bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5472: Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44.
Authors: Zhang Suping , Wu Christina , Farrah-Fecteau Jessie , Cui Bing , Chen Liguang , Zhang Ling , Wu Rongrong , Rassenti Laura , Lao Fitzgerald S. , Weigand Stefan , Kipps Thomas J. 
Published: August 2014

Abstract
Chronic lymphocytic leukemia (CLL) cells express high levels of CD44, a cell-surface glycoprotein receptor of hyaluronic acid (HA). We evaluated the cytotoxic potential of a humanized anti-CD44 mAb (RG7356), which currently is undergoing clinical evaluation for the treatment of patients with solid-tumor malignancies. We found that the mAb was directly cytotoxic for leukemia B cells, but had little effect on normal B cells. Moreover, independent of compliment or cytotoxic effector cells, RG7356 could induce leukemia cells to undergo caspase-dependent apoptosis, particularly those CLL cells that expressed the zeta-associated protein of 70 kD (ZAP-70). The cytotoxic effect of this mAb was not mitigated when the CLL cells were co-cultured with mesenchymal stromal cells (MSC) or HA, or stimulated via ligation of the B-cell receptor (BCR) with anti-μ. RG7356 induced rapid internalization of CD44 on CLL cells at 37oC, resulting in reduced expression of ZAP-70, which we found complexed with CD44. Administration of 1 mg/kg of this mAb to immune-deficient mice engrafted with human CLL cells resulted in complete clearance of engrafted leukemia cells. These studies indicate that this mAb might have therapeutic activity, particularly in patients with CLL that express ZAP-70.
Citation Format: Suping Zhang, Christina Wu, Jessie Farrah-Fecteau, Bing Cui, Liguang Chen, Ling Zhang, Rongrong Wu, Laura Rassenti, Fitzgerald S. Lao, Stefan Weigand, Thomas J. Kipps. Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5472. doi:10.1158/1538-7445.AM2013-5472
Abstract 5477: Engineered toxin body demonstrating CD20-specific binding and cell kill in B-cell non-Hodgkin's lymphoma cells.
Authors: Wirth Rachel , Rajagopalan Sangeetha , Willert Erin , Null William , Erdman Jennifer , Liu Jen-Sing , Higgins Jack P. 
Published: August 2014

Abstract
Non-Hodgkin's lymphoma (NHL) offers an attractive area for therapeutic biologics. The most successful example of this targeted approach is rituximab, which is approved for front and second line therapy of NHL. Rituximab targets the CD20 antigen expressed on 90% of B-cell NHL cells. However, rituximab has limited direct cell-kill effects, acting instead primarily through indirect immune responses induced by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC). Direct-cell kill approaches to CD20 have been limited to radioimmunotherapy because CD20 does not efficiently internalize. Despite improved clinical efficacy seen over Rituximab with both 131 tositumomab and ibritumomab tiuxetan, challenges around the administration of radioimmunotherapies have severely curtailed therapeutic use. We have developed an engineered toxin body (ETB) comprising a CD20 scFv and a modified Shiga-like Toxin A (3F7) capable of specifically recognizing and killing CD20 expressing cells. Utilizing a flow cytometry based binding affinity assay, 3F7 demonstrated selective binding to CD20 positive Raji cells whereas no significant binding was observed in CD20 negative BC-1 cells. Further, direct competition of 3F7 binding to Raji cells was observed in the presence of rituximab or the parent monoclonal antibody. 3F7 demonstrated CD20-specific direct cell kill of Raji, Daudi and Ramos cells with minimal cell kill of CD20 negative BC-1 or Jurkat cells. Initial dose finding studies in mice found that a therapeutic dosing schedule was well tolerated. Raji xenograft studies in mice are ongoing. 3F7 is a novel therapeutic approach with direct cell-kill activity against CD20-expressing cells which could expand treatment options for B-cell lymphoma.
Citation Format: Rachel Wirth, Sangeetha Rajagopalan, Erin Willert, William Null, Jennifer Erdman, Jen-Sing Liu, Jack P. Higgins. Engineered toxin body demonstrating CD20-specific binding and cell kill in B-cell non-Hodgkin's lymphoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5477. doi:10.1158/1538-7445.AM2013-5477
Abstract 5480: Characterization of anti-human APRIL monoclonal antibodies capable of inhibiting APRIL-dependent B cell function and hyperproliferation.
Authors: Guadagnoli Marco , Cameron Katherine , Veraar Elise , Kimberley Fiona , van Elsas Andrea , van Eenennaam Hans , Medema Jan Paul 
Published: August 2014

