bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3485: Inhibition of Notch signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells
Authors: Wei Ping , Qiu Ming , Jiang Ivy , Carroll Christopher , Han Guangzhou , Rymer Isha , Kraynov Eugenia , Wu Aidong , Thibault Stephane , Stone Donna , Gao Yijie , Sofia Susan , Gallo Jorge , White Janet , Li Gary , Yang Jennifer , Los Gerrit 
Published: August 2012

Abstract
Triple negative breast cancer (TNBC) is characterized by lack of estrogen receptor (ER), progesterone receptor (PR) or Her2/neu. It is known to be particularly aggressive and refractory to current chemotherapies. Tumor-initiating cells (TICs) have been postulated as responsible for treatment failure for this type of cancer. Recent evidence suggests that Notch signaling may play a role in regulation of TIC self-renewal and differentiation hence present a promising target for development of novel therapies for TNBC. We previously discovered a mouse monoclonal Ab (mu-hN1) that produces robust efficacy in both T-cell acute lymphoblastic leukemia and TNBC by specifically blocking human Notch1 signaling in tumor cells. We subsequently produced a humanized Notch1 mAb (hu-hN1) that retained similar characteristics and activities compared to the mouse prototype mu-hN1. To gain insights into the mechanisms of Notch1 blockade on TNBC tumor grow inhibition (TGI), we evaluated the effect of hu-hN1 on apoptosis, proliferation and TIC self-renewal in Notch-driven Sum149 and a patient derived xenograft (PDX) TNBC models. We showed that hu-hN1 inhibited Notch signaling by reduction of NICD (Notch intracellular domain) and target genes Hes-1 and cMyc in Sum149 tumors. Inhibition of Notch signaling led to significant TGI either as a single agent or in combination with Docetaxel. TGI of hu-hN1 appeared to be in part due to induction of apoptosis in the tumor cells. More interestingly, treatment with this Ab caused reduction in mammosphere formation and CD44+/CD133+/ESA+ cell population. It also resulted in decrease in tumor incidence and delay in tumor recurrence, suggesting an anti-TIC activity of the agent. Further investigation in a PDX TNBC model confirmed the robust tumor efficacy and anti-TIC effect of hu-hN1. Taken together, our findings suggest that anti-Notch1 mAbs may provide novel therapies to improve the efficacy of conventional treatments by directly targeting the TIC niche. They may also delay tumor recurrence and hence have a major impact on cancer patient survival.
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 3485. doi:1538-7445.AM2012-3485
Abstract 3486: Novel cell models of ovarian cancer for target discovery and validation obtained through stem cell culturing technology
Authors: Young Peter F. , Pan Zhuangyu , Roberts Penny , Hooley Jeff , Smith Doug , Chen Francine , Loo Deryk , Bonvini Ezio , Mather Jennie , Moore Paul A. 
Published: August 2012

Abstract
Introduction: Ovarian cancer is the leading cause of death from gynecological malignancies with greater than 50% of patients succumbing to the disease within 5 years of initial diagnosis. Contributors to the overall poor survival rate include late diagnosis, development of drug resistance and persistence of cancer stem cell (CSC) populations. With increasing evidence that CSC drive tumor initiation and metastases, development of model systems to better characterize such populations are needed. We recently reported use of stem cell culturing conditions to generate cancer stem like cells (CSLC) from colon and lung cancer that exhibit CSC properties (1-2). Here we apply a similar approach to ovarian cancer. Methodology: Freshly resected ovarian cancer tissue was obtained, processed and cultured using serum-free defined culture media evolved from conditions previously employed to culture tissue-specific progenitor stem cells. Expanded cell lines were characterized for their tumor initiating properties in NSG mice upon implantation under the sub-renal capsule. Xenografts were analyzed by H&E and immunostaining with ovarian cancer associated markers. Cell surface protein profile was examined by flow cytometry using mAbs against putative CSC markers and with those generated through de novo whole cell immunization of the putative ovarian cancer stem cell lines. Results: Ovarian CSLC were successfully cultured from independent serous ovarian tumor specimens. These lines can be indefinitely passaged in vitro while retaining ability to form tumors that faithfully recapitulate original patient tumor morphology and metastasize. The CSLC express EpCAM consistent with their epithelial origin and both CD44 and CD133. Analyses of mAbs generated from whole cell immunization identified B7-H3 as an additional target expressed on the ovarian CSLC. IHC analyses demonstrated B7-H3 expression also on primary and metastatic ovarian CSLC xenografts consistent with expression observed on patient derived specimens. Conclusion: Ovarian cancer cell lines have been generated using conditions previously established for tissue stem cells. These lines, which can be maintained indefinitely in vitro while retaining cancer stem cell properties, provide opportunity to identify and characterize novel ovarian cancer targeting strategies such as those designed against B7-H3. References: 1: Roberts (2011) AACR Abstract #5211; 2: Young (2011) AACR Abstract #502.
