bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2466: Elafin, a serine protease inhibitor, is deregulated during breast cancer progression
Authors: Caruso Joseph A. , Karakas Cansu , Hunt Kelly , Keyomarsi Khandan 
Published: August 2012

Abstract
Deregulated protease activity promotes diverse aspects of tumorigenesis, including tumor growth, invasion, inflammation, and angiogenesis. Elafin is an endogenous inhibitor of the serine protease, Neutrophil Elastase (NE). Imbalance between NE and its inhibitors is implicated in the pathogenesis of many chronic inflammatory diseases. We hypothesize that elafin is deregulated during breast cancer progression, resulting in increased NE activity, accelerated tumor progression, and overall poor patient outcome. To test this hypothesis, we examined elafin expression by immunohistochemistry (IHC) in normal breast tissue from reduction mammoplasty, pre-malignant Ductal Carcinoma In Situ (DCIS), and invasive breast carcinoma (n&gt;1000, using Tissue Microarray [TMA]). We observed that elafin is intracellularly (predominate nuclear localization) expressed in normal breast tissue. In the majority (&gt;80%) of DCIS cases, intracellular elafin is expressed in a manner consistent with normal breast tissue. However, in cases of invasive breast cancer, intracellular elafin is largely downregulated (&gt;80% of cases) suggesting elafin loss may have a role in progression to invasive carcinoma. Interestingly, examination of elafin expression in invasive breast cancer also revealed a subset (10-20%) of tumors with robust cytoplasmic overexpression of elafin, correlating with poor outcome. Similar results were seen in TMAs of high-grade ovarian carcinoma (n&gt;200). Examination of publically available microarray data (TCGA) demonstrates that elafin measured at the mRNA level is correlates with poor outcome in ovarian cancer, consistent with our IHC results, and good outcome in breast cancer, incompatible with our IHC results. To further investigate the expression of elafin in breast cancer we examined by IHC a patient cohort (&gt;200 patients) for whom full sections (not TMA) were available. Using these patient samples we found a unique subset of breast cancer patients that demonstrate high-level secretion of elafin into the tumor stroma, significantly correlating with increased survival especially in ER negative patients. Collectively, these data suggest that the prognostic role of extracellular elafin is related to the well-characterized ability of elafin to modulate inflammation and immunity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2466. doi:1538-7445.AM2012-2466
Abstract 2480: High-level activation of the Notch pathway in diffuse intrinsic pontine glioma
Authors: Hutt Marianne , Lim Kah Jing , Warren Katherine , Chang Howard T. , Eberhart Charles G. , Raabe Eric H. 
Published: August 2012

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor. Due to its critical location within the brainstem, and its characteristic MRI signature, biopsy is rarely performed. Since many patients die at home in hospice care, autopsy specimens have traditionally been rare. Because of this difficulty in obtaining tissue, three institutions (Johns Hopkins, Children's National Medical Center, and the National Institutes of Health - Pediatric Oncology Branch) have formed the Mid-Atlantic DIPG Consortium (MADC), to collect and disseminate rapid-autopsy material from patients with DIPG. Using a fresh tissue specimen obtained from a rapid autopsy and disseminated through the MADC, we have established a human DIPG xenograft and neurosphere cell line, JHH-DIPG1. In vitro, these cells are GFAP positive and express human neural stem cell markers often observed in glioblastoma, including human specific SOX2 and NESTIN. They also show marked invasive properties in vitro as measured by transwell invasion assay. In vivo, JHH-DIPG1 forms tumor xenografts in approximately six months in immunocompromised mice. Tumor cells diffusely infiltrate distant brain structures, recapitulating the invasive phenotype of DIPG. Due to their high level expression of neural stem cell markers, and the well-known roles of the Notch pathway in stem cell biology and aggressive brain tumors, we examined the expression of members of the Notch pathway in DIPG. Notch downstream effectors, specifically Hes1, Hes5 and Hey1, are highly expressed in JHH-DIPG1, at levels equal to or exceeding those observed in neurosphere cell lines derived from adult supratentorial glioblastoma. The JHH-DIPG1 tumor cell line represents one of only a handful of pediatric DIPG cell lines extant, and the high level of Notch pathway activation in these cells suggests that blockade of the Notch pathway using gamma secretase inhibitors and shRNAs against the canonical Notch effector CBF may be efficacious in DIPG. Our laboratory is actively investigating the role of the Notch pathway in DIPG using this and other DIPG cell lines, with the goal of moving Notch inhibition into clinical trials for these currently highly lethal tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2480. doi:1538-7445.AM2012-2480
Abstract 2481: Exploiting BRAF mutation for therapy of childhood low-grade astrocytoma
Authors: Kibler Aaron , Manap Sagymbek , Bid Hemant K. , Phelps Doris A. , Kurmasheva Raushan T. , Pelloski Christopher E. , Houghton Peter J. 
Published: August 2012