Abstract
A Proliferation Inducing Ligand (APRIL) is a TNF ligand that, via its receptors TACI and BCMA, is involved in both B cell physiology as well as in proliferation and survival of malignant B cells. To target APRIL-dependent stimulation of B cell cancers, we recently produced and characterized two monoclonal antagonistic anti-human APRIL antibodies called humanAPRIL.01A (hA.01A) and humanAPRIL.03A (hA.03A). In a first biochemical assay to validate their blocking activity, hA.01A was shown to fully prevent APRIL from binding to its receptors, whereas a substantial difference was detected for hA.03A, which inhibited APRIL binding to BCMA less efficiently than hA.01A. Epitope mapping subsequently revealed that hA.01A and hA.03A bind distinct sites on APRIL, which provided a structural rationale of their different blocking activities. Importantly, this differential inhibition profile can be used to functionally dissect BCMA and TACI-dependent signals and indicated that B cell survival and IgA production are regulated differently by these receptors. Primary CLL cultures were shown to be sensitive to APRIL neutralization using hA.01A. hA.01A also inhibited hyperplasia in a transgenic mouse model reminiscent of B-CLL. Altogether, these data indicate that hA.01A is a novel tool potentially useful for the targeted treatment of B cell-derived cancers such as B-CLL and Multiple Myeloma.
Citation Format: Marco Guadagnoli, Katherine Cameron, Elise Veraar, Fiona Kimberley, Andrea van Elsas, Hans van Eenennaam, Jan Paul Medema. Characterization of anti-human APRIL monoclonal antibodies capable of inhibiting APRIL-dependent B cell function and hyperproliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5480. doi:10.1158/1538-7445.AM2013-5480
Abstract 5481: Therapy of human LN229 glioblastoma growing in the brain of nude mice by Macitentan, a dual endothelin receptor A and B antagonist, combined with Temozolomide.
Authors: Kim Sun Jin , Kim Seung Wook , Choi Hyun Jin , Lee Ho Jeong , Lehembre Francois , He Junqin , Regenass Urs , Conrad Charles A , Yung W.K. , Fidler Isaiah J. 
Published: August 2014

Abstract
Purpose: We determined whether the blockade of endothelin receptor pathways can reverse the chemoprotection mediated by astrocytes and produce therapy of Human LN 229 Glioblastoma cells growing in the brain of nude mice treated with the dual endothelin receptor antagonist, Macitentan and Temozolomide (TMZ).
Materials and Methods: In the first set of experiments, murine astrocytes were cultured with tumor cells in the presence or absence of Macitentan and TMZ. For therapy studies the leuciferas labeled LN229 cells were implanted (stereotactically) into the brains of nude mice. The mice were ear tagged and imaged by IVIS spectrometer at multiple times. On day 24 the mice were randomized to receive vehicle, TMZ (p.o., 7.5mg/kg, one week on and two weeks off), Macitentan (p.o., 10mg/kg, daily) and Macitentan plus TMZ. Survival of mice was compared by Kaplan-Meyer curve (log-rank test) and immunohistochemical analyses were carried out for multiple markers.
Results: Simultaneous blocking of endothelin receptor A and B pathways reversed the in culture protection induced by astrocytes against TMZ (p&lt;0.05). Therapy with Macitentan and TMZ significantly prolonged the survival of mice (p&lt;0.0001) .The blockade of endothelin receptor A and B significantly decreased the level of expression of phosphorylated AKT and MAPK, and down-regulated the expression of BCL2L1, TWIST1 and GSTA5 in LN 229 cells growing in the brain. Proliferation of tumor cells and tumor-associated endothelial cells was significantly decreased. Moreover the apoptosis of LN229 cells was significantly increased in the brain of the combination treatment group.
Conclusion: Blockade of endothelin receptor A and B pathways by Macitentan combined with TMZ provides a new approach for the treatment of patients with Glioblastoma.
Citation Format: Sun Jin Kim, Seung Wook Kim, Hyun Jin Choi, Ho Jeong Lee, Francois Lehembre, Junqin He, Urs Regenass, Charles A Conrad, W.K. Yung, Isaiah J. Fidler. Therapy of human LN229 glioblastoma growing in the brain of nude mice by Macitentan, a dual endothelin receptor A and B antagonist, combined with Temozolomide. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5481. doi:10.1158/1538-7445.AM2013-5481
Abstract 5485: Apoptosis-targeted cell and drug delivery to tumor.
Authors: Chi Lianhua , Bonaparte Napoleon , Park Rang-woon , Kim In-san , Lee Byung-heon 
Published: August 2014

