bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2822: Characterization of the effects of PLX4720 in the immunocompetent BRAF/PTEN mouse melanoma model
Authors: Marzuka Alexander , Bosenberg Marcus 
Published: August 2012

Abstract
Vemurafenib is a BRAF inhibitor approved by the FDA for the treatment of BRAF V600E-positive metastatic melanoma after a phase III clinical trial demonstrated improved survival in patients taking vemurafenib compared to dacarbazine. As the first personalized treatment for metastatic melanoma to show a survival benefit, vemurafenib is a major breakthrough in the field. Although tumors in patients frequently shrink significantly within weeks of initiation of treatment, resistance eventually develops in many patients, with a median progression free survival of approximately 7 months. Evaluation of the biomarker and phenotypic correlates of response are difficult to determine as paired pre-treatment and on-treatment biopsies generally only represent one on-treatment time point when available. A better in vivo understanding of the effects of BRAF inhibitor-treatment of relevant mouse models may yield insights into the nature of the clinical response and subsequent relapse. The conditional BRAF/PTEN mouse model of melanoma that we co-developed is ideal to study this process. In this non-xenograft model, expression of BRAF V600E and loss of PTEN is under control of the Cre-Lox recombination system. Expression of the Cre recombinase is under control of the tyrosinase promoter, ensuring that recombination is limited to melanocytes. The Cre recombinase is fused to an estrogen receptor that inhibits the activity of the recombinase. Activation of the Cre recombinase requires topical application of 4-hydroxytamoxifen, allowing for induction of recombination at specific time points in the life span of the mouse. The use of this mouse model allows for more thorough evaluation of the time course and phenotype of BRAF-inhibitor response in melanoma in an immunocompetent host. Specific studies include evaluation of the effect of PLX4720 on the expression, localization, and activation of proteins involved with growth arrest, apoptosis, and glucose uptake.
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 2822. doi:1538-7445.AM2012-2822
Abstract 2829: Activity of EP-100 in Non-Hodgkin's Lymphoma - synergy in combination
Authors: Leuschner Carola , Coulter Ann , Giardina Cody , Alila Hector W. 
Published: August 2012

Abstract
EP-100 is a targeted anti-cancer peptide comprised of Luteinizing Hormone Releasing Hormone (LHRH) fused to a membrane-disrupting peptide (MDP). It is currently in Phase 1 clinical trial in tumors that over-express LHRH receptors. EP-100 kills cancer cells directly via membrane disruption. We tested a combination of EP-100 and doxorubicin in multi-drug resistant Non-Hodgkin's Lymphoma (NHL) cell lines and primary cells from refractory/relapsed NHL patients. Cells were cultured in the presence of EP-100 (0.00001-100 μM) or unconjugated MDP alone or in combination with doxorubicin (0.0000056 - 56.5 µM) and EP 100 at 0.5, 5, 50 and 500 nM. Cytotoxicity was determined by membrane integrity and cell viability assays. LHRH receptor expression was determined by flow cytometry. The effect of EP-100 on purified human recombinant p-glycoprotein (h-pgp) pump was measured by ATPase activity. The IC50 values [µM] for EP-100 alone were 0.52±0.13, 0.95±0.2, 2.8±0.5, 0.9±0.13 and values for unconjugated MDP were 59±1.5, 25.6±1.7, 6.1±0.8 after 5 h of incubation for Daudi, Raji, Toledo, Hut78 cells, respectively. EP-100 specifically killed NHL patient cells and unconjugated MDP was ineffective. The IC50 values for EP-100 were 1.2 ± 0.1µM for cells obtained from three Mantle Cell Lymphoma patients (N=3), 2.3± 0.1 µM for Diffuse Large B Cell Lymphoma patient (N=1), 1.7± 0.3 µM for Follicular Lymphoma patients (N=4), and 1.6 ± 0.1 µM for one Waldenstr[[Unable to Display Character: &#337;]]m Macroglobunemia patient. EP-100 or unconjugated MDP did not kill B-cells from normal subjects (N=2) after 5 hour incubation. LHRH receptors were over-expressed on cell lines and patient cells. Combination of EP-100 with doxorubicin resulted in synergistic responses after 72 hours of incubation and Combination Index was &lt;1. EP-100 directly inhibited the h-pgp ATPase activity. These results show that specific killing of NHL cells by EP-100 is mediated via over-expression of LHRH receptors and the synergy between EP-100 and doxorubicin is due to direct inhibition of EP-100 on h-pgp pump.
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 2829. doi:1538-7445.AM2012-2829
Abstract 283: OOPs: Novel HIF-1α mimics
Authors: Grishagin Ivan V. , Olenyuk Bogdan Z. , Bullock Brooke , Arora Paramjit S. 
Published: August 2012

