ), for seven days. Immunoblot and comparative QT-PCR were used to measure Id-1 protein and mRNA expression post-TMZ, respectively. To evaluate Id-1 expression in patient samples, we constructed a tissue microarray (TMA), which included 77 tissue specimens from patients diagnosed with GBM. Detailed clinical information was available for all of the selected samples, including survival times, treatment regimens, and primary versus recurrent tumor status. Immunohistochemistry was performed on the TMA and Id-1 protein expression was subsequently quantified using Panoramic Image Analysis Software Platform. Id-1 expression was correlated to survival outcome, along with other clinically relevant variables. We also employed a bioinformatics approach, exploring survival data from The Cancer Genome Atlas (TCGA) database that were based on Id-1 expression for patients diagnosed with GBM.
Results: Id-1 expression in GSCs strongly increased in response to increasing doses of TMZ in vitro (0 uM, 25 uM, 100 uM). In patient tumor samples (n=77), Id-1 expression did not correlate with survival. However, among the recurrent patients who received chemotherapy after primary tumor resection (n=6), patients with increased Id-1 expression post-chemotherapy had a shorter latency to recurrence compared to patients with decreased Id-1 expression post-chemotherapy. Finally, the TCGA data corroborated our TMA patient data, finding comparable overall survival trends between patients with high versus low Id-1 expression.
Conclusion: These findings demonstrate that Id-1 levels increase in response to chemotherapy, suggesting its potential role in chemoresistance. Since resistance to chemotherapeutic drugs is one of the major reasons for treatment failure in glioblastoma, Id-1 inactivation may serve as a novel strategy for enhancing therapy and improving outcomes in patients with the disease.
Citation Format: Angela Celebre, Megan YiJun Wu, Marc Remke, Michael Taylor, Jason Karamchandani, Sunit Das. Id-1 mediates glioma stem cell chemoresistance to temozolomide. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A34.
Abstract A40: CD74: a potential mediator of resistance in the treatment of Glioblastoma
Authors: Magorrian Sinead , Coulter Jonathan , Flannery Tom , Scott Christopher , Burden Roberta 
Published: May 2016

Abstract
CD74 is a rapidly internalised transmembrane protein, highly expressed in a number of cancers and is associated with increased proliferation and invasion of tumourigenic cells. CD74 is an attractive biomarker to monitor tumour progression and predict overall survival as expression levels have shown to be increased on the cell surface. Recent studies have suggested CD74 plays a potential role in tumour cell response to treatment, showing direct correlation between expression and response. The overall survival of patients with glioblastoma is poor, as treatment options are limited and not well defined. The standard options for the majority of patients is a combination of surgical resection, radiation and chemotherapy. The aim of this study is to investigate the association between CD74 expression and response to radiation and chemotherapy. A panel of glioblastoma cells lines were analysed by RT-PCR and western blotting to examine CD74 expression. Results indicated LN229 and U87MG cells expressed CD74 and using two independent shRNA constructs, CD74 expression was successfully knocked-down in both these lines to enable further study. Interrogation of these CD74-depleted lines indicated a significant reduction in proliferation and migration compared to a non-targeting control. When exposed to increasing doses of radiation the survival fraction of CD74 deficient cells was greater than that of the non-targeting control, suggesting an association between CD74 expression and sensitivity to radiation therapy in glioblastoma cell lines. However, when cells were exposed to increasing doses of Temozolomide there was a decrease in survival fraction of CD74-depleted cells compared to non-targeting controls, which showed no response to treatment. This study aims to further investigate the mechanism by which these change in sensitivity to treatment are mediated and determine if CD74 could not only be used as a marker for tumour progression, but to determine the most appropriate treatment option for patients.
Citation Format: Sinead Magorrian, Jonathan Coulter, Tom Flannery, Christopher Scott, Roberta Burden. CD74: a potential mediator of resistance in the treatment of Glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A40.
Abstract B30: MicoRNA mediated regulation of antiangiogenic resistance in glioblastoma
Authors: Jain Meenu , Achyut Bhagelu , Shankar Adarsh , Angara Kartik , Iskander Asm , Arbab Ali S. 
Published: May 2016

Abstract
Anti-angiogeneic therapies are being used in glioma due to high expression of vascular and angiogenic growth factors but without improved survival and tumor recur. Our study used vatalanib (PTK) in U251 tumor cells which secretes proangiogenic and proinvasive proteins. We found 7 proteins (MMP-2, MMP-9, SDF-1α, Tie-2, MCP-1, IL-8, VE Cadherin, and VEGFA) which were altered greater than 20 fold in both U251 complete medium and lysate. We hypothesized that miRNA regulation may be involved in overexpression of these secreted factors that might be responsible for antiangiogenic resistance in glioma. We performed miRNA profiling (Affymetrix miRNA v3 platform) in U251 glioma cell line treated with or without PTK drug under hypoxia and normoxia conditions. Fold changes were estimated using normoxia group as control against normoxia+PTK, hypoxia, hypoxia+PTK, and changes greater than 5 fold were considered for further analysis to investigate potential targets. We found miR-15a and miR-21 were &gt; 7-fold upregulated in group with hypoxia+PTK treatment. Targetscan analysis showed mir-15a may target TNFAIP3, VEGFA and mir21 can target MMP-2, which were altered in U251 cell lysate. Our present study identified novel microRNAs and gene targets which may lead to antiangiogenic resistance in glioma and provide a basis for future clinical trials. In future, functional assays will confirm the role of candidate miRNAs in tumor vasculature development following antiangiogenic drug treatment.
Citation Format: Meenu Jain, Bhagelu Achyut, Adarsh Shankar, Kartik Angara, Asm Iskander, Ali S. Arbab. MicoRNA mediated regulation of antiangiogenic resistance in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B30.