Abstract
When tumor cells undergo apoptosis in response to chemotherapy, the levels of apoptotic biomarkers such as phosphatidylserine and histone H1 are increased at the cell surface. Here we hypothesized that the chemotherapy-induced apoptosis would amplify in situ apoptotic biomarkers (homing signals) for apoptosis-targeted drug carriers and enhance drug delivery. To examine this possibility, we employed a phage display-identified CQRPPR peptide (ApoPep-1) as a targeting moiety, which was able to recognize apoptotic cells by binding to histone H1 on the surface of apoptotic cells. When injected into tumor-bearing mice, ApoPep-1-labeled, fluorescent liposomes containing doxorubicin inhibited tumor growth more efficiently than untargeted or folate-labeled liposomes. Moreover, in vivo fluorescence imaging could enable monitoring of tumor response during the chemotherapy. The imaging signals at tumor were increased by the homing of apoptosis-targeted liposomes, which was correlated with the increase of apoptosis and the amount of doxorubicin (payloads) at the tumor and, conversely, with the decrease of tumor volume. Next, we harnessed the chemotherapy-induced apoptosis of tumor cells as a homing signal for the delivery of apoptosis-targeted
T cells to tumor. When labeled with ApoPep-1 using an oleyl acid-derived membrane anchor, targeted T cells preferentially bound to apoptotic tumor cells over living cells. In vivo imaging showed higher levels of tumor homing of targeted, fluorescent T cells in mice treated with chemotherapy more than those of untargeted T cells. These results demonstrate that the apoptosis-targeted delivery can efficiently enhance the delivery of cells or drugs to tumor and, when combined with imaging of apoptosis, provides a real-time monitoring of tumor response for cancer theragnosis.
Citation Format: Lianhua Chi, Napoleon Bonaparte, Rang-woon Park, In-san Kim, Byung-heon Lee. Apoptosis-targeted cell and drug delivery to tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5485. doi:10.1158/1538-7445.AM2013-5485
Abstract 5486: Cancer therapeutics and the βGBP cytokine. Activation of death pathways prior to and after PI3K inhibition, and efficacy in vivo.
Authors: Mallucci Livio , Wells Valerie 
Published: August 2014

Abstract
Phosphatidylinositol-3-OH kinase (PI3K) signaling is crucial to the viability of cancers and represents a selective target for therapeutic intervention. Our strategy against cancer is based on the use of a newly identified cytokine (βGBP), a natural inhibitor of both class IA and class IB PI3K that in cancer cells, but not in normal cells, is a potent activator of cell death: a novel therapeutic concept which carries no chemotherapeutic disadvantages and that can be tested and utilised in clinical trials.
Cell death by Hu-r-βGBP follows two modes:
1) Apoptosis consequent to downregulation of signaling downstream of PI3K where inhibition of PI3K activity by Hu-r-βGBP has two major outcomes: suppression of Ras-GTP loading leading to block of ERK activation, and negation of akt gene expression leading to loss of Akt, conditions that either by blocking the ability of cancer cells to proliferate or by impairing their ability to survive erase oncogenicity in many cancer cells including those from prostate, HER2-driven and triple negative breast cancer.
2) Apoptosis consequent to induction of protein-protein interactions from βGBP receptor to PI3K where conformational changes conveyed by allosteric modulation from the βGBP receptor to p110 lead to changes in PIP2 spatial distribution at the plasma membrane, loss of PIP2-actin linkages, increased macromolecular mobility within the plane of the plasma membrane, clustering of death receptors and devastating death in Kras-mutant cancer cells, therapeutically reproducible in vivo.
Citation Format: Livio Mallucci, Valerie Wells. Cancer therapeutics and the βGBP cytokine. Activation of death pathways prior to and after PI3K inhibition, and efficacy in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5486. doi:10.1158/1538-7445.AM2013-5486
Abstract 5487: Inhibitory effect of soluble EP2 receptor on ovarian tumor growth in nude mice and usefulness of TMPRSS4 as a molecular target for synergistic efficacy.
Authors: Takahashi Tetsuyuki , Uehara Hisanori , Izumi Keisuke 
Published: August 2014