Abstract
Alpha subunit of the hypoxia-inducible factor 1 (HIF-1α) is an important transcriptional regulator of hypoxia-inducible genes responsible for tumor proliferation and metastasis, and therefore HIF-1α is a valuable therapeutic target. In turn, the interaction between C-terminal activation domain (C-TAD) of HIF-1α and the cysteine-histidine rich domain (CH1) of its coactivator p300 is known to play the key role in the HIF-1 pathway. However, to date very few compounds have been reported to disrupt HIF-1α/p300 complex. We have rationally designed and synthesized non-peptidic mimics of HIF-1α CTAD αA-helix with novel oligooxopiperazine backbone (OOPs). These mimics exhibit relatively low toxicity and substantially downregulate expression levels of selected hypoxia-inducible genes (VEGF, c-MET, LOX, GLUT1, CXCR4) in cellulo in a dose-dependent manner.
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 283. doi:1538-7445.AM2012-283
Abstract 2830: Multikinase inhibition by TG02 is therapeutically effective in two forms of breast cancer
Authors: Ortiz-Ruiz M Jesús , Burrows Francis J. , Ré-Louhau M Florencia , Ocaña Alberto , Pandiella Atanasio , Esparís-Ogando Azucena 
Published: August 2012

Abstract
Breast cancer (BC) is a heterogeneous disease in which several distinct genetic and histopathological types have been defined. Triple-negative breast cancer (TNBC) lacking ER/PR and HER-2 is the most aggressive and untreatable form. In the case of HER2+ tumors, and despite the emergence of trastuzumab and lapatinib, in the metastatic setting these tumors remain incurable due to the innate or acquired drug resistance. A number of kinases are implicated in the proliferation and survival of breast cancer cells. Here, we characterize the antitumor activity of the multikinase inhibitor TG02 in TNBC and HER2+ BC. TG02 is a novel drug with a unique kinase inhibitory spectrum, targeting both the cell cycle regulatory CDKs 1/2 and the transcriptional regulators CDKs 7/9, along with the emerging oncogenic MAPK ERK5 and the DNA damage response mediator CDK5, all within a narrow low nanomolar potency range. In panels of breast cancer cell lines, TG02 was potently and consistently antiproliferative at low (100nM) and proapoptotic at moderate (250-1000nM), clinically-achievable concentrations. In TNBC cells, the drug usually induced a G2/M arrest, whereas blockade of cell cycle progression at the G1/S boundary was more common in HER2+ lines. Simultaneous multikinase inhibition was demonstrated in several cellular models, showing that cell cycle arrest induced by inhibition of CDK1 and CDK2 progresses to apoptosis associated with profound depletion of the short-lived survival proteins of the Bcl-2 and IAP families downstream of CDK9-dependent loss of RNA polymerase II-driven transcription. TG02 was synergistic in combination with chemotherapy in TNBC models in vitro and in vivo and with trastuzumab and lapatinib in HER2-overexpressing cell lines. A majority of TNBC and HER2+ lines expressed constitutively active ERK5, which was efficiently inhibited by TG02 and may contribute to the antitumor activity of the drug. A robust DNA damage response including CHK1/2 activation and formation of H2AX foci was induced in TNBC cells, presumably due to inhibition of CDK5 by TG02, so we will also report on the mechanism-based combination of TG02 with PARP inhibitors in this setting. These data support clinical development of this compound for the treatment of TNBC and HER2+ BC, especially in combination with standard of care treatments used in these breast neoplasias.
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 2830. doi:1538-7445.AM2012-2830
Abstract 2835: Discovery of novel inhibitors for ECT2 as a novel therapeutic strategy for lung cancer
Authors: Beyer Tracey E. , Smith Rachel M. , Song Zuohe , Gokhale Vijay , Moses Sylvestor A. , Meuillet Emmanuelle J. 
Published: August 2012

