bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-154: Generation of antagonistic anti-DDR1 monoclonal antibodies as a potential novel cancer therapeutic
Authors: Jun H. Toni , Hynes Brandon , Macomber John L. , Lassen Andrew , Altobell Larry , MacLaren Josh , King David , Horlick Robert A. 
Published: May 2015

Abstract
Discoidin domain receptor 1 (DDR1) is a nonintegrin tyrosine kinase receptor for collagen implicated in diverse cellular roles, including cell adhesion, proliferation, and extracellular matrix remodeling. Multiple tumor types have been shown to overexpress DDR1, including lung, esophageal, breast, ovarian, and pediatric brain cancers, suggesting a potential role for DDR1 in tumor progression. Inhibition of DDR1 signaling may therefore represent a novel therapeutic approach for treating these cancers. Potential therapeutic molecules that modulate human DDR1 activity were identified by screening the AnaptysBio Evolvable Library (ABEL) of fully human germline antibodies. The initial ABEL screen used the soluble DDR-1 extra cellular domain, followed by secondary screening on cell-surface DDR-1. The resulting panel of human antibodies was affinity matured using SHM-XELTM which uses mammalian cell display of human IgG followed by in vitro somatic hypermutation (SHM) as described for a number of other antibodies (Bowers et al., 2014, Methods 65, 44-56). The matured antibodies bound specifically to DDR1 with high affinity (KD&lt;1nM as measured by Biacore), and were able to functionally inhibit collagen triggered DDR1 signaling in multiple cell-based assays. The antibody panel shows selectivity for DDR1 over closely related molecules such as DDR2 and has other properties suitable for preclinical development, including cross-reactivity with the cynomolgus monkey DDR-1 ortholog and good biophysical properties. These antibodies are being further explored for their therapeutic efficacy in tumor types where DDR1 signaling plays a role in disease progression.
Citation Format: H. Toni Jun, Brandon Hynes, John L. Macomber, Andrew Lassen, Larry Altobell, Josh MacLaren, David King, Robert A. Horlick. Generation of antagonistic anti-DDR1 monoclonal antibodies as a potential novel cancer therapeutic. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-154. doi:10.1158/1538-7445.AM2014-LB-154
Abstract LB-191: Astrocytes promote colonization of human brain with breast cancer cells via inhibition of KISS1 expression
Authors: Ulasov Ilya V. , Kaverina Natalya V. , Yoon JG , Lee Hwahyung , Sarvaiya Purvaba , Malin Dmitry , Cryns Vincent L. , Welch Danny R. , Cobbs Charles K. 
Published: May 2015

Abstract
Introduction: KISS1 metastatic suppressor is a negative regulator of tumor progression. Recently, we described that breast cancer metastatic cells to the brain exhibit much lower level of KISS1 expression detected by real time PCR and IHC. However little is known about the mechanism that regulates KISS1 in the brain metastatic cells and promotes brain metastases. We hypothesized that loss of KISS1 allows persistence of metastatic cells in the brain.
Results: Given the fact that some migrating breast cancer cells possess stem cells (CSC) properties, we stained the primary breast cancer and brain metastatic clinical specimens contain breast cancer cells using CD24, CD44, ESA1 and KISS1 markers. We observed that in the brain metastases, the CSC exhibit low/lack of KISS1 expression, whereas in the MDA-MB-231 model, blood derived circulating cells express comparative to primary xenografts level of KiSS1 expression. Then we co-cultured MDA-231-Br or CN34Br cells with either human microglia (HM) or human astrocytes (HA) to determine the conditions that affect KISS1 expression. We observed that primary human astrocytes downregulate the expression of KISS1, whereas HM conditional media had little effect. Furthermore, we detected that inhibition of KISS1 expression in breast metastatic cells is dependent on the expression of chemokines such CCL2 and CXCL12. This effect was dose dependent and required activation of cellular signaling in the tumor cells. Our data demonstrate that interaction of breast cancer cells with astrocytes inhibits KISS1 metastatic suppressor and contributes to tumorigenesis.
Conclusions: Our results provide a new insight into the mechanism that promotes brain metastases, and may have implications for the treatment and prevention of brain metastases.
Citation Format: Ilya V. Ulasov, Natalya V. Kaverina, JG Yoon, Hwahyung Lee, Purvaba Sarvaiya, Dmitry Malin, Vincent L. Cryns, Danny R. Welch, Charles K. Cobbs. Astrocytes promote colonization of human brain with breast cancer cells via inhibition of KISS1 expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-191. doi:10.1158/1538-7445.AM2014-LB-191
Abstract LB-227: Preclinical pharmacology and clinical efficacy of AZD9150 (ISIS-STAT3Rx), a potent next-generation antisense oligonucleotide inhibitor of STAT3
Authors: Hong David , Kim Youngsoo , Younes Anas , Nemunaitis John , Fowler Nathan , Hsu Jeff , Zhou Tianyuan , Fayad Luis , Zhang Nancy , Piha-Paul Sarina , Woessner Richard , Nadella Murali V. , Lawson Deborah , Reimer Corinne , Jo Minji , Schmidt Joanna , Xiao Xiaokun , Greenlee Sarah , Hung Gene , Yamashita Mason , Blakey David C. , Monia Brett P. , Macleod A. Robert , Kurzrock Razelle 
Published: May 2015

