bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3288: The anti-tumour efficacy of the novel peptide inhibitor of angiogenesis ALM-201
Authors: O'Rourke Martin , Valentine Andrea , McLean Estelle , Page Natalie , Cotton Graham , Robson Tracy , Hirst David , Harrison Timothy , James Iain 
Published: June 2012

Abstract
Neovascularization is critical to tumour growth and metastasis and this has led to the development of a number of marketed anti-angiogenic agents which target VEGF/VEGFR2 receptors, for clinical use in specific types of cancer. However, incomplete responses and/or resistance to these therapies has highlighted the need for new agents targeting alternative pathways. Here we describe the characterisation of a novel peptide derived from the natural protein FKBP-like binding protein (FKBPL), which has extremely potent anti-angiogenic activity, is very effective in mouse xenograft models at low doses, and exerts its effects through microtubule binding using CD44 as a cell-entry mechanism.
ALM-201 has been profiled in a range of human microvascular endothelial cell (HMEC-1) assays and potently inhibited migration, tubule formation and microvessel formation in vitro and in vivo. Although the peptide has a marked effect on migration, ALM-201 does not inhibit proliferation in a range of growth factor stimulated proliferation assays. Importantly, there is a significant disconnect between the pharmacokinetic and pharmacodynamic profiles of ALM-201 which allows for 3 q.d. dosing in mouse xenograft models. The peptide is well tolerated with no signs of toxicity observed in mouse xenograft models up to 80 days of dosing. The mechanism by which ALM-201 inhibits angiogenesis involves the cell surface receptor CD44, as determined by siRNA depletion of the receptor in migration assays. Furthermore, the peptide potently inhibits microtubule assembly and downstream signalling, thus promoting the anti-migratory phenotype.
In summary, ALM-201 is a novel, targeted microtubule binding agent which exhibits potent anti-angiogenic activity in vitro and in vivo. Pre-clinical development is in progress with a Phase 1 clinical study planned for 2011.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3288. doi:10.1158/1538-7445.AM2011-3288
Abstract 3290: REGN910, a fully-human, Ang2-specific monoclonal antibody, inhibits tumor growth as a monotherapy and dramatically potentiates the effects of VEGF Trap (aflibercept)
Authors: Daly Christopher , Castanaro Carla , Adler Alexander P. , Eichten Alexandra , Lalani Alshad S. , Papadopoulos Nicholas J. , Thurston Gavin 
Published: June 2012

Abstract
Inhibition of tumor angiogenesis via blockade of vascular endothelial growth factor (VEGF) has proven to be beneficial in several solid tumors. However, anti-VEGF therapies are not curative; thus, there is a significant opportunity to improve efficacy through combination therapy with agents that target other essential angiogenic pathways. Angiopoietin-2 (Ang2), a ligand for the endothelial cell-specific receptor Tie2, is selectively expressed in remodeling blood vessels such as those found in tumors. Furthermore, genetic and pharmacologic data indicate that Ang2 is essential for angiogenesis in several settings. These properties make Ang2 an attractive target for specific inhibition of tumor angiogenesis.
We generated a fully-human, Ang2-specific IgG1 monoclonal antibody (REGN910) using VelocImmune technology. REGN910 binds human Ang2 with very high affinity (KD ∼ 18 pM), and potently blocks its interaction with Tie2 (IC50 ∼ 50 pM), thereby inhibiting downstream signaling. In contrast, REGN910 exhibits no binding to Ang1, a Tie2 ligand that is broadly-expressed in normal tissues, and has no effect on Ang1/Tie2 signaling. In tumor xenograft models, REGN910 significantly inhibited the growth of several tumor types in a dose-dependent manner, including PC3 (prostate), Colo205 (colorectal) and A431 (epidermoid carcinoma). Furthermore, the combination of REGN910 plus the potent VEGF blocker aflibercept (VEGF Trap) inhibited tumor growth significantly better than the single agents in both the Colo205 and MMT models, promoting significant regression of Colo205 tumors. Consistent with the potent effect of this combination on tumor growth, REGN910 plus aflibercept reduced Colo205 tumor vascularity and tumor perfusion much more dramatically than the single agents, as monitored by histological and micro-ultrasound analyses. Thus, REGN910 significantly potentiates the effect of VEGF blockade on the function of tumor blood vessels, even in a tumor model (Colo205) that is very sensitive to anti-VEGF therapy. These results indicate that REGN910 is a promising candidate to selectively inhibit tumor angiogenesis, both as a single agent and in combination with anti-VEGF therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3290. doi:10.1158/1538-7445.AM2011-3290
Abstract 3293: Activity and safety of an antiangiogenic peptide in spontaneous head and neck squamous cell carcinoma in cats
Authors: McNiel Elizabeth A. , Madrill Nicole J. , Esteves-Villanueva Jose O. , Dominguez Pedro A. , Dings Ruud , Mayo Kevin H. , Griffin Robert J. 
Published: June 2012