Abstract
The Epithelial Cell Transforming sequence 2 (ECT2) proto-oncogene is a Guanine Exchange Factor (GEF) for RhoA, Rac1 and Cdc42 and is essential to the regulation of cytokinesis. ECT2 contains the Dbl homology and pleckstrin homology (PH) domains, which are the hallmarks of GEFs. ECT2 is over-expressed in primary non-small cell lung cancer (NSCLC) tumors, and injection of ECT2 transfectants into nude mice efficiently induces tumor formation. High level of ECT2 expression is associated with poor prognosis for patients with NSCLC. Knock down of ECT2 expression by small interfering RNAs effectively suppresses lung cancer cell growth, suggesting a specific role of ECT2 in lung cancer development. Taken together, ECT2 may represent an attractive molecular target for inhibiting lung tumor growth. Our studies are based on the hypothesis that ECT2 plays an important role in lung cancer progression and is a novel target for the development of drugs to treat lung cancer. We have built a model for ECT2 PH domain using protein homology modeling. Docking of new compounds selected from commercial drug-like libraries has led to the identification of novel inhibitors of ECT2 PH domain. We have identified several compounds that bind ECT2 PH domain in the low micromolar range (KD&lt;1μM) as measured using surface plasmon resonance spectroscopy and that inhibit the proliferation of a panel of 23 lung cancer cell lines (EC50&lt;50μM). Importantly, inhibition occurred only in mutant-KRAS cells. Two compounds were shown to inhibit actin polymerization using a phalloidin-rhodamine stain as well as in vitro tumor formation using a colony forming assay and migration using a wound healing assay. These two compounds are being evaluated for their anti-tumor activity against several human lung cancer xenografts in SCID mice. The objectives of our studies are 1) to conduct molecular mechanistic studies of the precise role of ECT2 in the development of lung cancer in vivo animal model of lung cancer; 2) to test the most active compounds in cells in culture to provide a mechanistic rationale for their biological activity and 3) to test the anti-tumor properties of the lead compounds in a in vivo model of lung cancer. The overall goals of our work are to validate ECT2 as a therapeutic target for lung cancer and to develop a novel therapeutic strategy and agents for the improved treatment and the eventual cure of lung 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 2835. doi:1538-7445.AM2012-2835
Abstract 2840: Development of a bioluminescent cell-based bioassay to measure Fc receptor functionality in antibody-dependent cellular cytotoxicity
Authors: Cheng Zhi-jie J. , Chung Shan , Garvin Denise , Moravec Rich , Paguio Aileen , Quarmby Valerie , Fan Frank , Surowy Teresa K. 
Published: August 2012

Abstract
Primary peripheral blood mononuclear cells (PBMCs) are routinely used in traditional bioassays to quantify antibody drug potency in antibody-dependent cellular cytotoxicity (ADCC). These bioassays are labor intensive and have high inherent assay variability. Here, we report the development of a bioluminescent cell-based bioassay which measures activation of effector cells via cross-linking of FcαRIIIA with target cell-bound antibodies. For this, Jurkat T-cell stable cell lines that stably express NFAT-luciferase reporter and human FcαRIIIA were generated to replace primary PBMCs as effector cells in ADCC bioassay. Effector cells were also developed in a frozen, thaw-and-use format, to minimize assay variability due to cell culture and handling. The resultant bioassay using this format demonstrated good assay precision and accuracy in bioassay qualification. Bioassay using the engineered effector cells is robust, specific and is able to quantify the potencies of rituximab and trastuzumab, two monoclonal antibody drugs for cancer. When used to measure effects of Fc glycosylation on effector functions of therapeutic antibodies, a linear correlation was observed between relative antibody activity and the extent of Fc glycosylation. Thus, the bioluminescent cell-based reporter bioassay provides a simple and robust approach to measure potency of therapeutic antibodies in ADCC with high precision.
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 2840. doi:1538-7445.AM2012-2840
Abstract 2845: Prostaglandin E receptor EP4 antagonist RQ00015986 inhibits breast cancer metastasis and protects natural killer cells from PGE-mediated immune suppression
Authors: Ma Xinrong , Holt Dawn , Kundu Namita , Nonomura Kazuhiko , Take Yukinori , Fulton Amy M. 
Published: August 2012