Abstract
Genomic technologies have greatly expanded our understanding of cancer biology, although they have not yet been effectively translated into improved cancer therapeutics, partly due to the inability of available therapeutic modalities to target the most promising cancer driver pathways. In contrast to other therapeutic approaches, antisense technology allows the rational design of potent, sequence-specific inhibitors based on genome sequencing information alone. Recent human clinical data have demonstrated the potent activity of antisense oligonucleotides (ASOs) targeted to genes expressed by the liver. Here we describe preclinical and clinical activity of a high affinity, new generation chemistry (constrained ethyl modified) ASO, AZD9150. AZD9150 targets the mRNA coding for the transcription factor STAT3, which is considered a difficult protein to target therapeutically. Systemic delivery of unformulated AZD9150 resulted in strong inhibition of STA3 RNA and protein levels in demonstrates in a broad range of preclinical cancer models in vivo including several patient-derived xenograft models. AZD9150 administration resulted in 2 partial responses highly treatment-refractory diffuse large B-cell lymphoma and in 2 mixed responses in Hodgkin's Lymphoma patients in the phase I dose escalation study. These findings suggest that this technology has the potential to help bridge the pharmacogenomic divide in cancer drug discovery.
[D.H. and Y.K. contributed equally to this work.]
Citation Format: David Hong, Youngsoo Kim, Anas Younes, John Nemunaitis, Nathan Fowler, Jeff Hsu, Tianyuan Zhou, Luis Fayad, Nancy Zhang, Sarina Piha-Paul, Richard Woessner, Murali VP Nadella, Deborah Lawson, Corinne Reimer, Minji Jo, Joanna Schmidt, Xiaokun Xiao, Sarah Greenlee, Gene Hung, Mason Yamashita, David C. Blakey, Brett P. Monia, A. Robert Macleod, Razelle Kurzrock. Preclinical pharmacology and clinical efficacy of AZD9150 (ISIS-STAT3Rx), a potent next-generation antisense oligonucleotide inhibitor of STAT3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-227. doi:10.1158/1538-7445.AM2014-LB-227
Abstract LB-256: Immunotherapy using genetically modified T lymphocytes to target CLEC14A on the tumor vasculature
Authors: Zhuang Xiaodong , Kaul Baksho , Bentley Michael , Nagy Zsuzsanna , Giraudo Enrico , Bendle Gavin , Gilham David , Bicknell Roy , Lee Steven P. 
Published: May 2015