Abstract
Anginex is a rationally designed, synthetic peptide that inhibits proliferation of human and mouse endothelial cells and demonstrates anti-tumor activity in murine tumor models. The anti-tumor and anti-angiogenic activity of Anginex is attributable, at least in part, to its interaction with galectin-1, a carbohydrate binding protein. As an intermediate step in the clinical translation of Anginex and related anti-vascular agents, we are investigating the effects of Anginex in spontaneous feline head and neck squamous cell carcinoma (HNSCC). Feline HNSCC shares morphology, clinical behavior, and biologic features such as intratumoral hypoxia and expression of EGFR, COX-2, and mutant p53 with its human counterpart. Our objectives were to investigate the activity of Anginex in feline cells and provide evidence of its safety in a phase I trial in cats with HNSCC. To establish Anginex activity in vitro, we evaluated the effect of 24 hour exposure to Anginex doses ranging from 2.5 – 25 uM on proliferation of both feline aortic endothelial cells (FAECs) and feline HNSCC cells (SCCF1) using flow cytometry and labeling with propidium iodide and bromodeoxyuridine (BrdU). With increasing Anginex dose, we observed accumulation of FAECs in G1 and decreased uptake of BrdU. We observed no effect in SCCF1 cells. To investigate safety, cats were treated with Anginex in cohorts of at least three animals at doses of 1, 3, and 9 mg/kg daily for 5 days. Clinical, laboratory and histologic features were evaluated before and after treatment. There were no serious adverse events during treatment. Continuous variables including body weight and laboratory variables were compared before and after treatment using a Wilcoxon signed rank test. No statistically significant changes occurred in these parameters. These data indicate that Aniginex is active against feline endothelial cells specifically and appears to be safe in cats. We are currently investigating the effects of Anginex on tumor physiology and in combination with radiation therapy for feline HNSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3293. doi:10.1158/1538-7445.AM2011-3293
Abstract 3297: Endothelial cells function as a niche to cancer stem-like cells by providing notch ligands in glioblastoma
Authors: Zhu Thant S. , Costello Mark A. , Hervey-Jumper Shawn , DiMeco Francesco , Vescovi Angelo L. , Heth Jason A. , Muraszko Karin M. , Fan Xing 
Published: June 2012