Abstract
The cyclooxygenase-2 (COX-2) pathway is upregulated in breast and other malignancies. The COX-2 product prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on a family of G-protein-coupled receptors (EP1-EP4). In breast and colon malignancies, EP4 is a principle mediator of pro-tumorigenic and pro-metastatic activities. Our previous studies demonstrated that targeting EP4 with shRNA or by pharmacologic antagonists of EP4 leads to reduced metastasis in a preclinical model of metastatic breast cancer. These studies and others establish EP4 as a potential therapeutic target, however, there is a paucity of effective EP4 antagonists available for preclinical and clinical investigation. Using a novel orally available EP4 selective antagonist, RQ00015986, we have evaluated efficacy in a syngeneic murine model of metastatic breast cancer. Murine and human breast cancer cells express EP4 and receptor occupation with PGE2 (binds all EP) or with PGE1-OH (EP4 agonist) results in adenyl cyclase activation and elevated intracellular cAMP. RQ00015986, in uM/L concentrations, was able to prevent EP4-mediated adenyl cyclase activation in murine mammary tumor cell lines 66.1 and 410.4. Breast tumor cells migrate in response to either PGE2 or PGE1-OH and RQ00015986 inhibited this response. Pretreatment of 66.1 cells with RQ00015986 prior to i.v. injection into syngeneic mice resulted in 58-69% inhibition in numbers of lung tumor colonies. Natural Killer (NK) cells are critical to the control of metastatic dissemination. The ability of RQ00015986 to inhibit lung tumor colonization was completely lost in hosts depleted of mature NK cells. We have reported previously that NK cell functions in tumor-bearing mice are severely depressed through the actions of tumor-derived PGE2 acting on EP4 receptors expressed on the NK cell. The capacities of NK cells to migrate, to produce cytokines and to lyse mammary tumor target cells are each inhibited through PGE2. In the presence of RQ00015986, the capacity of cultured NK cells to migrate and to produce Interferon-α was restored to normal levels. More interestingly, treatment of tumor-bearing mice with RQ00015986 in vivo also restored NK cell functions. This report provides evidence that a novel EP4 antagonist may have therapeutic potential in cancer and may act by antagonizing EP4 prometastatic functions on the malignant cell as well as protecting NK effector cells from PGE2-mediated immune suppression.
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 2845. doi:1538-7445.AM2012-2845
Abstract 2846: Exploring ERBB3 as novel drug target in lung cancer
Authors: Noto Alessia , Aurisicchio Luigi , Vitis Claudia De , Marra Emanuele , Roscilli Giuseppe , Mancini Rita , Ciliberto Gennaro 
Published: August 2012