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 3486. doi:1538-7445.AM2012-3486
Abstract 3488: Targeting ligands and nanotherapeutics against acute myeloid leukemia stem cell
Authors: Zhang Hongyong , Luo Juntao , Li Yuanpei , Henderson Paul T , Wang Yanchun , Wachsmann-Hogiu Sebastian , Lam Kit S. , Pan Chongxian 
Published: August 2012

Abstract
Background: Acute myeloid leukemia (AML) stem cells (LSC) can survive the conventional-dose chemotherapy, generate more differentiated leukemic cells and cause recurrence. In order to cure AML, LSC must be eradicated. This project was to develop targeting therapeutics to overcome chemoresistance and eradicate LSC. Materials and Methods: The phage-display library was panned to identify ligands targeting C-type lectin-like molecule-1 (CLL1) expressed on LSC, but not on normal hematopoietic stem cells. A CLL1-targeting ligand was used to decorate the surface of micelle nanocarrier developed by our group to deliver chemotherapeutic drugs to LSC. Target-specific drug delivery was determined using A549 adherent cells expressing CLL1 and CD34+CD38- leukemia cells freshly isolated from clinical specimens. Toxicology study was performed in Balb/c mice. Results: After three rounds of panning against A549 cells expressing CLL1, 35 out of 36 clones contained the same amino acid motif LR(S/T). These ligands did not bind to any peripheral blood cells and normal hematopoietic stem cells. One ligand named CLL1-L1 was used to decorate the surface of nanomicelles loaded with chemotherapeutic drug daunorubicin (DNR). These targeting nanomicelles were approximately 15 nm in diameter. The loading capacity was around 5 mg of daunorubicin per 20 mg of nanomicelle, a clinically useful degree of drug loading. High-resolution tomography showed that targeting nanomicelles delivered the drug load directly to the intracellular space including nucleus much more efficiently than the non-targeting nanomicelles (p&lt;0.05). These targeting nanomicelles could deliver the drug load to CD34+CD38- leukemic cells (containing LSC) isolated from clinical specimens, but did not bind to normal blood or normal hematopoietic stem cells. Chemotheapeutic drug formulated in these nanomicelles is about three times less toxic than the parental free drug, suggesting this nanoformulation may allow administration of high-dose chemotherapy without the associated severe toxicity. Conclusion: This is the first report on the development of targeting ligands and nanotherapeutics against AML stem cells. Nanomicelles decorated with CLL1-targeting peptides can potentially deliver high-dose chemotherapeutic drugs directly into LSC and eradicate this cell population, in addition to treating leukemic cells throughout the body and decreasing toxicity.