Abstract
Prostaglandin E2 (PGE2) plays an important role in cancer cell growth, progression, and metastasis and exerts its effects by binding to E-prostanoid receptor (EP). In the previous study, we showed that soluble fragment of EP2 receptor containing the second extracellular region (FuEP2/Ex2) has neutralizing activity to PGE2 and inhibits the growth of prostate and endometrial cancer cells. Here, we established a stable transfectant expressing FuEP2/Ex2 from human ovarian cancer SKOV/ip cells (SKOV/ip-FuEP2/Ex2) and SKOV/ip-FuEP2/Ex2 and vector-control cells were injected into nude mice intraperitoneally. Tumor weight and ascites volume in SKOV/ip-FuEP2/Ex2-injected mice decreased significantly compared to control cell-injected mice. Furthermore, microvessel density and numbers of M2-poralized macrophage in tumor lesion were significantly decreased in SKOV/ip-FuEP2/Ex2-injected mice. By using RNAs from tumor lesion in each group, the cDNA microarray analysis was also conducted. Six of upregulated genes and eight of downregulated genes in SKOV/ip-FuEP2/Ex2-derived tumor were identified. In upregulated genes, MMP-7, TMPRSS4, and CYP1B1, which is involved in cancer progression and metastasis, were included. Treatment with AEBSF, an inhibitor of TMPRSS4, or siRNA for TMPRSS4 further reduced cell growth of SKOV/ip-FuEP2/Ex2 cells in vitro and in vivo. Our results suggest that FuEP2/Ex2 has a suppressive effect in peritoneal metastasis model of ovarian cancer and that MMP-7, TMPRSS4, and CYP1B1 may act as a survival factor under the condition in which EP-mediated signaling are inhibited. Moreover, targeting of TMPRSS4 may enhance the inhibitory effect of FuEP2/Ex2 on ovarian cancer metastasis.
Citation Format: Tetsuyuki Takahashi, Hisanori Uehara, Keisuke Izumi. Inhibitory effect of soluble EP2 receptor on ovarian tumor growth in nude mice and usefulness of TMPRSS4 as a molecular target for synergistic efficacy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5487. doi:10.1158/1538-7445.AM2013-5487
Abstract 549: MAGI3-Akt3, a novel fusion protein in the PI 3-K pathway in cancer.
Authors: Brown Kristin , Toker Alex 
Published: August 2014

Abstract
Aberrant activation of the PI3-K/Akt pathway is found in approximately 70% of breast cancers. We recently identified a recurrent rearrangement that produces an in-frame fusion protein containing Akt3 and the scaffolding protein MAGI3 (1). MAGI3-Akt3 is the first fusion protein that has been identified in the PI 3-K pathway. We propose that MAGI3-Akt3 is a novel oncogene in breast cancer and that the oncogenic activity of the fusion protein results from disruption of the PI 3-K/Akt pathway. Within the fusion, Akt3 has a disrupted PH domain prior to glutamate 17 (E17). As a result the fusion protein is constitutively phosphorylated in the Akt3 kinase domain and expression of MAGI3-Akt3 in breast cancer cells enhances Akt substrate phosphorylation. Constitutive MAGI3-Akt3 kinase activity can be inhibited by ATP-competitive small molecule Akt inhibitors but is resistant to the allosteric Akt inhibitor MK2206 which is currently in phase II clinical trials. Our results indicate that ATP competitive Akt inhibitors should be evaluated in clinical trials for the treatment of fusion-positive breast cancers.
The fusion protein also contains a severely truncated portion of the scaffolding protein MAGI3. In particular, the fusion lacks the second PDZ domain of MAGI3 that has been reported to bind to PTEN and be required for the inhibitory effect of PTEN on PI 3-K pathway activity. We have demonstrated that disruption of MAGI3 in breast cancer cell lines does indeed promote PI 3-K pathway hyperactivity in a PTEN-dependent manner. In addition, the fusion lacks the fifth PDZ domain of MAGI3 and our studies indicate that this disrupts the interaction of MAGI3 with PHLPP2, a phosphatase that directly dephosphorylates Akt at pS473.
Our studies therefore demonstrate that the MAGI3-Akt3 translocation significantly perturbs PI 3-K pathway activity via activation of an oncogene (Akt3) and dysregulation of two tumor suppressors (PTEN and PHLPP2). We are currently continuing studies to elucidate the oncogenic mechanism(s) of MAGI3-Akt3 in breast cancer.
Citation Format: Kristin Brown, Alex Toker. MAGI3-Akt3, a novel fusion protein in the PI 3-K pathway in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 549. doi:10.1158/1538-7445.AM2013-549
Abstract 5490: The cytotoxic activity of the anti-mesothelin immunotoxin SS1P is enhanced by the PKC inhibitor enzastaurin.
Authors: Mattoo Abid R. , Pastan Ira , Fitzgerald David 
Published: August 2014