Abstract
Chimeric antigen receptor (CAR) therapy combines the specificity of a monoclonal antibody with the potent cytotoxic and immune regulatory activity of self-replicating T cells. This approach has shown remarkable efficacy in recent clinical trials targeting T cells to hematological cancers. More limited benefit has been reported with solid tumors, possibly because of lack of suitable target antigens, immune evasion mechanisms in the malignant cells and/or lack of T cell infiltration into the tumor tissue. An alternative approach that avoids some of these problems is to use a CAR that targets the tumor vasculature rather than the malignant cells directly.
CLEC14A is a glycoprotein recently identified to be selectively overexpressed on the surface of the tumor vasculature in a wide range of human cancers, including ovarian, liver, bladder, prostate, breast and kidney, and is therefore of considerable interest for tumor therapy. Here we explore for the first time the feasibility of targeting the tumor vasculature using CLEC14A-specific CARs. Initially we generated CARs from several CLEC14A-specific monoclonal antibodies and then expressed them in T cells. In vitro T cell functional assays demonstrated that these CARs can trigger potent antigen-specific activation including cytotoxicity in engineered T cells. These CARs recognize both human and mouse forms of CLEC14A, so safety/efficacy studies could be conducted using mouse models. Following infusion of escalating doses of engineered T cells into healthy mice, circulating CAR-T cells persisted for at least the next 5 weeks without signs of toxicity. To explore anti-tumor effects, Lewis lung carcinoma cells were subcutaneously implanted into C57BL6 mice and 4 days later mice received a single dose of CLEC14A-specific CAR-T cells. Our recent data demonstrate statistically significant inhibition of tumor growth in mice treated with CAR-T cells compared with mock-transduced T cells. The engineered cells also appeared to expand/accumulate at the tumor site. These data suggest CLEC14A can be safely and effectively targeted with CAR-T cells, potentially offering a potent and widely applicable cancer therapy.
Citation Format: Xiaodong Zhuang, Baksho Kaul, Michael Bentley, Zsuzsanna Nagy, Enrico Giraudo, Gavin Bendle, David Gilham, Roy Bicknell, Steven P. Lee. Immunotherapy using genetically modified T lymphocytes to target CLEC14A on the tumor vasculature. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-256. doi:10.1158/1538-7445.AM2014-LB-256
Abstract LB-4: Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice
Authors: Kataoka Hiroaki , Kawaguchi Makiko , Kanemaru Ai , Fukushima Tsuyoshi , Matsumoto Nobuhiro , Nakazato Masamitsu 
Published: May 2015

Abstract
Background and aim: Ghrelin is a 28-amino-acid peptide, capable of stimulating growth hormone release. Because of its orexigenic effect, ghrelin is being developed as a therapeutic option for post-operative support and anorexia-cachexia syndrome of cancer patients. However, ghrelin has a multiplicity of physiological functions in various organs and immune system, and also affects cell proliferation. Therefore, it is important to know the effect of ghrelin administration on carcinogenesis and cancer progression in patients who are susceptible to cancer. This study aimed to test the effect of ghrelin on cancer promotion using murine intestinal carcinogenesis models.
Method: Effect of ghrelin knockout or exogenous ghrelin administration (3 nmoles/day, i.p.) on intestinal tumorigenesis was analyzed in two types of murine intestinal tumorigenesis models; ApcMin/+ mice (genetic cancer susceptibility model) and AOM/DSS-treated mice (inflammation-associated colon cancer model).
Results: The absence of ghrelin did not affect the number of intestinal tumors formed in ApcMin/+ mice and AOM/DSS-treated mice. Administration of ghrelin did not affect the number of intestinal tumors formed in ApcMin/+ mice, either. However, in AOM/DSS-treated mice, the administration of ghrelin significantly suppressed the formation of colon tumors (p &lt; 0.001). The intestinal mRNA levels of inflammatory cytokines after DSS treatment were also suppressed by the administration of ghrelin.
Conclusion: Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis, which is possibly mediated by anti-inflammatory effects of ghrelin.
Citation Format: Hiroaki Kataoka, Makiko Kawaguchi, Ai Kanemaru, Tsuyoshi Fukushima, Nobuhiro Matsumoto, Masamitsu Nakazato. Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-4. doi:10.1158/1538-7445.AM2014-LB-4
Abstract LB-92: Using immunohistochemistry to evaluate FGFR3 gene fusion recurrence and clinical associations in astrocytomas
Authors: Granberg Kirsi J. , Lehtinen Birgitta , Annala Matti J. , Haapasalo Hannu , Nykter Matti , Zhang Wei 
Published: May 2015