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 3488. doi:1538-7445.AM2012-3488
Abstract 349: Leptin-induced epithelial-mesenchymal transition in breast cancer cells requires β-catenin activation via Akt/GSK3-dependent and MTA1/Wnt1-dependent pathways
Authors: Yan Dan , Avtanski Dimiter B. , Saxena Neeraj K. , Sharma Dipali 
Published: August 2012

Abstract
Perturbations in the adipocytokines-profile, especially higher levels of leptin, are a major cause of breast tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether leptin is involved in epithelial-mesenchymal transition (EMT). Here, we provide first molecular evidence that leptin induces breast cancer cells to undergo a transition from epithelial to spindle-like mesenchymal morphology. Investigating the downstream mediator(s) that may direct leptin-induced EMT, we found functional interactions between leptin, metastasis-associated protein 1 (MTA1) and Wnt1 signaling components. Leptin increases accumulation and nuclear translocation of β-catenin leading to increased promoter recruitment. Silencing of β-catenin or treatment with small molecule inhibitor, ICG-001, inhibits leptin-induced EMT, invasion and tumorsphere formation. Mechanistically, leptin stimulates phosphorylation of glycogen synthase kinase 3β (GSK3β) via Akt activation resulting in a substantial decrease in the formation of GSK3β-LKB1-Axin complex which leads to increased accumulation of β-catenin. Leptin treatment also increases Wnt1 expression that contributes to GSK3β phosphorylation. Inhibition of Wnt1 abrogates leptin-stimulated GSK3β phosphorylation. We also discovered that leptin increases the expression of an important modifier of Wnt1 signaling, MTA1, which is integral to leptin-mediated regulation of Wnt/β-catenin pathway as silencing of MTA1 inhibits leptin-induced Wnt1 expression, GSK3β phosphorylation and β-catenin activation. Furthermore, analysis of leptin-treated breast tumors show increased expression of Wnt1, pGSK3β and Vimentin along with higher nuclear accumulation of β-catenin and reduced E-cadherin expression providing in vivo evidence for a previously unrecognized crosstalk between leptin and MTA1/Wnt signaling in epithelial-mesenchymal transition of breast cancer cells.
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 349. doi:1538-7445.AM2012-349
Abstract 3495: The novel phospholipid ether analog CLR1404 decreases glioblastoma stem cell proliferation, suppresses GBM growth, and improves survival
Authors: Clark Paul A. , Chen Hong-En , Mohamed Mohamed , Kandela Irawati K. , Longino Marc A. , Pinchuk Anatoly , Weichert Jamey P. , Kuo John S. 
Published: August 2012

Abstract
Most patients treated for glioblastoma multiforme (GBM), the most common primary brain malignancy, have less than 2 years survival due to rapid recurrence. The GBM stem cell (GSC) sub-population exhibits therapeutic resistance and is hypothesized to drive tumor recurrence. Therefore, GSC-specific targeting is likely critical for improving outcome. Phospholipid ether analog, CLR1404 and its radioiodinated isosteres, exhibit cancer cell-specific uptake and prolonged retention in 57/61 cancer cell lines and xenografts (including GBM) due to affinity for cancer cell lipid rafts. In this study, we investigated the therapeutic potential of CLR1404 against GBM and its GSC subpopulation. Multiple sphere-forming GSC lines were isolated from patient specimens with IRB approval, and rigorously validated for self-renewal, multi-lineage potential, and high efficiency orthotopic tumor initiation in NOD-SCID mice. Proliferation assays were performed by addition of CLR1404 in serum-free medium for 24 hours. To test effects on stem cell properties, GSCs were treated with CLR1404, dissociated to single cells, plated at 500 cells in a 96-well plate, and allowed to form spheres (≥2-4 weeks). CLR1404 inhibition of the AKT oncogenic signaling pathway in GSCs was assayed with immunoblot analysis. In vivo, GSCs were pre-treated for 24 hours with CLR1404 prior to orthotopic injection of 200,000 live cells into immunodeficient mice. Subsequent survival curves were then constructed. CLR1404 anti-proliferative effects were seen on all 7 different GSC and GBM lines tested with IC50 values ranging between 5-10 µM using MTS assay; control normal differentiated neural cells exhibited an IC50 of approximately 40 µM. CLR1404 treatment also decreased sphere-forming ability of multiple GSC lines with IC50 values between 5-10 µM. CLR1404 inhibition of AKT activation was observed using immunoblot analysis. CLR1404 pre-treatment of GSCs significantly increased survival time in an orthotopic mouse model (Control: 59±6.1 days; CLR1404: 94±4.4 days), suggesting CLR1404 treatment of the GSC tumor initiating cells improves outcome. This data of CLR1404's therapeutic potential against GBM and its GSCs, combined with previously demonstrated tumor cell targeting specificity of CLR1404 and its radioactive isosteres, provides strong evidence for the potential of novel CLR1404-based therapies to improve GBM outcomes.