Abstract
The activation of protein kinase C (PKC) contributes to tumor survival and proliferation provoking the development of inhibitory agents that may function as cancer therapeutics. Pseudomonas exotoxin-based immunotoxins are antibody-based recombinant proteins that employ an ADP-ribosylation domain for the enzymatic inhibition of protein synthesis of target cancer cells. Combining PKC inhibitors with immunotoxins was undertaken to explore possible synergy. Enzastaurin but not two other PKC inhibitors (Sortastaurin and G06976) combined with immunotoxins directed to surface mesothelin or the transferrin receptor to produce synergistic or additive cell death via apoptosis. Enhancement of killing was noted with enzastaurin concentrations of 5 uM or greater. Mechanistic insights of the combined immunotoxin-enzastaurin killing centered on the rapid complete loss of the prosurvival Bcl2 protein, Mcl-1, and the activation of caspase 3/7. Moreover, efficient cell killing was associated with loss of Akt and the BH3-only protein Bad. Enzastaurin-mediated enhanced cell killing was specific to Pseudomonas exotoxin-based immunotoxins as there was no enhancement with other agents that inhibit protein synthesis such as cycloheximide and diphtheria toxin. Immunotoxin-enzastaurin combinations could be useful for the treatment of human cancers that express mesothelin and are not efficiently killed by SS1P alone.
Citation Format: Abid R. Mattoo, Ira Pastan, David Fitzgerald. The cytotoxic activity of the anti-mesothelin immunotoxin SS1P is enhanced by the PKC inhibitor enzastaurin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5490. doi:10.1158/1538-7445.AM2013-5490
Abstract 5496: ‘Salan’ titanium(IV) complexes: A new class of anti-cancer agents.
Authors: Braitbard Ori , Meker Sigalit , Stolarov Maya , Hochman Jacob , Tshuva Edit 
Published: August 2014

Abstract
Early attempts at using titanium compounds (derivatives of titanocene dichloride and budotitane) as anti-cancer treatment were essentially unsuccessful. The main reason was their rapid hydrolysis in biological media, leading to a variety of unidentified products that hampered the elucidation of mechanistic aspects. Lately, we have introduced a new class of Ti(IV) complexes of salan type diamino bis(phenolato) ligands. These compounds demonstrate substantially enhanced hydrolytic stability, as well as cytotoxic activity towards a variety of cancer cell lines in vitro. The IC50 of different derivatives of these compounds towards murine mammary carcinoma, lymphoma, multi-drug resistant lymphoma, as well as human leukemia, melanoma and pancreatic cancer cell lines, is in the range of 0.6 - 5.7μM, as compared to 70-100μM of the older titanium compounds and to 50-60μM of cisplatin (Manna C.M. et al. ChemMedChem, 7, 703 (2012)). Exposure of murine T-69 and human OVCAR-1 and HT-29 cell lines to one of the salan Ti(IV) compounds resulted in increased levels of p53 and growth arrest in G-1 of the cell cycle implying activation of the apoptotic pathway in response to Ti(IV) complexes.The well-identified and highly stable hydrolysis products of the titanium compounds, which had previously been formulated into nanoparticles to enhance solubility and assist cellular penetration (Meker, S. et al. Angew. Chem. Int. Ed. 51,10515 (2012)), were active both in vitro (IC50 -0.45μM) in murine lymphoma and in vivo (50% tumor growth inhibition) of the same lymphoma cells following their introduction into syngeneic mice. These findings suggest the potential use of solubilized active titanium compound derivatives as a new class of anti-cancer agents.
Citation Format: Ori Braitbard, Sigalit Meker, Maya Stolarov, Jacob Hochman, Edit Tshuva. ‘Salan’ titanium(IV) complexes: A new class of anti-cancer agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5496. doi:10.1158/1538-7445.AM2013-5496