Abstract
Aberrant activation of fibroblast growth factor receptor 3 (FGFR3) has been reported to be tumorigenic in various cancer types. When FGFR3 is fused with another gene, most commonly with transforming acidic coiled coil 3 (TACC3), it can escape miRNA-mediated regulation and remain constitutively active most likely due to the dimerization via the domains of TACC3 or another fusion partner. Among brain cancers, gene fusions involving FGFR3 have been detected in glioblastoma and certain low grade gliomas. Furthermore, FGFR3-TACC3 fusion positive glioma cells have responded well to targeted therapies. The endogenous FGFR3 protein levels are extremely low in brain partly due to miR-99a-mediated regulation and gene fusions lead to prominent protein expression. In previous studies, FGFR3 fusion recurrence and fusion partners have been analyzed only in limited patient cohorts and there are no reports about their clinical associations. In this study, we have performed immunohistochemistry for FGFR3 on tissue microarrays with over 750 clinical astrocytoma samples (including grade 1-3 astrocytomas and glioblastomas). FGFR3 positive staining has been detected in subpopulations of all included tumor grades. The observed recurrences (1.8%-6.2%, depending on the grade) are consistent with previous sequencing-based studies. To validate immunohistochemistry-based approach for FGFR3 fusion detection, we are using frozen tumor material to confirm the presence of fusion with Western blotting and with PCR followed by Sanger sequencing. Furthermore, we have associated FGFR3 staining scores with clinical records for all the cases. FGFR3 staining is more common in females than males both in astrocytoma (7.6% vs 2.2%, pearson chi-square p-value 0.004, n=752) and glioblastoma cohorts (8.9% vs 2.1%, pearson chi-square p-value 0.008, n=494). In addition, FGFR3-staining negatively associates with aberrant p53 staining indicating p53 mutation (FGFR3-positive cases: 5.8% vs 1.8% in p53 low vs high groups, respectively, pearson chi-square p-value 0.030, n=399). Altogether, this study evaluates the suitability of immunohistochemical methods for FGFR3 fusion detection as well as investigates their recurrence and clinical significance in astrocytomas.
Citation Format: Kirsi J. Granberg, Birgitta Lehtinen, Matti J. Annala, Hannu Haapasalo, Matti Nykter, Wei Zhang. Using immunohistochemistry to evaluate FGFR3 gene fusion recurrence and clinical associations in astrocytomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-92. doi:10.1158/1538-7445.AM2014-LB-92
Abstract SY07-03: Gain-of-function activities of mutant p53
Authors: Lozano Guillermina 
Published: May 2015

Abstract
Mutations in p53 in tumors vary from deletions and nonsense mutations that lead to the absence of p53 protein to missense mutations that disrupt the DNA binding function of p53 and that exhibit gain-of-function phenotypes. The p53R172H protein manifests one of its gain-of-function activities as a metastatic phenotype in vivo. To understand the contribution of mutant p53 to metastasis, expression arrays were used to compare primary osteosarcomas from p53R172H/+ mice with metastasis to osteosarcomas from p53+/- mice lacking metastasis. Of 213 gene differences, Pla2g16 was overexpressed in metastatic osteosarcomas and was of particular interest as it encodes a phospholipase that catalyzes phosphatidic acid into lysophosphatidic acid and free fatty acid (both implicated in metastasis). Functional analyses showed that Pla2g16 knockdown decreased migration and invasion in mutant p53 expressing cells, and vice versa, overexpression of Pla2g16 increased the invasion of p53-null cells. Mechanistically, various mutant p53 proteins bind the Pla2g16 promoter at ETS binding motifs and knockdown of ETS2 in particular suppressed mutant p53 induction of Pla2g16. Thus, our study identifies a phospholipase as a transcriptional target of mutant p53 that contributes to metastasis.
Citation Format: Guillermina Lozano. Gain-of-function activities of mutant p53. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY07-03. doi:10.1158/1538-7445.AM2014-SY07-03
Abstract 22: RECQ1 promotes the expression of genes significantly associated with cancer progression
Authors: Lu Xing , Li Xiao Ling , Parvathaneni Swetha , Lal Ashish , Sharma Sudha 
Published: May 2015