Abstract
Recent evidences point to ERBB3 as a critical activator of the PI3K/Akt signaling axis and suggest that its trans-phosphorylation is linked to the occurrence of drug resistance in several cancers. Because of the absence of a functional tyrosine kinase, the best approach to target this receptor is through the development of selective monoclonal antibodies. For this purpose, our group has recently generated a set of mouse monoclonals with low nM affinity for human ERBB3. We have started to assess the effect of these antibodies in lung cancer using two systems: a) PC9 cells, known to be highly sensitive to gefitinib (IC50 0,03 uM), for the DelE746A750 in exon 19 of EGFR and its gefitinib-resistant counterpart PC9-ZD (Koizumi et al, 2005 Int J. Cancer 116, 36); b) primary lung adenocarcinoma cells isolated in our laboratory from Malignant Pleural Effusions (MPEs) and capable of efficient tumor propagation in vivo (Mancini et al, 2011, PlosONE 6: e21320). In PC9 cells anti-ERBB3 mabs, A3 and A4, strongly inhibit ligand-induced pHER3 and pAKT and induce receptor downmodulation. Furthermore, A3 and A4 potentiate the antiproliferative effect of gefitinib in a clonogenic assay, induce G0/G1 arrest, and increase the percentage of cells that undergo apoptosis. In the human primary MPE-derived lung adenocarcinoma culture PEd10, we observed that the expression of ERBB3 and its ligand are upregulated when cells are grown in spheroid vs adherent conditions. In this system, A3 and A4 antibodies significantly downmodulate spheroid propagation. Studies are ongoing to provide further insights as to the mechanism of action of anti-ERBB3 antibodies and to confirm efficacy in in vivo tumor models. Our results suggest that in a subset of lung adenocarcinomas which express high levels of ERBB3, this receptor contributes to cell growth and propagation and that targeting ERBB3 with antibodies capable of inducing receptor downmodulation can be considered a promising therapeutic approach.
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 2846. doi:1538-7445.AM2012-2846
Abstract 2848: Preclinical activity of OM-RCA-01, a humanized anti-FGFR1 antibody, in renal cell carcinoma (RCC)
Authors: Tsimafeyeu Ilya V. , Zaveleva Elina , Low Walter 
Published: August 2012

Abstract
Background: Fibroblast growth factor (FGF) receptor 1 (FGFR1) is a potential therapeutic target for treatment of metastatic RCC. Early we reported that anti-FGFR1 monoclonal antibody inhibited ligand-induced phosphorylation of FGFR1, activation of MAP kinase and Akt downstream signaling pathways in FGFR1 expressing endothelial (bovine adrenal cortex capillary endothelial cells) and human RCC (Caki-1) lines (Tsimafeyeu et al. AACR/JCA joint conference 2010). Today we investigated the preclinical activity of OM-RCA-01, a novel therapeutic humanized anti-FGFR1 antibody with high affinity (Kd of 1.59 nM), in RCC. Methods: To assess the effect of anti-FGFR1 antibody on FGF-mediated signaling, the human renal carcinoma Caki-1 FGFR1-expressing cells were incubated (0.5% FBS) and were dosed with OM-RCA-01 at 100, 10, and 1 mcg/ml. Control wells were left untreated. Three hours after dosing, basic FGF was added at a concentration of 50 ng/ml. Additional control wells were treated with OM-RCA-01 without FGF-stimulation. Cell growth inhibition was determined using Promega's Cell Titer-Glo® assay. Charles River female NCr nu/nu mice (6-12 weeks of age) were set up with 1 mm3 Caki-1 tumor fragments sc in flank. Tumor sizes were measured in a blind fashion twice a week with a vernier caliper. Mice with established tumors (an average size of 80 - 120 mg) were randomly divided into vehicle, non-specific IgG or OM-RCA-01 groups per 10 animals in group. Animals were treated with antibody using different doses (1 or 10 mg/kg). Endpoint was significant differences in tumor growth delay. Results: In vitro study showed that basic FGF significantly increased proliferation of the human FGFR1-expressing renal carcinoma cells (P=0.011). No effect of basic FGF on cell line proliferation was observed when the cells were incubated with OM-RCA-01 antibody at any concentrations up to 100 mcg/kg in comparison with FGF-untreated control (P=0.855). In vivo, the tumors in untreated mice or mice treated with non-specific IgG continued their aggressive growth to reach the size of 2000 cm3, at which point the mice were killed. In contrast, treatment with OM-RCA-01 not only significant arrested further growth of the tumors (P=0.006) but also demonstrated differences in tumor volume compared with vehicle already on Day 13. A similar anti-tumor activity of OM-RCA-01 was observed when the antibody was given in low (1 mg/kg) or high (10 mg/kg) doses (P=0.917). Conclusions: High-affinity humanized anti-FGFR1 antibody OM-RCA-01 suppressed ligand-induced proliferation of human RCC cells in vitro. OM-RCA-01 has significant early anti-tumor efficacy in Caki-1 xenograft model.
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 2848. doi:1538-7445.AM2012-2848