Abstract
Recent data show that endothelial cells function as a stem cell niche to promote CD133-positive cancer stem-like cells (CSLCs) self-renewal in glioblastoma (GBM). However, the molecular mechanism by which endothelial cells function as a stem cell niche is largely unknown. We had demonstrated recently that activation of NOTCH signaling is required for GBM CSLC propagation both in vitro and in vivo. To investigate if the acquisition of NOTCH activation in GBM CSLCs results from adjacent endothelial cells, we first examined the expression of NOTCH ligands JAG/DLL in primary GBM frozen samples. We found that JAG1, JAG2 and DLL4 are expressed mostly in endothelial cells adjacent to NESTIN- and NOTCH receptor-positive cancer cells. Some tumor cells also express JAG1, JAG2, and DLL1, but not DLL4, adjacent to NESTIN- and NOTCH-receptor positive cells in primary GBMs. Furthermore, we found that forced differentiated GBM cells from GBM neurospheres express a higher level of NOTCH ligands and a lower level of stem cell marker CD133, have reduced NOTCH activity, and are less tumorigenic in mice compared to GBM neurospheres. In addition, when we co-cultured GBM neurospheres with human brain microvascular endothelial cells (hBMECs) which express NOTCH ligands JAG/DLL, we found that hBMECs promote GBM neurosphere growth, increase the CD133-positive CSLC population and clonogenicity in vitro, whereas knocking down JAG1 or DLL4 in hBMECs abrogates hBMEC-induced GBM growth both in vitro and in vivo. Finally, we found that knockdown of JAG1 or DLL4 in hBMECs decreases growth of GBM intracranial xenograft in mice through reducing the CD133-positive population. In summary, we have demonstrated that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and surrounding endothelial cells, suggesting that targeting both CSLCs and their niche may provide an effective strategy to deplete GBM CSLCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3297. doi:10.1158/1538-7445.AM2011-3297
Abstract 3299: Targeting therapy-resistant glioma cells with novel compounds that inhibit action of survivin
Authors: Demir Habibe , Ray-Chaudhury Abhik , Li Tom , Li Chenglong , Nakano Ichiro 
Published: June 2012

Abstract
Introduction: Glioblastoma multiforme (GBM) is one of the most lethal diseases in adults. Despite intensive treatment with surgery, chemotherapy and radiation therapy, recurrence of tumors is inevitable in the majority of cases. It is therefore essential to determine the mechanism of establishment of therapy resistance in glioma cells and their effective targeting. Survivin is a member of the family of inhibitor-of-apoptosis (IAP) proteins, which functions as a key regulator of mitosis and apoptosis. Here, we sought to characterize survivin as a therapeutic target of GBM and identify a novel anti-glioma agent that inhibits survivin pathway.
Methods: Expression of survivin was analyzed immuohistochemically with 11 primary and recurrent GBM samples derived from the matched patients. In silico drug design was used to synthesize novel compounds that target dimerization of survivin. Effects of these compounds were tested with two distinct methods; (1) Treatment of patient-derived tumor spheres, and (2) direct injection into explants from surgical tissues of GBM.
Results: In 8 of 11 patients, survivin expression was increased in recurrent GBM samples compared to primary ones. Computational structure-based drug design suggested that two novel compounds, LLP3 and LLP9, inhibit survivin dimerization, which is essential for survivin function. Treatment of two patient-derived tumor spheres with 50 µM of LLP3 completely abolished sphere formation. The IC50 of LLP3 and LLP9 ranged between 25 and 50 µM, and between 40 and 70 µM, respectively, on 4 different GBM patient cells. Direct injection of LLP3 reduced proliferation and induced apoptosis in the tested GBM samples. Treatment of mouse tumors derived from GBM patient cells with LLP3 and LLP9 will also be described.
Conclusions: Upregulated survivin expression in recurrent tumors after chemoradiotherapy suggests that survivin is preferentially expressed in therapy-resistant GBM cells. Our novel compound, LLP3 strongly arrests tumor cell growth and induces apoptosis both in sphere cultures and in undissociated tumor blocks. Our results indicate a novel therapeutic strategy for GBM and, more specifically, for resistant recurrent tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3299. doi:10.1158/1538-7445.AM2011-3299
Abstract 3306: Screening potential drug candidates for treatment of glioblastoma patients utilizing an in-vivo mouse/ rat model system
Authors: Passarini Jenna , Cleary John P. , Kumar Preetham , Newton Trisha , Sharma Michael , Sharma Cristian , Panunzalan Rubio R. , Gill Parkash , Sharma Sherven , Srivastava Rakesh , Shankar Sharmila , Sharma Jay P. 
Published: June 2012