Abstract
Activating mutations of BRAF (predominantly V600E) are common in low-grade astrocytomas (∼23%), and xanthoastrocytomas (60%), with or without loss of the CDKN2A locus. Surgically inoperable astrocytoma has a poor prognosis with greater than half of these patients dying from disease. We have developed two models of low-grade astrocytoma (BT-35, BT-40) by direct heterografting patient tumor into immune-deficient mice. Both tumor lines have multiple copies of BRAF, but only BT-40 has an activating mutation (V600E), and is exquisitely sensitive to the MEK inhibitor AZD6244, whereas BT-35 is intrinsically resistant (Kolb et al. Ped Blood Cancer, 2010). Biochemical characterization showed that MEK1/2 were equally inhibited by AZD6244 treatment in both BT-35 and BT-40 xenografts, as demonstrated by the level and duration of inhibition of phospho-ERK1/2. However, inhibition of MEK1/2 had no effect on TORC1 signaling in BT-35 (insensitive) tumors whereas in BT-40 xenografts TORC1 signaling was completely inhibited by AZD6244. The pathway through which mutant BRAF controls TORC1 signaling is currently under evaluation. However, control of TORC1 by mutant BRAF potentially exposes these cells to therapeutic exploitation. We have shown previously that the TOR kinase inhibitor AZD8055 potently suppresses FANCD2, a protein involved in interstrand cross-link (ICL) repair of DNA damage. Similar to the effect of AZD8055, within 4 days treatment of mice with AZD6244, FANCD2 levels are dramatically reduced and were no longer detected in BT-40 xenografts. Preliminary results show that inhibition of TOR signaling by AZD8055 is synergistic with daily radiation in rhabdomyosarcoma xenografts. We hypothesize that because MEK inhibition leads to suppression of TORC1 signaling and FANCD2 in BT-40 astrocytoma xenografts, that combination of AZD6244 with ionizing radiation or drugs that induce ICL will be selectively synergistic in the context of BRAF mutation. Experiments to test the hypothesis are ongoing. Supported by a Peletonia grant from the Ohio State University.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2481. doi:1538-7445.AM2012-2481
Abstract 2488: Reovirus (Reolysin) as a potential therapy for malignant peripheral nerve sheath tumors
Authors: Sampson Valerie , Kamara Davida , Calio Brian , Kolb Edward A. 
Published: August 2012

Abstract
Malignant peripheral nerve sheath tumors (MPNST) are a rare form of soft tissue sarcoma which may occur sporadically in the general population or in association with neurofibromatosis type 1 (NF1), and are highly aggressive and often fatal. NF1 patients are at a greater risk for the development of malignant peripheral nerve sheath tumors than the general population. Current therapy relies upon surgical resection with adjuvant chemotherapy and/or radiotherapy. Clinical trials using Reolysin (Respiratory Enteric Orphan Virus) which is developed from the naturally-occurring human reovirus have demonstrated the efficacy of this reovirus as an oncolytic virotherapy. Reolysin selectively replicates in cancer cells with activated Ras (Ras-GTP), resulting in virus-mediated apoptotic cell death. Hence Reolysin demonstrates promising anticancer activity and has minimal toxicity in patients. Since MPNST is associated with neurofibromin (NF1) deficiency and active Ras we tested these tumors as therapeutic targets for Reolysin treatment using two NF1 deficient human MPNST-derived cell lines (CRL-2884, ST8814) with activated Ras and one sporadic MPNST cell line (STS26T) which expresses NF1 but not active Ras. These were compared with normal human Schwann cells (NHSC) which do not show active Ras and mammary gland cells derived from an NF1 patient (CRL-7329). Reolysin inhibited the proliferation and viability of the three MPNST cell lines at a dose of 0.1 to 10 virus particles/cell, including sporadic MPNST cells which do not have active Ras. In contrast, the NHSC and CRL-7329 cells were more resistant to viral treatment, with apoptosis induced at higher viral concentrations (10,000 and 100,000 virus particles/cell respectively). Furthermore, we examined the effects of Reolysin on the Ras-signaling pathway in a bladder cancer cell line (HTB-4) expressing NF1 and Ras and found that virus induced cytotoxicity was similar to the control cell lines (100,000 virus particles/cell). This study shows that MPNST-derived cell lines including sporadic MPNST without active Ras were efficiently transduced, promoted virus replication and were killed by the oncolytic reovirus. In contrast to the highly sensitive MPNST cell lines, NHSC, CRL-7329 and HTB-4 cells were resistant at similar viral concentrations. Our data suggests the use of oncolytic Reolysin may represent a novel treatment approach for patients with MPNST and provides the basis for preclinical testing of the antitumor effects. Therapeutic efficacy of Reolysin in a mouse model for MPNST is underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2488. doi:1538-7445.AM2012-2488
Abstract 2489: A phase II trial of poly-ICLC in the management of recurrent or progressive pediatric low grade gliomas
Authors: Hartman Lisa R. , Durden Donald L. 
Published: August 2012