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 3495. doi:1538-7445.AM2012-3495
Abstract 3507: Type 17-1-CD8+ T cells (Tc17-1) as potent effector cells for immunotherapy of brain tumors
Authors: Ohkuri Takayuki , Kosaka Akemi , Ikeura Maki , Litterman Adam , Ohlfest John , Okada Hideho 
Published: August 2012

Abstract
Malignant gliomas, such as glioblastoma multiforme (GBM), are the most common and dismal primary brain tumors, and there is a strong need for developing novel and effective therapeutic modalities. Although the central nervous system (CNS) and CNS tumors are often considered immunologically privileged, as demonstrated by studies on CNS autoimmunity, activated autoreactive T-cells, especially T helper (Th) 17 cells, infiltrate through the blood brain barrier (BBB) and mediate antigen-specific responses in the CNS. Especially, Th17 express high levels of CCR6, which has a crucial role in Th17 infiltration into the CNS. In addition to Th17 cells, a new putative subtype of IL-17-producing CD4+ T cells with CD4+IL-17+IFN-γ+ (Th17-1 cells) double-positive phenotype has also been identified. Based on our previous studies demonstrating a critical role of Th1-chemokine CXCL10 and its receptor CXCR3 for effective T-cell trafficking in CNS tumors, we hypothesized that Th17-1 cells and CD8+ T cells producing IL-17 and IFN-γ (hereby Type-17-1 CD8+ T-cells) will demonstrate superior CNS tumor infiltration compared with Th1 cells due to the activation of two CNS-relevant chemokine pathways, CXCL10-CXCR3 and CCL20-CCR6. Mouse Tc17, Tc17-1 and Tc1 cells generated from Pmel-1 mouse-derived naïve CD8+ T cells expressed high CCR6 and low CXCR3, high CCR6 and high CXCR3, and little CCR6 and high CXCR3, respectively. Although Tc17 displayed lower levels of antigen-specific cytotoxic activity compared with Tc17-1 and Tc1 in a 4 hr cytotoxic assay, Tc17 killed tumor cells more effectively than the other populations in long-term cultures (4 to 6 days). While Tc1 cells underwent apoptosis due to their exhausted state, Tc17-1 maintained strong cytotoxicity and proliferative activities even after 4 day co-culture with tumor cells. Moreover, the supernatant derived from activated Tc17 and Tc17-1 induced CCL20 and CXCL10 in the GL261 glioma cells while Tc1-derived supernatant induced CXCL10 but not CCL20. These results suggest a possibility that Tc17-1 may elicit persistent anti-CNS tumor responses and induce both CCL20 and CXCL10 in the CNS tumor microenvironment, thereby attracting additional effector cells to the site. In vivo studies in mice bearing CNS gliomas are warranted to determine whether adoptively transferred Tc17-1 infiltrate to the CNS tumor site and mediate superior anti-tumor response compared with Tc1.