Abstract
RecQ helicases (represented by five homologs in humans: RECQ1, WRN, BLM, RECQ4, and RECQ5) are vital to maintain genomic stability under replication stress and germ line mutations in WRN, BLM and RECQ4 are associated with cancer predisposition syndromes. Expression of RECQ1 has been associated with the process of cellular transformation and over-expression of RECQ1 has been reported in a variety of human cancers. Furthermore, siRNA-mediated knockdown of RECQ1 has a cancer cell specific effect in cell culture models and also suppresses tumor growth in mouse xenografts including lung, liver, pancreatic and colorectal cancer. In a panel of 60 human cancer cell lines (NCI-60), we have found that RECQ1 mRNA expression positively correlates with the mesenchymal marker Vimentin and negatively correlates with epithelial markers such as KRT8. We also observed significant positive correlation of RECQ1 expression with Vimentin and epithelial to mesenchymal transition (EMT) promoting proteins and negative correlation with CDH1 (epithelial marker) in cancer patient samples from TCGA (The Cancer Genome Atlas). Importantly, quantitative real-time PCR analyses in a set of 16 colorectal cancer patient samples revealed strong positive correlation of RECQ1 expression with Vimentin. Furthermore, lower expression of RECQ1 significantly correlated with better prognosis of recurrence-free survival in breast and ovarian cancer patients. Global analyses of gene expression upon knockdown of RECQ1 in HeLa (cervical adenocarcinomas) and MDA-MB-231 (breast adenocarcinoma) cells identified a subset of genes involved in cell invasion, migration and adhesion as most robustly regulated by RECQ1. Consistent with this result, we demonstrate that knockdown of RECQ1 significantly inhibits cell migration and invasion. These findings identify a novel function of RECQ1 in regulation of gene expression and suggest that RECQ1 contributes to tumor development and progression, in part, through regulating the expression of key genes that promote invasion and metastasis of cancer cells. Additionally, our data suggests that RECQ1 expression may serve as predictive marker of clinical outcome.
Citation Format: Xing Lu, Xiao Ling Li, Swetha Parvathaneni, Ashish Lal, Sudha Sharma. RECQ1 promotes the expression of genes significantly associated with cancer progression. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 22. doi:10.1158/1538-7445.CANSUSC14-22
Abstract IA18: Molecular basis for cancer susceptibility in Bloom's syndrome
Authors: Hickson Ian D. 
Published: May 2015

Abstract
BLM is a member of the RecQ family of DNA helicases, and is the protein defective in the cancer predisposition disorder, Bloom's syndrome. This autosomal recessive disorder is also associated with fertility, immune system and skin abnormalities. BLM forms part of an evolutionarily conserved complex of proteins including Topoisomerase IIIa, RMI1 and RMI2 (collectively called the BTRR complex). The BTRR complex has a well-defined role in S-phase, but our recent studies have uncovered a novel function in mitosis. All proliferating cells must faithfully segregate their newly replicated sister chromatids during mitosis. Any perturbation of this process, arising from either endogenous or exogenous sources, can lead to cell death or chromosomal instability. We have shown previously that common fragile site loci are difficult to segregate in anaphase and, as a result, create so-called ultra-fine anaphase bridges (UFBs). These bridges are present in virtually all cells in early anaphase and are decorated along their length by a SNF2 family protein, PICH, and the BTRR complex. We hypothesize that common fragile sites fail to complete replication in S-phase, which necessitates that action of the PICH and BTRR proteins to disentangle the incompletely replicated DNA in anaphase itself. We are analyzing these processes in yeast, chicken and human cells. For example, we have generated a PICH-deficient chicken DT-40 cell mutant, and have devised a system in yeast to generate a site-specific, artificial fragile site by blocking converging replication forks. Biochemically, we are analyzing the ability of purified PICH and BTRR proteins to disentangle a DNA substrate in vitro that mimics the structure that would form as two replication forks converge. We have also recently discovered a link between the action of DNA structure-specific nuclease, MUS81-EME1, and the frequency of fragile site expression and UFB formation. Results of these studies will be discussed.
Citation Format: Ian D. Hickson. Molecular basis for cancer susceptibility in Bloom's syndrome. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA18. doi:10.1158/1538-7445.CANSUSC14-IA18