Abstract
Low-grade astrocytomas and gliomas are the most common type of childhood brain tumor. Although children with low-grade gliomas often survive many years after conventional treatment with surgery and radiotherapy, there can be tremendous morbidity depending on the location of tumor and the effects of therapy. Newer forms of treatment with reduced side effects are much needed. We have designed a phase II trial to examine efficacy and safety of the biological response modifier poly-ICLC in children with low-grade gliomas, and to identify surrogate biomarkers for response to this agent. Poly-ICLC, a synthetic complex of polyinosinic and polycytidylic acid, stabilized with polylysine and carboxymethyl cellulose is a double stranded RNA (dsRNA) that is a ligand for the Toll-like Receptor 3 (TLR3), an important component of innate immunity. It has been shown to have direct antiviral and antineoplastic effects mediated by at least two interferon inducible nuclear enzyme systems of OAS and PKR. A previous Phase I/II trial of poly-ICLC conducted in pediatric patients with brain tumors (all histopathologic subtypes) suggested the low-grade glioma cohort had the best response to this therapy (50% PR rate). Additional clinical trials in adult patients have confirmed that the most responsive subgroup to poly-ICLC is low-grade glioma patients. We are currently conducting a multi-institutional phase II study of poly-ICLC administered at 20mcg/kg/dose intramuscularly twice weekly to children with recurrent or progressive low-grade gliomas. Simon's two-stage design will be used for statistical analysis. The primary goal of this study is determine the radiographic response rate. We will also characterize toxicity and determine if surrogate markers of tumor response and progression can be identified in patient serum, peripheral blood mononuclear cells (PBMC), and/or cerebrospinal fluid (CSF). To date, 4 pediatric subjects (ages 2-15) with recurrent low-grade gliomas have enrolled in the study. Poly-ICLC therapy has been well tolerated and none of the subjects have shown radiologic or clinical progressive disease. These results suggest that poly-ICLC may have a beneficial role in children with low-grade gliomas while minimizing treatment side effects. We have begun analyzing blood and CSF samples to attempt biomarker identification and correlation with subject responses, in hopes to yield a basis towards stratification and personalized therapy with recurrent disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2489. doi:1538-7445.AM2012-2489
Abstract 2490: High AXL promotes migration in non-MYCN amplified neuroblastoma cell lines
Authors: van Noesel Max M. , Duijkers Floor A.M. , Meijerink Jules P.P. , Pieters Rob 
Published: August 2012

Abstract
Background: Neuroblastomas (NBL) are tumors with a high rate of metastases (50% of patients). In general, in NBL MYCN amplification (NMA) is the most important prognostic factor. However NMA is infrequent and 70% of NBL are non-NMA tumors and not much is known about the driving oncogenic event. Recently, we identified among 17 NBL cell lines a group of non-NMA NBL cell lines with a distinct gene expression profile (HU133plus2.0 arrays, Affymetrix) and high expression of the AXL gene. AXL is a tyrosine kinase receptor, associated with the metastatic process of several cancers. We hypothesized that AXL contributes to metastsizing potential in non-NMA neuroblastomas and tested if AXL silencing diminishes malignant properties of high AXL expressing cell lines. Results: High expression of AXL was detected in G-IM-EN, SK-N-AS and two subclonal cell lines SH-EP-2 and SH-EP-21N. AXL was silenced (lentiviral AXL shRNA expression plasmids, pLKO.1_shAXL, Sigma-Aldrich) in GI-M-EN and SH-EP-2 with an infection efficiency of &gt;90% and 80-85% AXL-mRNA knockdown. We examined the silencing effect on migration and invasion. A significant reduction of migration (74.7%) and invasion (99.8%) was achieved in GI-M-EN. In the intermediate AXL expressing expressing cell line SH-EP-2 migration reduction was less (41.9%). Furthermore, GI-M-EN and SH-EP-2 were compared for cytoskeletal, morphological changes after silencing. Cells became rounded with small lamellipodia and filopodia and F-actin fluorescent staining showed induction of F-actin positive stress-fibers (17.3%), both most prominent in high AXL expressing GI-M-EN. In SH-EP-2 the number of cells with stress fibers was increased (9.9%). Expression of, matrix metalloproteinase 9 frequent down-stream target of EMT-like processes, was not changed upon silencing of AXL. Also, we observed no effects on cell proliferation, apoptosis or downstream pathways (PI3K-AKT, MAPK-ERK pathway). Conclusion: The AXL gene is highly expressed in a subset of non-NMA NBL cell lines and seems involved in migratory and invasion properties. AXL is a possible mediator of NBL metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2490. doi:1538-7445.AM2012-2490
Abstract 25: CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-beta signaling
Authors: Kang Jin Muk , Park Sujin , Kim Staci Jakyong , Kim Seong-Jin 
Published: August 2012