Abstract
Cancer stem cells (CSCs) are thought to be critical for engraftment and long-term growth of many tumors, including glioblastoma multiforme (GBM). The cells are at least partially spared by traditional chemotherapies and radiation therapies, and finding new treatments that can target CSCs may be critical for improving patient survival. Human glioblastoma multiforme is a heterogenous tumor composed from tumor cells and small portion of cancer stem cells, which have a high tumorigenic potential and a low proliferation rate. Glioblastoma cancer stem cells are phenotypically similar to the normal stem cells, they express CD133 gene and other genes characteristic of neural stem cells and posses self-renewal potential. The CD133+ GBM CSCs have been isolated with Celprogen Media and ECM and characterized as chemo-/radio-resistant tumor-initiating cells which are responsible as one of the many factors involved in post-treatment recurrence. In order to explore the molecular properties of tumorigenic CD133+ GBM CSCs that resist treatment, we isolated CD133+ GBM CSCs from tumors that are recurrent and have previously received chemo-/radio-therapy. We found that the purified CD133+ GBM CSCs sorted from the CD133+ GBM CSC spheres express SOX2,CD44 and are capable of clonal self-renewal. We generated in-vivo model systems in mice and rats to screen potential drug agents for the treatment of GBM patients. We were capable of generating brain tumors in mice and rats within 20 days by subcutaneously injecting 1000 GBM CSCs at the hind limbs of the rodents. Within day 5 the GBM CSCs were already present in the brain's of the rodents. At days 10, 15 & 20 the GBM CSCs labeled with GFP were located in the brain. We tested various compound candidates in this model system and we were able to show decrease in the migration of the GBM CSCs in the brain when we started the treatment at day 10 compared to non-treatment groups. We were able to demonstrate all the gene signatures associated with GBM CSCs in this model system. We do see a down regulation of certain cancer promotes genes in the treatment group when compared to non-treatment groups. The drug candidates were tested for TGFβ and STAT pathways. The chemotherapeutic agents tested were Among the 300 compounds tested Adria, Taxol, DTIC, Thalidomide, Paclitaxel, Abraxane, Ertibux and Velcade. We were able to show 4 compounds that were effective against GBM CSC targeting selected pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3306. doi:10.1158/1538-7445.AM2011-3306
Abstract 3307: The multitasking of Sox2: Maintaining the stemness and inducing the malignant phenotype of gliomas
Authors: Alonso Marta M. , Manterola Lorea , Diez-Valle Ricardo , Cortes-Santiago Nahir , Liu Dan , Rubio Angel , Garcia-Foncillas Jesus , Idoate Miguel Angel , Fueyo Juan , Gomez-Manzano Candelaria 
Published: June 2012

Abstract
Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, displays an enrichment gene expression related to a stem cell signature. Sox2, a major stemness factor involved in pluripotency and in the maintenance of neural stem cell identity, has been described as frequently overexpressed in poorly differentiated gliomas. However, the role that this molecule plays in brain tumors remains under investigation. In this study, we sought to ascertain the Sox2 potential function in the control of self-renewal of brain tumor stem cells (BTSCs) and the malignant phenotype of gliomas. Our results showed Sox2 expression in human surgical malignant gliomas. In addition, Sox2 expression was significantly higher in the BTSC lines than in established glioma cell lines. Downmodulation of Sox2 in BTSCs by using siRNA resulted in the loss of the self-renewal properties of this cell population, and modification in the pattern of expression of markers related with stem cells properties and differentiation. These results are of major importance since, in the TCGA, we observed Sox2 overexpression in more than 80% of the samples (n=188), gene amplification of SOX2 in 18% of the individuals, and hypomethylation of the promoter in about 90% of the samples when compared with normal tissue, suggesting the relevance of this transcription factor in the malignant phenotype of GBMs. In this regard, our results demonstrated that SOX2 plays a prominent role in the invasive and migratory capabilities of both BTSCs and established glioma cell lines. Thus, ectopic expression of Sox2 was sufficient to induce invasion of glioma cells and knockdown experiments demonstrated that Sox2 is essential for maintaining the invasive properties of glioma cells. Therefore, these results identify a multi-functional aspect of Sox2 as both, a stemness promoting molecule and an essential pro-invasive protein, elucidating the possibility of targeting Sox2 for glioma therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3307. doi:10.1158/1538-7445.AM2011-3307
Abstract 3312: Protein activation pathway analysis of glioblastoma stem cells reveals potential novel biomarkers
Authors: Federici Giulia , Signore Michele , Martino Simona Di , Pelacchi Federica , De Maria Ruggero , Liotta Lance A. , Petricoin Emanuel F. , Ricci-Vitiani Lucia 
Published: June 2012