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 3507. doi:1538-7445.AM2012-3507
Abstract 3509: Intracranial administration of activated NK-cells and mAb9.2.27 against NG2/CSPG4 activates microglial cytotoxicity and prolongs survival in glioblastoma xenograft model
Authors: Poli Aurelie , Wang Jian , Domingues Olivia , Yan Tao , Thorsen Frits , Brekke-Rygg Cecilie , Hentges Francois , Pedersen Paal Henning , Zimmer Jacques , Enger Per Øyvind , Chekenya Martha 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most malignant brain tumour in adults with dismal prognosis despite multimodal treatment. We have previously shown that the NG2 proteoglycan mediates an aggressive disease course in GBMs and therefore aimed to target it using the monoclonal antibody 9.2.27 and adoptively transferred natural killer (NK) cells in athymic rats. We demonstrated that intracranial administration of activated NK cells and mAb9.2.27 eradicated established GBM and led to significantly increased survival, mediated by diminished tumour proliferation and increased cell death. The mechanisms involved sustained activation of pro-inflammatory ED1+CD8+ microglia and subsequent development of a Th1 immune response in the combination therapy compared to monotherapy controls. The Th1 response was characterized by increased tumour infiltration by CD4+ and CD8+ T cells, as well as augmented IFN-γ and TNF-α release into the cerebrospinal fluid. Furthermore, we showed that activated NK cells released IFN-γ and TNF-α, they shifted activated microglia from M2- to highly cytotoxic M1-like phenotype and preferentially killed M2-microglia compared to M1-microglia in vitro. These findings implicate NK cells in the pro-inflammatory environment that facilitated the tumour cytotoxicity by microglia in vivo. Our results suggest that the administration of activated NK cells and mAb9.2.27 is a promising approach to treat GBM.
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 3509. doi:1538-7445.AM2012-3509
Abstract 3519: Appropriate crosslinking is required for co-stimulatory activity of human CD27 antibody in a transgenic mouse model
Authors: He Li-Zhen , Prostak Naseem , Crocker Andrea , Weidlick Jeffery , Widger Jenifer , Sisson Crystal , Vitale Laura , Glennie Martin J. , Keler Tibor 
Published: August 2012

Abstract
CD27 is a member of TNFR superfamily. It constitutively expresses on the majority of T cell and a subset of NK cells, playing key roles in T cell activation and survival and in NK cell proliferation and cytotoxicity upon interaction with ligand CD70. Some antibodies to mouse CD27 have been reported that display agonistic and anti-tumor activities while other mAbs had less anti-tumor activity and were depleting. We hypothesized that differences in these antibodies may be due to Fc receptor engagement, as has recently been shown for the adjuvant and anti-tumor activities of agonistic mouse CD40 mAbs, which is also member of TNFR superfamily. We have developed and previously described a human anti-human CD27 antibody (1F5) and a human CD27 transgenic mouse model (hCD27-Tg) to explore the therapeutic potential of targeting CD27. In this study, we examined the effect of modifying the constant regions of the 1F5 mAb on its ability to enhance antigen specific T cell responses. With the original 1F5 hIgG1 as template, a panel of 1F5 variants was made including 1F5 mIgG1, 1F5 mIgG2a, 1F5 mIgG1D265A and 1F5 hIgG1N297S using molecular cloning techniques. All of the variants retained equal binding to hCD27 as shown by ELISA and flow cytometry studies. In addition, Biacore analysis confirmed the expected pattern of binding to human and mouse FcαRs. Co-injection of 1F5 or its variants with ovalbumin enhanced antigen-specific CD8 T cell response to different extents, as detected by SIINFEKL-specific IFNα-ELISPOT and ICS. The 1F5 mIgG1 induced the highest number of IFNα-producing CD8+ cells, whereas 1F5 mIgG2a was very weak at enhancing the CD8 T cell response. The hIgG1 version of 1F5 was intermediate in activity. Introduction of the D265A mutation that disrupts FcαRs binding into the mIgG1 eliminated the co-stimulatory function of 1F5. Similarly, the 1F5 hIgG1N297S also showed reduced activity compared to the original 1F5 hIgG1. The isotype-specific effects on our anti-hCD27 mAb are surprisingly consistent with the findings described for the agonistic anti-mCD40 mAbs, and imply that engagement of the inhibitory Fcα receptors (FcαRIIb) is driving the co-stimulatory activity in this model. Interestingly, the 1F5 hIgG1 triggered a significant T cell response, despite the lack of FcαRIIb binding by Biacore analysis. The effect of these variants on anti-tumor activity in hCD27 transgenic mice is currently being investigated. The 1F5 hIgG1 mAb (CDX-1127) is currently undergoing clinical evaluation in a phase 1 trial of patients with advanced cancers.
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 3519. doi:1538-7445.AM2012-3519