Abstract
CBL protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL highly expresses in breast cancer cells and significantly inhibits TGF-β tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-β target genes, SERPINE1 and CDK inhibitors such as p15INK4b and p21Cip1. Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues and the loss of CBL decreases a tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-β transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-β tumor suppressor activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 25. doi:1538-7445.AM2012-25
Abstract 2510: Increased Fc-FcR interaction of human phosphatidylserine targeting antibody enhances pro-inflammatory and ADCC anti-tumor mechanisms
Authors: Doerr Jeanette R. , Larson Gary , Archer Rich , Gong Jian , Nguyen Van , Iyengar Aditi , Johnson Amy E. , Wakabayashi Mary , Peacock Matthew , Hughes Christopher , Chang Connie , Freimark Bruce 
Published: August 2012

Abstract
Anionic phospholipids, principally phosphatidylserine (PS), become exposed on the external surface of vascular endothelial cells in tumors, providing an excellent marker for tumor vascular targeting. Binding of antibodies targeting PS on the tumor endothelial cells and tumors recruits immune cells and engages the immune system to destroy tumor vasculature. The antibodies also enhance anti-tumor immunity by blocking the immunosuppressive action of PS. A chimeric anti-PS antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in Phase II trials. We have engineered mutations in the Fc region of fully human PS-targeting antibody PGN635 that enhance the interaction with FcRgammaIIIa and have characterized their ability to exert anti-tumor effects through various mechanisms, including ADCC and cytokine induction. Mutations that enhance Fc-FcR interaction of PS targeting antibodies enhance production of pro-inflammatory chemokines such as MCP-1 (CCL2), MIP-1alpha (CCL3) and MIP-1beta (CCL4). In addition, the same Fc mutations enhance ADCC of PS expressing tumor targets. Our data indicate that improvement of multiple immune effector functions via enhanced interaction of Fc-FcR interaction of PS-targeting antibodies may improve the treatment of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2510. doi:1538-7445.AM2012-2510
Abstract 2515: Anti- GP88 (progranulin) antibody to GP88 (progranulin) inhibits breast tumor growth and restores sensitivity to tamoxifen
Authors: Serrero Ginette , Dong Jianping , Hayashi Jun 
Published: August 2012

Abstract
GP88 (Progranulin, PCDGF, acrogranin) is an 88 kDa glycoprotein that is the largest member of the granulin/epithelin family of growth modulators characterized by 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. Our laboratory demonstrated the role of GP88 as an autocrine growth and survival factor in breast cancer: 1) GP88 expression increases with tumorigenesis; 2) inhibition of GP88 expression by antisense transfection in MDA-MB-468 cells inhibited tumor formation in nude mice by 90%; 3) in ER+ breast cancer cells, GP88 stimulates proliferation and its overexpression confers estrogen independence; 4) GP88 is a strong survival factor that confers resistance to anti-estrogen and aromatase inhibitors in ER+ breast cancer; 5) GP88 is expressed in 80% invasive ductal carcinoma and 60% of ductal carcinoma whereas it is negative in benign lesions and normal mammary epithelial cells; 6) pathological studies with 530 cases of ER+ invasive ductal carcinoma showed that GP88 tumor expression is a prognostic indicator of recurrence in early stage breast cancer patients; 7) GP88 is secreted and can be detected in the serum of breast cancer patients at an increased level when compared to healthy subjects. Based on these results GP88 represents an ideal therapeutic and diagnostic target in breast cancer. We developed a neutralizing anti-GP88 antibody AG1. AG1 inhibits GP88 biological effect in a dose-dependent fashion. In the present study, we investigated the effect of AG1 on the tumor development of tamoxifen sensitive (MCF-7) and resistant (TamR) estrogen receptor positive breast cancer cells lines injected in nude mice. We show that AG1 alone (5mg/kg) inhibited tumor growth of MCF-7 cells injected into nude mice in a similar efficacy as tamoxifen. Interestingly, AG1 in combination with tamoxifen inhibited by more than 50% tumor formation of TamR cells, whereas tamoxifen only had no effect. These data suggest that inhibiting GP88 provide a novel and alternate pathway for restoration of tamoxifen sensitivity in ER+ breast cancer. This works is supported by grant 2R44CA124179 from the National Cancer Institute.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2515. doi:1538-7445.AM2012-2515