Abstract
The cancer stem cell (CSC) hypothesis postulates that within the tumor mass there exists cells that possess self-renewal characteristics and are the tumorigenic and chemoresistant component of the growing lesion. Currently, there are no therapies specifically targeting this population and thus, elucidation of the undermining molecular mechanisms responsible for these attributes are critical for all tumor types in order to identify therapeutics that target the deranged pathways within the CSCs. GBM is an incurable malignancy of the neural glia and it has been demonstrated the presence of CSCs within it. Indeed it has been shown that there is a population of cells expressing CD133, a putative CSC marker, that resides in the tumor and may lead to its progression. We studied a set of thirty CD133+ GBM cancer stem cell lines obtained from 30 GBM patients and performed a Reverse-phase Protein Microarray (RPMA) analysis to investigate the activation state of more than 100 key signaling proteins involved in proliferation, inflammation, adhesion, survival and migration. This screening allowed the characterization and functional mapping of activated intracellular signaling networks within the GBM cancer stem cell lines and identified 8 clear subgroups based on molecular signatures of functional signaling activation. Unsupervised and supervised/statistical analysis of the differentially activated signaling architectures revealed the incidence of several phosphorylated proteins that underpinned these subclasses, such as members of the growth factor receptor tyrosine kinase family (e.g. EGFR, IGFR, VEGFR and PDGFR); proteins that control cell cycle division (Histone H3, PLK1 and Aurora) and members of calcium signaling/energy metabolism (S100A7, AMPK and PKC family), amongst others. It is hoped that ongoing and further characterization of the signaling architecture of a diverse number of GBM CSCs will help establish the key therapeutic targets that could be validated for causal significance and graduate to the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3312. doi:10.1158/1538-7445.AM2011-3312
Abstract 3316: An alpha-secretase inhibitor decreases glioma stem cell growth by inhibiting the Notch pathway and LMW Cyclin E
Authors: Floyd Desiree H. , Kefas Benjamin , Seleverstov Olexsandr , Dominguez Charli , Comeau Laurey , Purow Benjamin W. 
Published: June 2012

Abstract
The Notch pathway is deregulated in glioblastoma. Previous work suggests the inhibition of this pathway will have therapeutic benefits. The only inhibitors of Notch available block the gamma-secretase enzymatic complex necessary for processing Notch into the active form. However, Notch is also cleaved by alpha-secretase outside the plasma membrane, with the sheddases ADAM10 and 17. INCB3619 is a potent inhibitor of both ADAM10 and 17, and has been shown to inhibit growth of MCF-7 breast tumor cells when used with lapatinib. In this work, INCB3619 was used to inhibit endogenous Notch cleavage and downstream CBF-1 reporter activity in 0308 and 0822 human glioma stem cell lines. A microarray analysis of INCB3619 vs. DMSO treatment of 0308 cells identified many downregulated Notch pathway targets, but also identified new targets of INCB3619, such as CHI3L1/YKL40, an important prognostic indicator of many inflammatory diseases. Treatment of 0308 and 0822 glioma stem lines with INCB3619 inhibited their growth in culture due to a cell cycle arrest in G1 and a decrease in S phase cells. Growth inhibition by INCB3619 can be rescued with transfection of the active form of two Notch family members, NICD1 and 2. The growth inhibition of INCB3619 treated glioma stem cells is also stems from a shift in Cyclin E expression from a hyperactive low-molecular-weight form to the usual high-molecular-weight form. Also, INCB3619 induces higher expression of both p53 and p21, which can inhibit Cyclin E. Unlike with INCB3619, The treatment of glioma stem cells with DAPT, a well-known and potent gamma secretase inhibitor that cleaves Notch downstream of ADAM10 and 17, does not have a noticeable effect on Cyclin E processing or p21/p53 expression. INCB3619 therefore decreases glioma stem cell growth partly through a mechanism of Notch inhibition and also through inhibition of production of the hyperactive low-molecular-weight form of Cyclin E.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3316. doi:10.1158/1538-7445.AM2011-3316